https://www.explorationpub.com/Journals/etat Most Recent Articles : Exploration of Targeted Anti-tumor Therapy. en-us Tue, 26 May 2026 23:48:13 GMT https://www.explorationpub.com/Journals/etat/Article/10021 Not applicable. Editorial Sat, 29 Feb 2020 00:00:00 GMT NicolaNormanno, GrahamPackham, Sat, 29 Feb 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10021 https://www.explorationpub.com/Journals/etat/Article/10022 Cancer development is frequently associated with dysregulation of mRNA translation to enhance both increased global protein synthesis and translation of specific mRNAs encoding oncoproteins. Thus, targeted inhibition of mRNA translation is viewed as a promising new approach for cancer therapy. In this article we review current progress in investigating dysregulation of mRNA translation initiation in mature B-cell neoplasms, focusing on chronic lymphocytic leukemia, follicular lymphoma and diffuse large B-cell lymphoma. We discuss mechanisms and regulation of mRNA translation, potential pathways by which genetic alterations and the tumor microenvironment alters mRNA translation in malignant B cells, preclinical evaluation of drugs targeted against specific eukaryotic initiation factors and current progress towards clinical development. Overall, inhibition of mRNA translation initiation factors is an exciting and promising area for development of novel targeted anti-tumor drugs. Review Sat, 29 Feb 2020 00:00:00 GMT JoeTaylor, Alison MYeomans, GrahamPackham, Sat, 29 Feb 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10022 https://www.explorationpub.com/Journals/etat/Article/10023 The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach. Review Sat, 29 Feb 2020 00:00:00 GMT Sarah JTaylor, Mark JArends, Simon PLangdon, Sat, 29 Feb 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10023 https://www.explorationpub.com/Journals/etat/Article/10024 Colorectal carcinoma (CRC) is an heterogeneous disease in which different genetic alterations play a role in its pathogenesis and progression and offer potential for therapeutic intervention. The research on predictive biomarkers in metastatic CRC (mCRC) mainly focused on the identification of biomarkers of response or resistance to anti-epidermal growth factor receptor monoclonal antibodies. In this respect, international guidelines suggest testing mCRC patients only for KRAS, NRAS and BRAF mutations and for microsatellite instability. However, the use of novel testing methods is raising relevant issue related to these biomarkers, such as the presence of sub-clonal RAS mutations or the clinical interpretation of rare no-V600 BRAF variants. In addition, a number of novel biomarkers is emerging from recent studies including amplification of ERBB2, mutations in ERBB2, MAP2K1 and NF1 and rearrangements of ALK, ROS1, NTRK and RET. Mutations in POLE and the levels of tumor mutation burden also appear as possible biomarkers of response to immunotherapy in CRC. Finally, the consensus molecular subtypes classification of CRC based on gene expression profiling has prognostic and predictive implications. Integration of all these information will be likely necessary in the next future in order to improve precision/personalized medicine in mCRC patients. Review Sat, 29 Feb 2020 00:00:00 GMT Anna MariaRachiglio, AlessandraSacco, LauraForgione, ClaudiaEsposito, NicolettaChicchinelli, NicolaNormanno, Sat, 29 Feb 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10024 https://www.explorationpub.com/Journals/etat/Article/10026 Aim: Single biomarker diagnostic test of BRAFV600 locus in metastatic melanoma is mandatory for treatment decision; however, multiple-gene based techniques, such as targeted next-generation sequencing (NGS) are being used to maximize the number of patients that can benefit from a targeted therapy. The main objective of this study is to investigate whether an NGS panel could be adopted in routine clinical care for advanced melanoma. Methods: Patients diagnosed with advanced melanoma at our center from 2017 to 2019 were included. Presence of genetic alterations was performed using two methods: real-time polymerase chain reaction-based Idylla test (Biocartis) and NGS with the oncomine solid tumor DNA kit (Thermo Fisher Scientific). Total genomic DNA was extracted from formalin-fixed and paraffin embedded samples for sequencing. Results: A total of 155 samples were evaluated for molecular analysis but 40 samples (25.8%) were inadequate for sequencing. The clinical utility of BRAFV600 real-time polymerase chain reaction and targeted-NGS was compared in 29 samples and a very good concordance was observed (Kappa = 0.89, 95% confidence interval 0.68 ± 1.05). An oncogenic mutation by NGS was found in 75 samples (65%)–53% of whom were candidates for personalized therapies. The most prevalent mutated genes were BRAF (39%), TP53 (23%), and NRAS (14%). Other genes identified at lower incidence (< 5%) were: PIK3CA, ERBB4, CTNNB1, STK11, FGFR1, SMAD4, KRAS, FGFR3, PTEN and AKT. Co-occurrence of oncogenic mutations was detected in 40% of the samples. Among the mutations identified, TP53 was significantly more prevalent in men (men 31.8% versus women 12.2%, P = 0.03) and NRAS in women (men 9.1% versus women 24.4%, P = 0.03). Conclusions: Targeted-NGS testing is a feasible technique to implement in the routine clinical practice. Based on our results, NGS has provided more information on target-genes than RT-PCR technique, maximizing the benefit for patients with advanced melanoma. Original Article Wed, 01 Apr 2020 00:00:00 GMT PaolaCastillo, MartaMarginet, PedroJares, MireiaGarcía, ElenaGonzalvo, AnaArance, AdrianaGarcía, LluciaAlos, CristinaTeixido, Wed, 01 Apr 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10026 https://www.explorationpub.com/Journals/etat/Article/10025 Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H+-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets. Review Thu, 09 Apr 2020 00:00:00 GMT CarolWard, JamesMeehan, Mark EGray, Alan FMurray, David JArgyle, Ian HKunkler, Simon PLangdon, Thu, 09 Apr 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10025 https://www.explorationpub.com/Journals/etat/Article/10027 All-trans retinoic acid (ATRA) induces complete remission in a high proportion of acute promyelocytic leukemia (APL). Nevertheless it is be associated with adverse drug reactions that might be life-threatening including differentiation syndrome, myocarditis, myositis, Sweet’s syndrome and ulcers. We describe a case of APL who during induction therapy developed ATRA syndrome, cardiac arrhythmia and multiple episodes of intestinal necrosis that required surgery. In particular, we report here for the first intestinal necrosis attributable to ATRA treatment in the absence of histological evidence of promyelocytes infiltration or leukocytoclastic vasculitis. Case Report Tue, 28 Apr 2020 00:00:00 GMT ValeriaFerla, MariaritaSciumé, UmbertoGianelli, LucaBaldini, Nicola StefanoFracchiolla, Tue, 28 Apr 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10027 https://www.explorationpub.com/Journals/etat/Article/10028 Several preclinical studies suggested a potential benefit from combined treatment with inhibitors of epidermal growth factor receptor (EGFR) and angiogenesis, both effective in patients with advanced non-small-cell lung cancer (NSCLC). In pretreated patients with advanced EGFR wild type NSCLC, bevacizumab plus erlotinib improved progression-free survival as second-line therapy in the BeTa study and as maintenance therapy in the ATLAS trial, although the benefit was modest and did not translate into an advantage in overall survival. Disappointing results were reported with oral VEGF inhibitors plus erlotinib in pretreated patients with EGFR wild type NSCLC. On the contrary, erlotinib plus bevacizumab or ramucirumab showed a clinically relevant improvement of progression-free survival in naïve patients with EGFR mutations, leading to the approval of these two regimens as first-line treatment of NSCLC patients with EGFR mutant tumors. Several clinical studies are evaluating the feasibility and activity of osimertinib plus bevacizumab or ramucirumab. However, limits that could affect its use in clinical practice are the need of an intravenous infusion for angiogenesis inhibitors, the increased incidence of treatment associated adverse events, the exclusion of patients with tumors located in central position or at risk of hemorrhage. The identification of predictive biomarkers is an important goal of research to optimize the combined use of these agents. Review Tue, 28 Apr 2020 00:00:00 GMT GiulianoPalumbo, GiovannaEsposito, GuidoCarillio, AnnaManzo, AgneseMontanino, VincenzoSforza, RaffaeleCostanzo, ClaudiaSandomenico, CarmineLa Manna, NicolaMartucci, AntonelloLa Rocca, GiuseppeDe Luca, Maria CarmelaPiccirillo, RossellaDe Cecio, FrancescoPerrone, GiuseppeTotaro, PaoloMuto, CarminePicone, NicolaNormanno, AlessandroMorabito, Tue, 28 Apr 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10028 https://www.explorationpub.com/Journals/etat/Article/10029 Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing. Review Mon, 29 Jun 2020 00:00:00 GMT RachaelArthur, BeatrizValle-Argos, Andrew J.Steele, GrahamPackham, Mon, 29 Jun 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/10029 https://www.explorationpub.com/Journals/etat/Article/100210 Tanshinone is a herbal medicinal compound described in Chinese medicine, extracted from the roots of Salvia miltiorrhiza (Danshen). This family of compounds, including Tanshinone IIA and Tanshinone I, have shown remarkable potential as anti-cancer molecules, especially against breast, cervical, colorectal, gastric, lung, and prostate cancer cell lines, as well as leukaemia, melanoma, and hepatocellular carcinoma among others. Recent data has indicated that Tanshinones can modulate multiple molecular pathways such as PI3K/Akt, MAPK and JAK/STAT3, and exert their pharmacological effects against different malignancies. In addition, preclinical and clinical data, together with the safety profile of Tanshinones, encourage further applications of these compounds in cancer therapeutics. In this review article, the effect of Tanshinones on different cancers, challenges in their pharmacological development, and opportunities to harness their clinical potential have been documented. Review Mon, 29 Jun 2020 00:00:00 GMT IrumNaz, MyriamMerarchi, ShanayaRamchandani, Muhammad RashidKhan, Muhammad NoumanMalik, SumairaSarwar, Acharan SNarula, Kwang SeokAhn, Mon, 29 Jun 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100210 https://www.explorationpub.com/Journals/etat/Article/100212 Immunotherapy has shifted the therapeutic landscape in thoracic cancers. However, assessment of biomarkers for patient selection and disease monitoring remain challenging, especially considering the lack of tissue sample availability for clinical and research purposes. In this scenario, liquid biopsy (LB), defined as the study and characterization of biomarkers in body fluids, represents a useful alternative strategy. In other malignancies such as colorectal cancer, breast cancer or melanoma, the potential of LB has been more extensively explored for monitoring minimal residual disease or response to treatment, and to investigate mechanisms of resistance to targeted agents. Even if various experiences have already been published about the applications of LB in immunotherapy in thoracic cancers, the standardization of methodology and assessment of its clinical utility is still pending. In this review, the authors will focus on the applications of LB in immunotherapy in non-small cell lung cancer, small cell lung cancer, and malignant pleural mesothelioma, describing available data and future perspectives. Review Mon, 29 Jun 2020 00:00:00 GMT RaimondoDi Liello, FloraCimmino, SorayaSimón, Emilio FrancescoGiunta, VincenzoDe Falco, PalomaMartín-Martorell, Mon, 29 Jun 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100212 https://www.explorationpub.com/Journals/etat/Article/100211 Poly-ADP-ribose polymerase inhibitors (PARP-I) represent one of the most attractive and promising class of biological agents studied both in relapsed ovarian cancer (OC) and in the advanced setting. The availability of this new class of drugs has changed the clinical management of OC ensuring an unprecedented advance in such an aggressive cancer. Three oral PARP-I are currently available: olaparib, niraparib and rucaparib. Another two are in active clinical exploration: veliparib and talazoparib. Here the authors report clinical data with PARP-I with a particular emphasis on the phase II and III trials that support PARP-I approval by regulatory agencies in OC patients. Review Mon, 29 Jun 2020 00:00:00 GMT AntonellaPietragalla, FrancescaCiccarone, CamillaNero, GiovanniScambia, DomenicaLorusso, GennaroDaniele, Mon, 29 Jun 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100211 https://www.explorationpub.com/Journals/etat/Article/100213 Cancer remains the second leading cause of mortality globally. In combating cancer, conventional chemotherapy and/or radiotherapy are administered as first-line therapy. However, these are usually accompanied with adverse side effects that decrease the quality of patient’s lives. As such, natural bioactive compounds have gained an attraction in the scientific and medical community as evidence of their anticancer properties and attenuation of side effects mounted. In particular, quassinoids have been found to exhibit a plethora of inhibitory activities such as anti-proliferative effects on tumor development and metastasis. Recently, bruceine D, a quassinoid isolated from the shrub Brucea javanica (L.) Merr. (Simaroubaceae), has come under immense investigation on its antineoplastic properties in various human cancers including pancreas, breast, lung, blood, bone, and liver. In this review, we have highlighted the antineoplastic effects of bruceine D and its mode of actions in different tumor models. Review Wed, 22 Jul 2020 00:00:00 GMT Zi WayneSin, VipulBhardwaj, Amit KumarPandey, ManojGarg, Wed, 22 Jul 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100213 https://www.explorationpub.com/Journals/etat/Article/100215 Lung cancer represents the world’s most common cause of cancer death. In recent years, we moved from a generic therapeutic strategy to a personalized approach, based on the molecular characterization of the tumor. In this view, liquid biopsy is becoming an important tool for assessing the progress or onset of lung disease. Liquid biopsy is a non-invasive procedure able to isolate circulating tumor cells, tumor educated platelets, exosomes and free circulating tumor DNA from body fluids. The characterization of these liquid biomarkers can help to choose the therapeutic strategy for each different case. In this review, the authors will analyze the main aspects of lung cancer and the applications currently in use focusing on the benefits associated with this approach for predicting the prognosis and monitoring the clinical conditions of lung cancer disease. Review Fri, 14 Aug 2020 00:00:00 GMT Alessia MariaCossu, MariannaScrima, AngelaLombardi, AnnaGrimaldi, MargheritaRusso, AlessandroOttaiano, MicheleCaraglia, MarcoBocchetti, Fri, 14 Aug 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100215 https://www.explorationpub.com/Journals/etat/Article/100216 Not applicable. Commentary Fri, 14 Aug 2020 00:00:00 GMT FedericaPapaccio, Fri, 14 Aug 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100216 https://www.explorationpub.com/Journals/etat/Article/100217 BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-XL is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-XL inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-XL for survival. In this review, the authors discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. The authors summarize the progress in the development of BCL-XL PROTACs. The authors highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-XL PROTACs can significantly improve the therapeutic window compared to conventional BCL-XL inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity. Review Tue, 18 Aug 2020 00:00:00 GMT PeiyiZhang, XuanZhang, XinguiLiu, SajidKhan, DaohongZhou, GuangrongZheng, Tue, 18 Aug 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100217 https://www.explorationpub.com/Journals/etat/Article/100214 Cancer is the second death causing disease worldwide after cardiovascular abnormalities. The difficulty in treating tumor cells with more precise targeted interventions and recurrence of cancer after treatment may pose great difficulty in developing sustainable therapeutic regimens. These limitations have prompted the need to explore several compounds with ability to cease tumor growth while at the same time induce apoptosis of tumor cells. Several studies have emphasized the use of natural compounds as antitumor agents due to their high efficacy against cancer cells and low toxicity in normal cells. Salvianolic acid B (SAB), a naturally occurring phenolic compound extracted from the radix of Chinese herb Salvia miltiorrhiza can induce apoptosis in different types of tumor cells. It can be used to treat cardiovascular and neurodegenerative disorders, hepatic fibrosis, and cancers. Several studies have shown that SAB can mitigate tumorigenesis by modulating MAPK, PI3K/AKT, and NF-ĸB signaling pathways. It also sensitizes the tumor cells to different anti-cancer agents by reversing the multi-drug resistance mechanisms found in tumor cells. This review summarizes the studies showing antitumor potential of SAB in different types of cancer cell lines, animal models and highlights the possible mechanisms through which SAB can induce apoptosis, inhibit growth and metastasis in tumor cells. Moreover, the possible role of nano-technological approaches to induce targeted delivery of SAB to eradicate tumor cells has been also discussed. Review Mon, 31 Aug 2020 00:00:00 GMT IramShahzadi, ZainAli, SidraBukhari, Acharan SNarula, BushraMirza, RezaMohammadinejad, Mon, 31 Aug 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100214 https://www.explorationpub.com/Journals/etat/Article/100220 Lung cancer is still one of the main causes of cancer-related death, together with prostate and colorectal cancers in males and breast and colorectal cancers in females. The prognosis for non-small cell lung cancer (NSCLC) is strictly dependent on feasibility of a complete surgical resection of the tumor at diagnosis. Since surgery is indicated only in early stages tumors, it is necessary to anticipate the timing of diagnosis in clinical practice. In the diagnostic and therapeutic pathway for NSCLC, sampling of neoplastic tissue is usually obtained using invasive methods that are not free from disadvantages and complications. A valid alternative to the standard biopsy is the liquid biopsy (LB), that is, the analysis of samples from peripheral blood, urine, and other biological fluids, with a simple and non-invasive collection. In particular, it is possible to detect in the blood different tumor derivatives, such as cell-free DNA (cfDNA) with its subtype circulating tumor DNA (ctDNA), cell-free RNA (cfRNA), and circulating tumor cells (CTCs). Plasma-based testing seems to have several advantages over tumor tissue biopsy; firstly, it reduces medical costs, risk of complications related to invasive procedures, and turnaround times; moreover, the analysis of genes alteration, such as EGFR, ALK, ROS1, and BRAF is faster and safer with this method, compared to tissue biopsy. Despite all these advantages, the evidences in literatures indicate that assays performed on liquid biopsies have a low sensitivity, making them unsuitable for screening in lung cancer at the current state. This is caused by lack of standardization in sampling and preparation of specimen and by the low concentration of biomarkers in the bloodstream. Instead, routinely use of LB should be preferred in revaluation of patients with advanced NSCLC resistant to chemotherapy, due to onset of new mutations. Review Fri, 09 Oct 2020 00:00:00 GMT GiovanniVicidomini, RobertoCascone, AnnalisaCarlucci, AlfonsoFiorelli, MarinaDi Domenico, MarioSantini, Fri, 09 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100220 https://www.explorationpub.com/Journals/etat/Article/100218 PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design. Review Mon, 12 Oct 2020 00:00:00 GMT Robert I.Troup, CharleneFallan, Matthias G. J.Baud, Mon, 12 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100218 https://www.explorationpub.com/Journals/etat/Article/100221 Aim: Tamoxifen (TAM) resistance remains a clinical issue in breast cancer. The authors previously reported that 15-hydroxyprostaglandin dehydrogenase (HPGD) was significantly downregulated in tamoxifen-resistant (TAMr) breast cancer cell lines. Here, the authors investigated the relationship between HPGD expression, TAM resistance and prediction of outcome in breast cancer. Methods: HPGD overexpression and silencing studies were performed in isogenic TAMr and parental human breast cancer cell lines to establish the impact of HPGD expression on TAM resistance. HPGD expression and clinical outcome relationships were explored using immunohistochemistry and in silico analysis. Results: Restoration of HPGD expression and activity sensitised TAMr MCF-7 cells to TAM and 17β-oestradiol, whilst HPGD silencing in parental MCF-7 cells reduced TAM sensitivity. TAMr cells released more prostaglandin E2 (PGE2) than controls, which was reduced in TAMr cells stably transfected with HPGD. Exogenous PGE2 signalled through the EP4 receptor to reduce breast cancer cell sensitivity to TAM. Decreased HPGD expression was associated with decreased overall survival in ERα-positive breast cancer patients. Conclusions: HPGD downregulation in breast cancer is associated with reduced response to TAM therapy via PGE2-EP4 signalling and decreases patient survival. The data offer a potential target to develop combination therapies that may overcome acquired tamoxifen resistance. Original Article Tue, 20 Oct 2020 00:00:00 GMT MileneVolpato, MicheleCummings, Abeer M.Shaaban, BalkeesAbderrahman, Mark A.Hull, Philipp Y.Maximov, Bradley M.Broom, ReinerHoppe, PingFan, HiltrudBrauch, V. CraigJordan, ValerieSpeirs, Tue, 20 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100221 https://www.explorationpub.com/Journals/etat/Article/100222 Immunotherapy dramatically changed the management of several malignancies including non-small cell lung cancer (NSCLC). Since immune checkpoint inhibitors have a different mechanism of action from cytotoxic agents or small molecules against NSCLC, also tumor response may present with atypical features. Pseudoprogression (PP) is a distinct response pattern defined by a transient enlargement of the tumor burden, sustained by inflammatory cells and usually not associated with worsening of performance status (PS). Here the authors describe the case of a lung adenocarcinoma patient treated with pembrolizumab, who developed an early symptomatic PP with a dramatic global worsening of PS. Subsequently an improvement in general condition and a brilliant tumor response were observed. Tumor re-biopsy was collected after the treatment in order to support the identification of PP and to describe microenvironment modifications induce by immunotherapy. Case Report Wed, 28 Oct 2020 00:00:00 GMT GiuliaMeoni, Nicola LibertàDecarli, MaurizioBenucci, ClaudioRaspanti, Angela StefaniaRibecco, Wed, 28 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100222 https://www.explorationpub.com/Journals/etat/Article/100219 Cancer is one of the most dreadful diseases in the world with a mortality of 9.6 million annually. Despite the advances in diagnosis and treatment during the last couple of decades, it still remains a serious concern due to the limitations associated with currently available cancer management strategies. Therefore, alternative strategies are highly required to overcome these glitches. The importance of medicinal plants as primary healthcare has been well-known from time immemorial against various human diseases, including cancer. Commiphora wightii that belongs to Burseraceae family is one such plant which has been used to cure various ailments in traditional systems of medicine. This plant has diverse pharmacological properties such as antioxidant, antibacterial, antimutagenic, and antitumor which mostly owes to the presence of its active compound guggulsterone (GS) that exists in the form of Z- and E-isomers. Mounting evidence suggests that this compound has promising anticancer activities and was shown to suppress several cancer signaling pathways such as NF-κB/ERK/MAPK/AKT/STAT and modulate the expression of numerous signaling molecules such as the farnesoid X receptor, cyclin D1, survivin, caspases, HIF-1α, MMP-9, EMT proteins, tumor suppressor proteins, angiogenic proteins, and apoptotic proteins. The current review is an attempt to summarize the biological activities and diverse anticancer activities (both in vitro and in vivo) of the compound GS and its derivatives, along with its associated mechanism against various cancers. Review Thu, 29 Oct 2020 00:00:00 GMT SosmithaGirisa, DeyParama, ChoudharyHarsha, KishoreBanik, Ajaikumar B.Kunnumakkara, Thu, 29 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100219 https://www.explorationpub.com/Journals/etat/Article/100223 Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC properties, modulate binding kinetics and substantially impacts the potency and selectivity. In this review, the authors briefly discuss the recent findings in PROTAC design approaches with focus on the linker. For each PROTAC such linker parameters as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved stability, bioavailability cell membrane permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase. Thus rational linker design with respect to composition, length and attachment sites is essential for the development of potent PROTAC compounds. Computer-aided design and novel innovative linker strategies, such as PROTAC shortening, photo-switchable PROTACs, in-cell click-formed CLIPTACs, “click chemistry” approaches are also discussed in the review. Review Fri, 30 Oct 2020 00:00:00 GMT AlmazZagidullin, VasiliMilyukov, AlbertRizvanov, EmilBulatov, Fri, 30 Oct 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100223 https://www.explorationpub.com/Journals/etat/Article/100224 Liquid biopsy has emerged as a minimally invasive alternative to tumor tissue analysis for the management of lung cancer patients, especially for epidermal growth factor receptor (EGFR) oncogene addicted tumor. In these patients, despite the clear benefits of tyrosine kinase inhibitors therapy, the development of acquired resistance and progressive disease is inevitable in most cases and liquid biopsy is important for molecular characterization at resistance and, being non-invasive, may be useful for disease monitoring. In this review, the authors will focus on the applications of liquid biopsy in EGFR-mutated non small cells lung cancer at diagnosis, during treatment and at progression, describing available data and possible future scenarios. Review Tue, 24 Nov 2020 00:00:00 GMT MarialuciaIacovino, VincenzaCiaramella, FernandoParagliola, GabriellaSuarato, GesualdinaBusiello, FrancescaSparano, Tue, 24 Nov 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100224 https://www.explorationpub.com/Journals/etat/Article/100225 Cancer drug discovery is currently dominated by clinical trials or clinical research. Several potential drug candidates have been brought into the pipeline of drug discovery after showing very promising results at the pre-clinical level and are waiting to be tested in human clinical trials. Interestingly, among the potential drug candidates, a few of them have targeted transcription factors highlighting the fundamental undruggable nature of these molecules. However, using advanced technologies, researchers were recently successful in partly unlocking this undruggable nature, which was considered as a ‘grey area’ in the early days of drug discovery, and as a result, several potential candidates have emerged recently. The purpose of the review is to highlight some of the recently reported studies of targeting transcription factors in cancer and their promising outcomes. Review Fri, 04 Dec 2020 00:00:00 GMT ParthaMitra, Fri, 04 Dec 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100225 https://www.explorationpub.com/Journals/etat/Article/100226 Cancer is one of the leading causes of mortality, contributing to 9.6 million deaths globally in 2018 alone. Although several cancer treatments exist, they are often associated with severe side effects and high toxicities, leaving room for significant advancements to be made in the field. In recent years, several phytochemicals from plants and natural bioresources have been extracted and tested against various human malignancies using both in vitro and in vivo preclinical model systems. Cardamonin, a chalcone extracted from the Alpinia species, is an example of a natural therapeutic agent that has anti-cancer and anti-inflammatory effects against human cancer cell lines, including breast, lung, colon, and gastric, in both in vitro culture systems as well as xenograft mouse models. Earlier, cardamonin was used as a natural medicine against stomach related issues, diarrhea, insulin resistance, nephroprotection against cisplatin treatment, vasorelaxant and antinociceptive. The compound is well-known to inhibit proliferation, migration, invasion, and induce apoptosis, through the involvement of Wnt/β-catenin, NF-κB, and PI3K/Akt pathways. The good biosafety and pharmacokinetic profiling of cardamonin satisfy it as an attractive molecule for the development of an anticancer agent. The present review has summarized the chemo-preventive ability of cardamonin as an anticancer agent against numerous human malignancies. Review Mon, 21 Dec 2020 00:00:00 GMT ShanayaRamchandani, IrumNaz, NamrataDhudha, ManojGarg, Mon, 21 Dec 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100226 https://www.explorationpub.com/Journals/etat/Article/100227 Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in non-small cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments. Letter to the Editor Tue, 29 Dec 2020 00:00:00 GMT MartaBrambilla, Giuseppe LoRusso, RobertoFerrara, SaraManglaviti, Marina ChiaraGarassino, MarioOcchipinti, Tue, 29 Dec 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100227 https://www.explorationpub.com/Journals/etat/Article/100228 Malignant pleural mesothelioma (MPM) is an aggressive tumor strictly connected to asbestos exposure. Prognosis is dismal as diagnosis commonly occurs in advanced stage. Radiological screenings have not proven to be effective and also pathological diagnosis may be challenging. In the era of precision oncology, validation of robust non-invasive biomarkers for screening of asbestos-exposed individuals, assessment of prognosis and prediction of response to treatments remains an important unmet clinical need. This review provides an overview on current understanding and possible applications of liquid biopsy in MPM, mostly focused on the utility as diagnostic and prognostic test. Review Tue, 29 Dec 2020 00:00:00 GMT GiuseppeViscardi, DavideDi Natale, MorenaFasano, MartaBrambilla, RiccardoLobefaro, AlessandroDe Toma, GiuliaGalli, Tue, 29 Dec 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100228 https://www.explorationpub.com/Journals/etat/Article/100229 Although breast cancer is not traditionally considered an immunogenic type of tumor, the combination of immunotherapy and chemotherapy has recently emerged as a novel treatment option in triple-negative subtype in the advanced setting and other similar combinations of immune checkpoint inhibitors with chemotherapy are expected to become part of the neoadjuvant management in the near future. In addition, encouraging results have been observed with the combination of immune checkpoint blockade with diverse biological agents, including anti-HER2 agents, CDK 4/6 inhibitors, PARP-inhibitors. The present review summarized the available evidence coming from clinical trials on the role of immune checkpoint inhibitors in the management of breast cancer, both in advanced and early setting. Review Tue, 29 Dec 2020 00:00:00 GMT FedericaMiglietta, Maria SilviaCona, Maria VittoriaDieci, ValentinaGuarneri, NiclaLa Verde, Tue, 29 Dec 2020 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100229 https://www.explorationpub.com/Journals/etat/Article/100230 The introduction of immune checkpoint inhibitors (ICIs) in non-oncogene addicted non-small cell lung cancer (NSCLC) has revolutionized the treatment scenario and led to a meaningful improvement in patient prognosis. Disappointingly, the success of ICI therapy in NSCLC has not been fully replicated in other thoracic malignancies as small cell lung cancer (SCLC), malignant pleural mesothelioma (MPM), and thymic epithelial tumors (TETs), due to the peculiar biological features of these disease and to the difficulties in the conduction of well-designed, biomarker-driven clinical trials. Therefore, combination strategies of ICIs plus conventional therapies (either chemotherapy, alternative ICIs or targeted agents) have been implemented. Although first approvals of ICI therapy have been recently granted in SCLC and MPM (in combination with chemotherapy and different ICIs), results remain somewhat modest and limited to a small proportion of patients. This work reviews the trial results of ICI therapy in mesothelioma, SCLC, and TETs and discusses the potential of combining ICIs with old drugs. Review Fri, 29 Jan 2021 00:00:00 GMT LucaCantini, FedericaPecci, FilippoMerloni, AndreaLanese, EdoardoLenci, FrancescoPaoloni, Joachim G.J.V.Aerts, RossanaBerardi, Fri, 29 Jan 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100230 https://www.explorationpub.com/Journals/etat/Article/100231 Transcription factors (TFs) are modular protein groups that preferably bind to DNA sequences and guide genomic expression through transcription. Among these key regulators, “pioneer factors” are an emerging class of TFs that specifically interact with nucleosomal DNA and facilitate accessible genomic binding sites for the additional TFs. There is growing evidence of these specialized modulators in particular malignancies, as highlighted by agents’ clinical efficacy, specifically targeting nuclear hormone receptors. They have been implicated in multiple cancers more recently, with a high proportion inculpating on hormone influential cancers. Moreover, extended crosstalk and cooperation between ERα pioneering factors in estrogen-dependent breast cancer (BC) remain elucidated. This review discusses on the recent advances in our understanding of pioneer TFs in cancer, especially highlighting its potentiality to modulate chromatin condensation to permit ERα recruitment in BC cells. Through the study it was concluded that the highly prospected pioneer TFs in BC, including FOXA1, TLE1, PBX1, and GATA3, possess the potential therapeutic significance and further innovations in the field could yield targeted therapy in cancer treatment. Review Wed, 10 Feb 2021 00:00:00 GMT HoneyPavithran, RanjithKumavath, Wed, 10 Feb 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100231 https://www.explorationpub.com/Journals/etat/Article/100233 Immunotherapy has changed the natural history of several malignancies that, a decade ago, had a very poor prognosis, such as lung cancer and melanoma. Consequently, many attempts have been done to expand the indications of immunotherapy agents, predominantly immune checkpoint inhibitors (ICIs), in other cancers, including gynecological malignancies. Alongside promising results in cervical and endometrial neoplasms, there are not clear data on the benefit of ICIs as single agent or in combination with antiangiogenic agents in ovarian cancer (OC) and ongoing trials are focusing on combining ICIs with standard chemotherapy or PARP inhibitors. This chapter summarized the evidences of ICIs in gynecological malignancies and report the ongoing trials in cervical, endometrial and OC. Review Fri, 19 Feb 2021 00:00:00 GMT DomenicaLorusso, ValentinaCeni, GennaroDaniele, AntonellaPietragalla, VandaSalutari, MargheritaMuratore, CamillaNero, FrancescaCiccarone, GiovanniScambia, Fri, 19 Feb 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100233 https://www.explorationpub.com/Journals/etat/Article/100232 The occurrence of phenotype switch from an epithelial to a mesenchymal cell state during the activation of the epithelial mesenchymal transition (EMT) program in cancer cells has been closely associated with the generation of invasive tumor cells that contribute to metastatic dissemination and treatment failure. Liquid biopsy represents an emergent non-invasive tool that may improve our understanding of the molecular events leading to cancer progression and initiating the metastatic cascade through the dynamic analysis of tumor-derived components isolated from body fluids. The present review will primarily focus on the applications of liquid biopsy in lung cancer patients for identifying EMT signature, elucidating molecular mechanisms underlying the acquisition of an invasive phenotype and detecting new targets for therapy. Review Fri, 19 Feb 2021 00:00:00 GMT VivianaDe Rosa, RosaFonti, Silvana DelVecchio, FrancescaIommelli, Fri, 19 Feb 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100232 https://www.explorationpub.com/Journals/etat/Article/100234 Multiple myeloma (MM), the second most common hematologic cancer, is caused by accumulation of aberrant plasma cells in the bone marrow. Its molecular causes are not fully understood and its great heterogeneity among patients complicates therapeutic decision-making. In the past decades, development of new therapies and drugs have significantly improved survival of MM patients. However, resistance to drugs and relapse remain the most common causes of mortality and are the major challenges to overcome. The advent of high throughput omics technologies capable of analyzing big amount of clinical and biological data has changed the way to diagnose and treat MM. Integration of omics data (gene mutations, gene expression, epigenetic information, and protein and metabolite levels) with clinical histories of thousands of patients allows to build scores to stratify the risk at diagnosis and predict the response to treatment, helping clinicians to make better educated decisions for each particular case. There is no doubt that the future of MM treatment relies on personalized therapies based on predictive models built from omics studies. This review summarizes the current treatments and the use of omics technologies in MM, and their importance in the implementation of personalized medicine. Review Sun, 28 Feb 2021 00:00:00 GMT SaraOvejero, JeromeMoreaux, Sun, 28 Feb 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100234 https://www.explorationpub.com/Journals/etat/Article/100235 The goal of an efficacious cancer therapy is to specifically target diseased cells at high accuracy while sparing normal, healthy cells. Over the past three decades, immunotherapy, based on the use of monoclonal antibodies (mAbs) directed against tumor-associated antigens, to inhibit their oncogenic function, or against immune checkpoints, to modulate specific T cell responses against cancer, has proven to be an important strategy for cancer therapy. Nevertheless, the number of mAbs approved for clinical use is still limited because of significant drawbacks to their applicability. Oligonucleotide aptamers, similarly to antibodies, form high-affinity bonds with their specific protein targets, thus representing an effective tool for active cancer targeting. Compared to antibodies, aptamers’ use as therapeutic agents benefits from their low size, low/no immunogenicity, simple synthesis and design flexibility for improving efficacy and stability. This review intends to highlight recently emerged applications of aptamers as recognition elements, from biomarker discovery to targeted drug delivery and targeted treatment, showing aptamers’ potential to work in conjunction with antibodies for attacking cancer from multiple flanks. Review Sun, 28 Feb 2021 00:00:00 GMT LisaAgnello, SimonaCamorani, MonicaFedele, LauraCerchia, Sun, 28 Feb 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100235 https://www.explorationpub.com/Journals/etat/Article/100236 Fungal compounds have long been used for centuries as food supplements. β-glucans have been identified as the most interesting molecules with beneficial effects in several chronic diseases. In vitro studies have shown that they are able to elicit the immune cells maturation and activation with the result of an increased release of proinflammatory cytokines and chemokines and a stimulation of anti-bacterial activity of macrophages and neutrophils. As β-glucans enhance pathogen elimination through non-self antigens identification, they can also direct immune response against tumor cells. These compounds also stimulate the activity on adaptive immune cells and they have been regarded as biological response modifiers. In this way, β-glucans can be exploited as adjuvant cancer therapy, in particular by a synergic action with chemotherapy or immunotherapy. In the immuno-oncology era, the need is to identify innovative drugs that can simultaneously target and inhibit different biological processes relevant for cancer cells survivors. Recent clinical studies showed promising results about the combination of β-glucans and immune checkpoint inhibitors for patients affected by different solid tumors. This review aims to investigate molecular mechanisms of action of β-glucans and is focused on their application in clinical practice as immune-adjuvants for treatment of cancer patients. Review Tue, 09 Mar 2021 00:00:00 GMT ValeriaCognigni, NicolettaRanallo, FrancescaTronconi, FrancescaMorgese, RossanaBerardi, Tue, 09 Mar 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100236 https://www.explorationpub.com/Journals/etat/Article/100237 About 15–20% of all breast cancers (BCs) are defined human epidermal growth factor receptor 2 (HER2)-positive, based on the overexpression of HER2 protein and/or amplification of ERBB2 gene. Such alterations lead to a more aggressive behavior of the disease, but also predict response to treatments targeting HER2. Indeed, several anti-HER2 compounds have been developed and approved in the last two decades, significantly improving our ability to cure patients in the early setting, and greatly extending their survival in the advanced setting. However, recent evolutions in this field promise to improve outcomes even further, through advancements in established HER2-targeting strategies, as well as the exploration of novel strategies. In particular, the engineering of new antibody-drug conjugates, with higher drug-to-antibody ratios (DARs) and cleavable linkers, has already led to the development of a highly effective drug, namely trastuzumab deruxtecan, recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of advanced HER2-positive (HER2+) BC, and currently in study in the early setting. Moreover, the novel tyrosine kinase inhibitor tucatinib was recently approved by FDA and EMA, showing to improve survival of HER2+ advanced BC patients, particularly in those with brain metastasis. Immunotherapy is also being investigated in the HER2+ subtype, through immune-checkpoint inhibition, cancer vaccines and adoptive-cell therapies. Overall, the enlarging arsenal of promising anti-HER2 compounds is expected to deliver significant improvements in the prognosis of both early and advanced HER2+ BC in the years to come. Moreover, some of such agents are showing encouraging activity in the much wider population of HER2-low advanced BC patients, challenging current BC classifications. If confirmed, this new paradigm would potentially expand the population deriving benefit from HER2-targeted treatments to up to 70% of all advanced BC patients, leading to a revolution in current treatment algorithms, and possibly to a redefinition of HER2 classification. Review Tue, 23 Mar 2021 00:00:00 GMT PaoloTarantino, StefaniaMorganti, GiuseppeCurigliano, Tue, 23 Mar 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100237 https://www.explorationpub.com/Journals/etat/Article/100238 Lung cancer is the most common cancer and the leading cause of cancer mortality worldwide. To date, tissue biopsy has been the gold standard for the diagnosis and the identification of specific molecular mutations, to guide choice of therapy. However, this procedure has several limitations. Liquid biopsy could represent a solution to the intrinsic limits of traditional biopsy. It can detect cancer markers such as circulating tumor DNA or RNA (ctDNA, ctRNA), and circulating tumor cells, in plasma, serum or other biological fluids. This procedure is minimally invasive, reproducible and can be used repeatedly. The main clinical applications of liquid biopsy in non-small cell lung cancer (NSCLC) patients are the early diagnosis, stratification of the risk of relapse, identification of mutations to guide application of targeted therapy and the evaluation of the minimum residual disease. In this review, the current role of liquid biopsy and associated markers in the management of NSCLC patients was analyzed, with emphasis on ctDNA and CTCs, and radiotherapy. Review Tue, 13 Apr 2021 00:00:00 GMT AnnaritaPerillo, Mohamed Vincenzo AgbajeOlufemi, JacopoDe Robbio, Rossella MargheritaMancuso, AnnaRoscigno, MaddalenaTirozzi, Ida RosaliaScognamiglio, Tue, 13 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100238 https://www.explorationpub.com/Journals/etat/Article/100239 Immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 inhibitors, programmed cell death 1 inhibitors and programmed cell death-ligand 1 inhibitors, have recently emerged as novel drugs in the anti-cancer therapy. Their use in different types of advanced cancer has shown good results and an increase in survival rates. However, immune-related adverse events (irAEs) are frequent and often require special care. IrAEs may affect all the organs, but they are most commonly seen in skin, lungs, endocrine glands and in the gastrointestinal tract where small bowel, colon, the liver and/or the pancreas can be involved. Despite being usually mild and self-resolving, irAEs may present in severe and life-threatening forms, causing the withdrawal of anti-cancer therapy. IrAEs, therefore, represent a challenging condition to manage that often requires the cooperation between the oncologists and the gastroenterologists in order to identify and treat them adequately. Review Tue, 13 Apr 2021 00:00:00 GMT DanieleBalducci, ClaudiaQuatraccioni, AntonioBenedetti, MarcoMarzioni, LucaMaroni, Tue, 13 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100239 https://www.explorationpub.com/Journals/etat/Article/100240 Aim: Nuclear factor erythroid 2-related factor 2 (NRF2) is a key component in the cell’s response to oxidative and electrophilic stress and is a transcription factor regulating the expression of a collection of anti-oxidative and cytoprotective genes. Human epidermal growth factor receptor 4 (HER4/erbB4) regulates growth and differentiation in many cancer types. Here, NRF2 and HER4 receptor interactions were investigated in a panel of ovarian cancer cell lines. Methods: Pharmacological [tert-butylhydroquinone (tBHQ) and retinoid/rexinoid, bexarotene] and genetic [small interfering RNA (siRNA)] manipulations were used to activate or inhibit NRF2 function in the cell line panel (PE01, OVCAR3, SKOV3). Activity of the HER-targeted tyrosine kinase inhibitors, erlotinib (ERL) and lapatinib (LAP), was evaluated after NRF2 activation. Results: While tBHQ increased the levels of both phosphorylated-NRF2 (pNRF2) and HER4 in PE01, OVCAR3 and SKOV3 cells, bexatorene and NRF2-target siRNA treatment decreased pNRF2 and total HER4 levels. The tBHQ-dependent pharmacological activation of NRF2 attenuated the therapeutic effectiveness of ERL and LAP. Analyses of gene expression data from a HER4 driven reporter system and in vitro or in vivo cancer models, support NRF2 regulation of HER4 expression. Conclusions: These results support the presence of signaling interaction between the NRF2 and HER4 receptor pathways and suggest that intervention modulating this cross-talk could have anticancer therapeutic value. Original Article Tue, 20 Apr 2021 00:00:00 GMT Ibrahim H.Kankia, PoornimaParamasivan, MatthewElcombe, Simon P.Langdon, Yusuf Y.Deeni, Tue, 20 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100240 https://www.explorationpub.com/Journals/etat/Article/100241 Not applicable. Editorial Tue, 20 Apr 2021 00:00:00 GMT Carminia Maria DellaCorte, FloraCimmino, FlorianaMorgillo, Tue, 20 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100241 https://www.explorationpub.com/Journals/etat/Article/100242 Aim: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high heterogeneity, rapid progression, and paucity of treatment options. The most effective chemotherapeutic drug used to treat TNBC is doxorubicin (Doxo) which is an anthracycline antibiotic. However, Doxo treatment alters cytosolic calcium dynamics leading to drug-resistance condition. The aim of this study is to capture the alterations in the activity of various calcium channels and pumps during Doxo treatment and their consequences on cytosolic calcium dynamics that ultimately result in drug resistance. Methods: In the present study, a mathematical model is proposed to capture the complex dynamical landscape of intracellular calcium during Doxo treatment. This study provides an insight into Doxo remodeling of calcium dynamics and associated drug-resistance effect. The model was first analyzed analytically and then explored through numerical simulation using techniques like global sensitivity analysis, parameter recalibration, etc. Results: The model is used to predict the potential combination therapy for Doxo that can overcome Doxo associated drug resistance. The results show targeting the dysregulated Ca2+ channels and pumps might provide efficient chemotherapy in TNBC. It was also observed that the indispensability of calcium influx rate is paramount in the Doxo drug resistance. Finally, three drugs were identified from existing literature that could be used as a combination therapy along with Doxo. Conclusions: The investigation highlights the importance of integrating the calcium signaling of various calcium regulating compounds for their effective anti-tumor effects deliverance along with chemotherapeutic agents. The results from this study might provide a new direction to the experimental biologists to explore different combination therapies with Doxo to enhance its anti-tumor effect. Original Article Fri, 30 Apr 2021 00:00:00 GMT GarhimaArora, SumanaGhosh, SamratChatterjee, Fri, 30 Apr 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100242 https://www.explorationpub.com/Journals/etat/Article/100243 Aim: The role of tumor burden (TB) for patients with non-small cell lung cancer (NSCLC) receiving immunotherapy is still unknown. The aim of this analysis was to analyze the prognostic value of TB in a real-world sample of advanced NSCLC patients. Methods: Sixty-five consecutive patients with advanced NSCLC treated with immunotherapy as first or second line therapy were retrospectively analyzed between August 2015 and February 2018. TB was recorded at baseline considering sites and number of metastases, thoracic vs. extrathoracic disease, measurable disease (MD) vs. not-MD (NMD) and evaluating dimensional aspects as maximum lesion diameter (cut-off = 6.3 cm), sum of the 5 major lesions diameters (cut-off = 14.3 cm), and number of sites of metastases (cut-off > 4). All cut-offs were calculated by receiver operating characteristic curves. Median overall survival (OS) was estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses. Results: Median age was 70 years and most patients (86.2%) had a good performance status (PS-Eastern Cooperative Oncology Group < 2). No significant difference in OS was noted between subgroups of patients according to TB. Bone metastases (BM) had a negative prognostic impact [median OS (mOS), 13.8 vs. 70.0 months, P = 0.0009; median progression free survival in the second line (mPFS2) 2.97 vs. 8.63 months; P = 0.0037]. Patients with NMD had a poorer prognosis (mOS, 15.9 months vs. not reached, P < 0.0001; mPFS2 3.8 vs. 12.2 months; P = 0.0199). Patients with disease limited to the thorax had a better prognosis compared to patients with involvement of extrathoracic sites (mOS, 70 vs. 17.3 months; P = 0.0136). Having more than 4 metastatic sites resulted as a negative prognostic factor (mOS, 15.9 vs. 25.2 months; P = 0.0106). At multivariate analysis, BM, NMD, extrathoracic disease and number of sites of metastases > 4 were negative prognostic factors (P < 0.0001). Conclusions: This study underlines the negative prognostic impact of specific metastatic sites, presence of NMD and extrathoracic disease in advanced NSCLC patients treated with immunotherapy. However, TB does not appear to affect the outcome of these patients. Original Article Fri, 28 May 2021 00:00:00 GMT EdoardoLenci, GiuliaMarcantognini, ValeriaCognigni, AlessioLupi, SilviaRinaldi, LucaCantini, IlariaFiordoliva, Anna LisaCarloni, MarcoRocchi, LinaZuccatosta, StefanoGasparini, RossanaBerardi, Fri, 28 May 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100243 https://www.explorationpub.com/Journals/etat/Article/100244 Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in mismatch repair (MMR) genes leading to increased risk of colon cancer as well as other cancer types. Non-small cell lung cancer (NSCLC) is not among typical Lynch syndrome-associated tumors: pembrolizumab, an immune checkpoint inhibitor, is actually approved for the treatment of NSCLC patients and represents a promising treatment option for patients with advanced metastatic MMR-deficient cancer, regardless of tumor origin. This case report describes the clinical presentation and management of a 74-year-old female with a history of rectal adenocarcinoma and ovarian cancer, who has a documented frameshift pathogenic variant in the exon 8 of MSH6 gene and an intronic variant in the BRCA2 gene (classified as a variant of uncertain significance), affected by NSCLC with brain metastases. Despite these premises, the patient was treated with pembrolizumab and she did not benefit from this kind of treatment. Case Report Fri, 28 May 2021 00:00:00 GMT ElenaMaccaroni, EdoardoLenci, VeronicaAgostinelli, ValeriaCognigni, RiccardoGiampieri, PaolaMazzanti, MarziaDi Pietro Paolo, FrancescaBianchi, CristianaBrugiati, LauraBelvederesi, SilviaPagliaretta, AlessandraMandolesi, MarinaScarpelli, AlbertoMurrone, FrancescaMorgese, ZelmiraBallatore, RossanaBerardi, Fri, 28 May 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100244 https://www.explorationpub.com/Journals/etat/Article/100245 Intracellular Ca2+ ions that are thought to be one of the most important second messengers for cellular signaling, have a substantial diversity of roles in regulating a plethora of fundamental cellular physiology such as gene expression, cell division, cell motility and apoptosis. It has been suggestive of the Ca2+ signaling-dependent cellular processes to be tightly regulated by the numerous types of Ca2+ channels, pumps, exchangers and sensing receptors. Consequently, dysregulated Ca2+ homeostasis leads to a series of events connected to elevated malignant phenotypes including uncontrolled proliferation, migration, invasion and metastasis, all of which are frequently observed in advanced stage lung cancer cells. The incidence of bone metastasis in patients with advanced stage lung cancer is estimated in a range of 30% to 40%, bringing about a significant negative impact on both morbidity and survival. This review dissects and summarizes the important roles of Ca2+ signaling transduction in contributing to lung cancer progression, and address the question: if and how Ca2+ signaling might have been engaged in metastatic lung cancer with bone metastasis, thereby potentially providing the multifaceted and promising solutions for therapeutic intervention. Review Fri, 28 May 2021 00:00:00 GMT Manh TienTran, Fri, 28 May 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100245 https://www.explorationpub.com/Journals/etat/Article/100246 Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca2+) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca2+ currents form Ca2+ oscillations that can be decoded by Ca2+-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca2+-related signals in these events. Review Mon, 21 Jun 2021 00:00:00 GMT ChaochuCui, YongxiZhang, GangLiu, ShuhongZhang, JinghangZhang, XianweiWang, Mon, 21 Jun 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100246 https://www.explorationpub.com/Journals/etat/Article/100247 Phosphorylation of cytoskeletal proteins regulates the dynamics of polymerization, stability, and disassembly of the different types of cytoskeletal polymers. These control the ability of cells to migrate and divide. Mutations and alterations of the expression levels of multiple protein kinases are hallmarks of most forms of cancer. Thus, altered phosphorylation of cytoskeletal proteins is observed in most cancer cells. These alterations potentially control the ability of cancer cells to divide, invade and form distal metastasis. This review highlights the emergent role of phosphorylation in the control of the function of the different cytoskeletal polymers in cancer cells. It also addresses the potential effect of targeted inhibitors in the normalization of cytoskeletal function. Review Tue, 29 Jun 2021 00:00:00 GMT ClaraLlorente-González, MartaGonzález-Rodríguez, MiguelVicente-Manzanares, Tue, 29 Jun 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100247 https://www.explorationpub.com/Journals/etat/Article/100248 Aim: Anticancer drugs (chemotherapeutics) used in cancer treatment (chemotherapy) lead to drug resistance. This study was conducted to investigate the possible effect of iron on calcium homeostasis in epithelial ovarian cancer cells (MDAH-2774) and cisplatin-resistant cells of the same cell line (MDAH-2774/DDP). Methods: To develop MDAH-2774/DDP cells, MDAH-2774 (MDAH) cells were treated with cisplatin in dose increases of 5 μM between 0 μM and 70 μM. The effect of iron on the viability of MDAH and MDAH/DDP cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test at the end of 24 h incubation. Results: At increasing iron concentrations in MDAH and MDAH/DDP cells, the mRNA gene of fifteen genes [inositol 1,4,5-triphosphate receptor (IP3R)1/2/3, ryanodine receptor (RYR)1/2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA)1/2/3, Na+/Ca2+ exchange (NCX)1/2/3, and plasma membrane Ca2+ ATPase (PMCA)1/2/3/4] associated with Ca2+ differences in expression were determined by quantitative reverse transcription-polymerase chain reaction. Changes in IP3R2, RYR1, SERCA2, NCX3, PMCA1, and PMCA3 gene expressions were observed in iron treatment of MDAH/DDP cells, while changes were detected in iron treatment of MDAH cells in IP3R1/2/3, RYR1/2, SERCA1/2/3, NCX2/3, and PMCA1 expressions. Conclusions: This changes in the expression of calcium channels, pumps, and exchange proteins in the epithelial ovarian cancer cell line and in cisplatin-resistant epithelial ovarian cancer cells suggest that iron may have an important role in regulating calcium homeostasis. Due to differences in the expression of genes that play of an important role in the regulation of calcium homeostasis in the effect of iron, drug resistance can be prevented by introducing a new perspective on the use of inhibitors and activators of these genes and thus cytostatic treatment strategies. Original Article Wed, 11 Aug 2021 00:00:00 GMT BahireKucukkaya, DemetErdag, FahriAkbas, LemanYalcintepe, Wed, 11 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100248 https://www.explorationpub.com/Journals/etat/Article/100249 In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies. Review Tue, 24 Aug 2021 00:00:00 GMT DeyParama, VarshaRana, SosmithaGirisa, ElikaVerma, Uzini DeviDaimary, Krishan KumarThakur, AviralKumar, Ajaikumar B.Kunnumakkara, Tue, 24 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100249 https://www.explorationpub.com/Journals/etat/Article/100250 The treatment landscape for multiple myeloma (MM) has dramatically changed over the last three decades, moving from no US Food and Drug Administration approvals and two active drug classes to over 19 drug approvals and at least eight different active classes. The advances seen in MM therapy have relied on both a structured approach to obtaining new labels and cautious off-label drug use. Although there are country and regional differences in drug approval processes, many of the basic principles behind off-label drug use in MM can be summarized into four main categories: 1) use of a therapy prior to the current approval regulations; 2) widespread use of a therapy following the release of promising clinical trial results but prior to drug approval; 3) use of a cheap therapy supported by clinical safety and efficacy data but without commercial backing; and 4) niche therapies for small well-defined patient populations where large clinical trials with sufficient power may be difficult to perform. This review takes a historical approach to discuss how off-label drug use has helped to shape the current treatment approach for MM. Review Tue, 24 Aug 2021 00:00:00 GMT James HStoeckle, Faith EDavies, LouisWilliams, Eileen MBoyle, Gareth JMorgan, Tue, 24 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100250 https://www.explorationpub.com/Journals/etat/Article/100251 The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term “microbiome” is used to describe the diverse community of micro-organisms existing within the gastrointestinal tract. The gut microbiome plays an important role in oestrogen metabolism through its ability to deconjugate oestrogens within the gut resulting in their reabsorption. Therefore, it is not unsurprising that “dysbiosis”, the disruption of normal gut microbiota composition, is now thought to play a role in the development of the disease, as women with breast cancer have been shown to have altered gut microbiota and this has been correlated with tumour characteristics. There is emerging evidence to suggest that the gut microbiota may also impact on breast cancer treatment, by mediating both drug efficacy and toxicity. The present review will discuss the influence of the gut microbiota on systemic treatments for breast cancer, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, endocrine therapy and immunotherapy as well as other targeted treatments. Review Tue, 24 Aug 2021 00:00:00 GMT EilidhBruce, StanislauMakaranka, GordonUrquhart, BeatrixElsberger, Tue, 24 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100251 https://www.explorationpub.com/Journals/etat/Article/100252 Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70–80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid hormone estrogen [17β-estradiol (E2)] plays a vital role both in the initiation and progression of BC. The E2-ERα mediated actions involve genomic signaling and non-genomic signaling. The specificity and magnitude of ERα signaling are mediated by interactions between ERα and several coregulator proteins called coactivators or corepressors. Alterations in the levels of coregulators are common during BC progression and they enhance ligand-dependent and ligand-independent ERα signaling which drives BC growth, progression, and endocrine therapy resistance. Many ERα coregulator proteins function as scaffolding proteins and some have intrinsic or associated enzymatic activities, thus the targeting of coregulators for blocking BC progression is a challenging task. Emerging data from in vitro and in vivo studies suggest that targeting coregulators to inhibit BC progression to therapy resistance is feasible. This review explores the current state of ERα coregulator signaling and the utility of targeting the ERα coregulator axis in treating advanced BC. Review Tue, 31 Aug 2021 00:00:00 GMT Kristin A.Altwegg, Ratna K.Vadlamudi, Tue, 31 Aug 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100252 https://www.explorationpub.com/Journals/etat/Article/100253 Cancer is an aging-associated disease and caused by genomic instability that is driven by the accumulation of mutations and epimutations in the aging process. Although Ca2+ signaling, reactive oxygen species (ROS) accumulation, DNA damage response (DDR) and senescence inflammation response (SIR) are processed during genomic instability, the underlying mechanism for the cause of genomic instability and cancer development is still poorly understood and needs to be investigated. Nociceptive transient receptor potential (TRP) channels, which firstly respond to environmental stimuli, such as microbes, chemicals or physical injuries, potentiate regulation of the aging process by Ca2+ signaling. In this review, the authors provide an explanation of the dual role of nociceptive TRP channels in regulating cancer progression, initiating cancer progression by aging-induced genomic instability, and promoting malignancy by epigenetic regulation. Thus, therapeutically targeting nociceptive TRP channels seems to be a novel strategy for treating cancers. Review Sun, 26 Sep 2021 00:00:00 GMT Wen-LiHsu, MamiNoda, TohruYoshioka, EtsuroIto, Sun, 26 Sep 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100253 https://www.explorationpub.com/Journals/etat/Article/100254 Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor (FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a “precision medicine” strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment. Review Sat, 09 Oct 2021 00:00:00 GMT Maria GiuseppinaPrete, AntonellaCammarota, AntonioD’Alessio, ValentinaZanuso, LorenzaRimassa, Sat, 09 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100254 https://www.explorationpub.com/Journals/etat/Article/100255 Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options. Although targeted therapies directed towards specific mutations found in CCA are becoming available and are showing great potential, many tumors do not carry actionable mutations and, in those that do, the emergence of drug resistance is a likely consequence of treatment. Therapeutic targeting of enzymes and other proteins that show elevated activity in CCA cells but which are not altered by mutation is a potential strategy for the treatment of target negative and drug-resistant disease. Protein kinase CK2 (CK2) is a ubiquitously expressed kinase that has increased expression and increased activity in a variety of cancer types including CCA. Several potent CK2 inhibitors are in pre-clinical development or under assessment in a variety of clinical trials often in combination with drugs that induce DNA damage. This review outlines the importance of CK2 in CCA and assesses the progress that has been made in the evaluation of CK2 inhibition as a treatment strategy in this disease. Targeting CK2 based on the expression levels or activity of this protein and/or in combination with drugs that induce DNA damage or inhibit cell cycle progression, could be a viable option for tumors that lack actionable mutations, or for tumors that develop resistance to targeted treatments. Review Sat, 09 Oct 2021 00:00:00 GMT Padma-SheelaJayaraman, KevinGaston, Sat, 09 Oct 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100255 https://www.explorationpub.com/Journals/etat/Article/100256 Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs. Review Mon, 01 Nov 2021 00:00:00 GMT GiacomoAimar, ChiaraParatore, CliziaZichi, DonatellaMarino, ElisaSperti, AndreaCaglio, TeresaGamba, FrancescaDe Vita, MassimoDi Maio, Mon, 01 Nov 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100256 https://www.explorationpub.com/Journals/etat/Article/100257 Multiple myeloma (MM) is a malignant proliferative disease of monoclonal plasma cells (PCs) and is characterized by uncontrolled proliferation of PCs and excessive production of specific types of immunoglobulins. Since PCs are terminally differentiated B cells, the World Health Organization (WHO) classifies MM as lymphoproliferative B-cell disease. The incidence of MM is 6–7 cases per 100,000 people in the world every year and the second most common cancer in the blood system. Due to the effects of drug resistance and malignant regeneration of MM cells in the microenvironment, all current treatment methods can prolong both overall and symptom-free survival rates of patients with MM but cannot cure MM. Both basic and clinical studies have proven that targeted therapy leads to a clear and significant prolongation of the survival of patients with MM, but when the disease recurs again, resistance to the previous treatment will occur. Therefore, the discovery of new targets and treatment methods plays a vital role in the treatment of MM. This article introduces and summarizes targeted MM therapy, potential new targets, and future precision medicine in MM. Review Mon, 01 Nov 2021 00:00:00 GMT ShanZhou, RenxiWang, Mon, 01 Nov 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100257 https://www.explorationpub.com/Journals/etat/Article/100258 Aim: Since SARS-CoV-2 infection rapidly spread around the world, Italy has quickly become one of the most affected countries. Healthcare systems introduced strict infection control measures to ensure optimal care, especially in frail groups such as cancer patients (pts). This study investigated the efficacy of SARS-CoV-2 pre-procedure screening and whether COVID-19 influenced timely diagnosis and therapy. Methods: Data of oncological procedures of pts with confirmed or suspected cancer diagnosis, treated at Oncology Department or coming from Emergency Department of San Luigi Gonzaga Hospital between June 2020 and March 2021 were retrospectively collected. A nasopharyngeal swab (NPS) was performed in outpatients 24/48 h before procedures. Inpatients were tested by NPS before and after hospitalization. Results: Two hundred and twenty-one pts were included in this analysis. Median age was 73 years, males were 58%. Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 or 1 in 88% of pts. The most frequent cancer type was lung cancer (57%). Stages IV were 77%. Two hundred and forty-three scheduled procedures were performed with diagnostic (n: 142; 58%), therapeutic (n: 55; 23%), and palliative (n: 46; 19%) intent. One hundred and four and 139 procedures were performed in out- and in-pts, respectively. Of the 234 NPS performed, 10 (4%) were positive. Two pts were infected during hospitalization, 8 in community. Most of them were asymptomatic, while only 2 had mild symptoms. Eight procedures (3%) were postponed, 1 cancelled, while 2 were performed in positive pts. Median time to resolution of the infection was 17 days (11–36). Median delay in the procedures was 25 days (14–55). Five pts started systemic treatment, after a median time of 37.5 days (13–57). Conclusions: SARS-CoV-2 infection led to the postponement of a small, but not negligible percentage of oncological procedures. However, the low infection rate observed suggests that structured screening for COVID-19 is critical for the best management of scheduled procedures during pandemic. Original Article Mon, 01 Nov 2021 00:00:00 GMT MaristellaBungaro, ValentinaBertaglia, MarcoAudisio, ElenaParlagreco, ChiaraPisano, ValeriaCetoretta, IrenePersano, FrancescaJacobs, ChiaraBaratelli, LorenaConsito, Maria LuciaReale, FabrizioTabbò, PaoloBironzo, Giorgio VittorioScagliotti, SilviaNovello, Mon, 01 Nov 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100258 https://www.explorationpub.com/Journals/etat/Article/100259 Adjuvant hormonal therapy is one of the most important treatments of hormone-receptor-positive breast cancer and includes selective estrogen receptor modulators, aromatase inhibitors, and luteinizing hormone-releasing hormone analogs. In patients receiving these drugs, a progressive recession of frontal-temporal hairlines is often observed, such as a certain grade of hair miniaturization in the same areas and the central scalp area, producing a pseudo-female androgenic alopecia, which has to be considered oncotherapy-induced alopecia. The aim of this work, is to describe the clinical aspects and pathogenesis of this type of alopecia and to analyze the different drugs which have been proposed until now. The authors concude that topical hormones should not be considered as a therapeutic approach because of their direct or indirect oncogenic potential. A therapeutic approach that could be both safe and effective is proposed. Review Mon, 01 Nov 2021 00:00:00 GMT AlfredoRossi, GemmaCaro, FrancescaMagri, Maria CaterinaFortuna, MartaCarlesimo, Mon, 01 Nov 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100259 https://www.explorationpub.com/Journals/etat/Article/100260 Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estrogen receptor alpha positive (ERα+) and human epidermal growth factor receptor 2-positive (HER2+), respectively; therefore, ER and HER2 targeted therapies have been employed in BC treatment. However, resistance to these therapies has been reported, indicating a need for developing novel therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) are new, promising therapeutic tools designed with a bimodular structure: one module allows specific binding to target proteins, and the other module allows efficient degradation of these target proteins. In this paper, PROTACs and their potential in controlling the progression of ERα and HER2+ BC are discussed. Review Wed, 17 Nov 2021 00:00:00 GMT Angeles C.Tecalco-Cruz, JesúsZepeda-Cervantes, Josué O.Ramírez-Jarquín, AlbertoRojas-Ochoa, Wed, 17 Nov 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100260 https://www.explorationpub.com/Journals/etat/Article/100261 Proteolysis targeting chimeras (PROTACs) are a class of small molecules designed to target proteins for degradation. Their novel and unique modes of action provide PROTACs with the potential for their application in the management of both solid and hematologic malignancies. Since its initial discovery, the technology of targeted protein degradation, especially in the form of PROTACs, has had significant advances. A number of PROTACs have entered a late stage of preclinical development. Several of them are either in phase 1/2 clinical trials or approaching approval for initial clinical evaluation. This article discusses the preclinical and clinical findings of PROTACs of clinically relevant protein targets in cancer. Review Thu, 02 Dec 2021 00:00:00 GMT HaoXie, JunjiaLiu, Diego M.Alem Glison, Jason B.Fleming, Thu, 02 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100261 https://www.explorationpub.com/Journals/etat/Article/100262 The dismal prognosis of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) prompted recent advances in the field of therapeutic approaches beyond cytotoxic cancer therapy. In recent years, the deeper and increasing knowledge on the genomic landscape and the upcoming new data on immunotherapy enacted by HNSCCs have led to successful therapeutic targeting of the immune system. Immune checkpoint inhibitors (ICIs) have changed state of the art in R/M patients and could have a potential role even in early disease. The purpose of this work is to summarize the role of immunotherapy for R/M HNSCC in clinical practice, with insights about future perspectives. Updated immunotherapy results in other R/M head and neck cancers such as thyroid, salivary glands, nasopharynx, sinonasal cancers, and nuclear protein in testis (NUT) are presented. Review Tue, 07 Dec 2021 00:00:00 GMT StefanoCavalieri, Daria MariaFilippini, AriannaOttini, CristianaBergamini, CarloResteghini, ElenaColombo, RobertaLombardo, ImperiaNuzzolese, SalvatoreAlfieri, LisaLicitra, Laura D.Locati, Tue, 07 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100262 https://www.explorationpub.com/Journals/etat/Article/100263 Aim: To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival. Methods: The expression of 275 transcripts, encoding components of the Ca2+ toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout. Results: Of the 275 Ca2+-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). CACNA1D, JPH1, and ATP2C2 were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets. Conclusions: This study has unveiled alterations of the Ca2+ toolkit in OAC, compared to normal tissue. Such Ca2+ signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents. Original Article Tue, 14 Dec 2021 00:00:00 GMT Alana L.Cutliffe, Sharon L.McKenna, Darshan S.Chandrashekar, AlvinNg, GinnyDevonshire, Rebecca C.Fitzgerald, Tracey R.O’Donovan, John J.Mackrill, Tue, 14 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100263 https://www.explorationpub.com/Journals/etat/Article/100264 Aim: Direct analytical comparison of two major drug-linkers in the antibody-drug conjugate (ADC) field was conducted. Methods: Four different analytical methods [AlogP calculation, reverse phase (RP) high-performance liquid chromatography (HPLC; RP-HPLC), size exclusion chromatography HPLC (SEC-HPLC), and differential scanning calorimetry (DSC)] were tested for this comparison. Results: Maytansinoid-based ADCs showed less hydrophobicity than auristatin-based ADCs. Regardless of the drug-linker and drug-to-antibody ratios (DARs), the stability detected by DSC was decreased by conjugation. Conclusions: The cost and time-efficient analytical comparison described in this manuscript may be useful information for an initial characterization of ADCs prior to detailed biological studies. Original Article Wed, 22 Dec 2021 00:00:00 GMT TomohiroFujii, CallisteReiling, ColetteQuinn, MichalKliman, Brian A.Mendelsohn, YutakaMatsuda, Wed, 22 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100264 https://www.explorationpub.com/Journals/etat/Article/100266 Obesity has dramatically increased over the past fifty years. In the last decade, it has been noted that augmented body mass, metabolic abnormalities, and the relevant “obese” tumor microenvironment (TME) are connected with signaling molecular networks, which in turn, may contribute to aggressive tumor biology in some patients with breast malignancies. This article presents the associations between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of triple-negative breast cancer (TNBC) in African American (AA) women. It also describes some abnormal molecular signaling patterns in the “obese” TME with relevance to TNBC biology. Ethnic disparities in TNBC can be due to a variety of biological features (e.g., genetic mutations and tumor heterogeneity), comorbidities (e.g., cardio-metabolic diseases, including diabetes mellitus), and reproductive factors (e.g., multiparty or short breastfeeding period). Such a constellation of biological variables potentially leads to the association between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of TNBC in AA women. Since the TNBC and its TME can display very aggressive behavior, it is crucial that the afflicted AA women make efforts to maintain healthy body weight, “flexible” metabolism, and a well-functioning immune system. Further studies are merited to explore the multi-disciplinary factors that can affect TNBC prevention, management, and outcomes to optimize treatment strategies and survival among AA women. Review Fri, 31 Dec 2021 00:00:00 GMT KatarzynaRygiel, Fri, 31 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100266 https://www.explorationpub.com/Journals/etat/Article/100265 Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degraders are chimeric compounds comprising of a BET inhibitor, which allows the binding to BET bromodomains, linked to a small molecule, binder for an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These degraders, called proteolysis-targeting chimeras (PROTACs), can exhibit greater target specificity compared to BET inhibitors and overcome some of their limitations, such as the upregulation of the BET proteins themselves. Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET inhibitor as a comparison. Methods: Established lymphoma cell lines were exposed for 72 h to increasing doses of the compounds. Cell proliferation was evaluated by using an 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assay. Fluorescent-Activated Cell Sorter (FACS) analysis was performed to measure apoptotic activation and RNA sequencing (RNA-Seq) to study the transcriptional changes induced by the compounds. Results: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC50) of 49 nmol/L. MZ1 was more in vitro active than the BET inhibitor birabresib (OTX015). Importantly, MZ1 induced cell death in all the ABC DLBCL cell lines, while the BET inhibitor was cytotoxic only in a fraction of them. BET degrader and inhibitor shared partially similar changes at transcriptome level but the MZ1 effect was stronger and overlapped with that caused cyclin-dependent kinase 9 (CDK9) inhibition. Conclusions: The BET degrader MZ1 had strong cytotoxic activity in all the ABC DLBCL cell lines that were tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations. Original Article Fri, 31 Dec 2021 00:00:00 GMT ChiaraTarantelli, EleonoraCannas, HillarieEkeh, CarmeloMoscatello, EugenioGaudio, LucianoCascione, SaraNapoli, CesareRech, AndreaTesta, ChiaraManiaci, AndreaRinaldi, EmanueleZucca, AnastasiosStathis, AlessioCiulli, FrancescoBertoni, Fri, 31 Dec 2021 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100265 https://www.explorationpub.com/Journals/etat/Article/100267 Targeted immunotherapy has arisen over the past decade to the forefront of cancer care. Notably, targeted therapies such as antibody-drug conjugates (ADCs) are becoming more recognized for a novel approach in cancer treatment. The mechanism of action of ADCs incorporates a monoclonal antibody portion directed against the tumor cell antigen and attached to the tumoricidal portion via chemical linkage. The binding of the monoclonal antibody portion allows for tumor cell internalization of the ADC and precise release of the toxic payload within the cancer cell. Multiple myeloma (MM) is an incurable cancer for which belantamab mafodotin was the first-in-class ADC to achieve United States Food and Drug Administration (FDA) approval for treatment of this disease. Clinical trials are currently evaluating other ADCs in the treatment of MM. In this review, a look at the current ADCs being tested in MM clinical trials with a focus on those that are more promising and a potential next-in-line for FDA approval for treatment of MM is discussed. Review Fri, 14 Jan 2022 00:00:00 GMT MoniqueHartley-Brown, PaulRichardson, Fri, 14 Jan 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100267 https://www.explorationpub.com/Journals/etat/Article/100268 Aim: B-cell lymphoma-2 (Bcl-2)-like protein-10 (Bcl2L10) is the less studied member of Bcl-2 family proteins, with the controversial role in different cancer histotypes. Very recently, Bcl2L10 expression in melanoma tumor specimens and its role in melanoma response to therapy have been demonstrated. Here, the involvement of Bcl2L10 on the in vitro and in vivo properties associated with melanoma aggressive features has been investigated. Methods: Endogenous Bcl2L10 protein expression was detected by western blotting analysis in a panel of patient-derived and commercially available human melanoma cells. In vitro assays to evaluate clonogenicity, cell proliferation, cell migration, cell invasion, and in vitro capillary-like structure formation [vasculogenic mimicry (VM)] have been performed by using human melanoma cells stably overexpressing Bcl2L10 or transiently transfected for loss/gain function of Bcl2L10, grown under two- or three-dimensional (3D) conditions Xenograft melanoma model was employed to evaluate in vivo tumor growth and angiogenesis. Results: Results demonstrated that Bcl2L10 acts as an inducer of in vitro cell migration, invasion, and VM, while in vitro cell proliferation, in vivo tumor growth, as well as colony formation properties were not affected. Dissecting different signaling pathways, it was found that Bcl2L10 positively affects the phosphorylation of extracellular-signal-regulated kinase (ERK) and the expression of markers of cell invasion, such as urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinases (MMPs). Of note, Bcl2L10-dependent in vitro migration, invasion, and VM are linked to uPAR. Bcl2L10 also negatively regulates the intracellular calcium level. Finally, reduced invasion capability in 3D spheroid invasion assay of melanoma cells transiently overexpressing Bcl2L10 was observed after treatment with inhibitors of MMPs and uPAR. Conclusions: Overall, data reported in this paper provide evidence supporting a positive role of Bcl2L10 in melanoma aggressive features. Original Article Sun, 30 Jan 2022 00:00:00 GMT Donatella DelBufalo, MartaDi Martile, ElisabettaValentini, IsabellaManni, IleniaMasi, AntonellaD’Amore, AntonioFilippini, CarmineNicoletti, MarcoZaccarini, CarloCota, Maria VictoriaCastro, María JosefinaQuezada, LauraRosanò, PabloLopez-Bergami, SimonaD’Aguanno, Sun, 30 Jan 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100268 https://www.explorationpub.com/Journals/etat/Article/100269 Antibody-drug conjugates (ADCs) have changed the treatment of breast cancer (BC) in more recent years. BC is a heterogenous group of malignancies with a broad range of histopathological characteristics. ADCs represent a class of therapeutics that combines an antigen-specific antibody backbone bound to a potent cytotoxic agent (the payload), via a linker, contributing to an improved therapeutic index. Currently, three ADCs received approval by the US Food and Drug Administration (FDA) and are in routine clinical use in different treatment settings; many more ADCs are in earlier and later stages of development, and their future approval will improve treatment options for patients with advanced but potentially also early-stage BC over time. Just recently, the results of three phase 3 trials (ASCENT, TULIP, and DESTINY-Breast03) evaluating sacituzumab govitecan (SG), trastuzumab duocarmazine, and trastuzumab deruxtecan (T-DXd) in different treatment settings were presented and showed promising results. This overview focuses on the newer ADCs, including T-DXd and SG, their pharmacology, mechanisms of action, and relevant studies. In addition, the latest results from trials investigating some newer ADCs, in further stages of development are presented. Review Fri, 25 Feb 2022 00:00:00 GMT Kira-LeeKoster, JensHuober, MarkusJoerger, Fri, 25 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100269 https://www.explorationpub.com/Journals/etat/Article/100270 Aim: T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated. Methods: The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation. Results: Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton’s tyrosine kinase (BTK). Conclusions: CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens. Original Article Fri, 25 Feb 2022 00:00:00 GMT Annabel R.Minton, Lindsay D.Smith, Dean J.Bryant, Jonathan C.Strefford, FrancescoForconi, Freda K.Stevenson, David A.Tumbarello, EddJames, Geir ÅgeLøset, Ludvig A.Munthe, Andrew J.Steele, GrahamPackham, Fri, 25 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100270 https://www.explorationpub.com/Journals/etat/Article/100271 During the past two decades, tremendous progress has been made in the dendrimer-based delivery of therapeutic molecules including, for instance, small molecules, macromolecules, and genes. This review deals with recent successes in the development of promising biocompatible phosphorus dendrimers, a specific type of dendrimer, to deliver genes to treat cancers. Review Fri, 25 Feb 2022 00:00:00 GMT SergeMignani, XiangyangShi, MariaBryszewska, DzmitryShcharbin, Jean-PierreMajoral, Fri, 25 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100271 https://www.explorationpub.com/Journals/etat/Article/100272 The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions of TPC2 and a discussion of its potential as a target for therapeutic intervention, including a summary of clinical trials examining the TPC2 inhibitors, naringenin, tetrandrine, and verapamil for the treatment of various cancers is provided. Review Mon, 28 Feb 2022 00:00:00 GMT Kathryn A.Skelding, Daniel L.Barry, Danielle Z.Theron, Lisa F.Lincz, Mon, 28 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100272 https://www.explorationpub.com/Journals/etat/Article/100273 Hilar cholangiocarcinoma is a rare primary malignancy associated with a dismal prognosis. Currently, complete extended right or left-sided hepatectomy is the primary curative therapy. Achieving a negative resection margin is associated with long-term survival and better quality of life, while post-hepatectomy liver failure (PHLF) due to insufficient liver remnant remains the most dreaded complication with a negative effect on overall survival. Precise preoperative management with sufficient future remnant liver (FRL) volume is the key to achieving good results in the treatment of bile duct carcinoma. To present a case report and a literature review for preoperative FRL optimization prior to major hepatectomies for hilar cholangiocarcinoma. Improvement of postoperative outcomes after extended liver resections in the case of hilar cholangiocarcinoma. A 62-year-old Caucasian woman with Lynch syndrome presented to our department with a hilar cholangiocarcinoma Bismuth type IIIa. The patient had an insufficient future liver volume for extended liver resection. She underwent preoperative preconditioning using a liver venous deprivation (LVD) and underwent two weeks later a right trisectorectomy without any interventional complications. Liver function remained stable postoperatively. The patient was discharged on the 20th postoperative day without major surgical post-operative complications or the need for readmission. LVD is a technically feasible, safe, and effective procedure to increase the FRL in a short period of time with low intra and post-operative complications and therefore improving the survival of patients with hilar cholangiocarcinoma. Case Report Mon, 28 Feb 2022 00:00:00 GMT RadoslavaStoyanova, HelmutKopf, WolfgangSchima, Wolfgang KarlMatzek, AlexanderKlaus, Mon, 28 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100273 https://www.explorationpub.com/Journals/etat/Article/100274 Aim: A model of progressively endocrine-resistant breast cancer was investigated to identify changes that can occur in signaling pathways after endocrine manipulation. Methods: The MCF7 breast cancer model is sensitive to estrogens and anti-estrogens while variant lines previously derived from wild-type MCF7 are either relatively 17β-estradiol (E2 )-insensitive (LCC1) or fully resistant to estrogen and anti-estrogens (LCC9). Results: In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. LCC1 and LCC9 cells had enhanced AKT phosphorylation relative to MCF7 which was reflected in downstream activation of phospho-mechanistic target of rapamycin (mTOR), phospho-S6, and phospho-estrogen receptor alpha Ser167 [ERα(Ser167)]. Both AKT2 and AKT3 were phosphorylated in the resistant cell lines, but small interfering RNA (siRNA) knockdown suggested that all three AKT isoforms contributed to growth response. ERα(Ser118) phosphorylation was increased by E2 and TGFα in MCF7, by E2 only in LCC1, but by neither in LCC9 cells. Multiple alterations in E2-mediated cell cycle control were identified in the endocrine-resistant cell lines including increased expression of MYC, cyclin A1, cyclin D1, cyclin-dependent kinase 1 (CDK1), CDK2, and hyperphosphorylated retinoblastoma protein (ppRb), whereas p21 and p27 were reduced. Estrogen modulated expression of these regulators in MCF7 and LCC1 cells but not in LCC9 cells. Seliciclib inhibited CDK2 activation in MCF7 cells but not in resistant variants; in all lines, it reduced ppRb, increased p53 associated responses including p21, p53 up-regulated modulator of apoptosis (PUMA), and p53 apoptosis-inducing protein 1 (p53AIP1), inhibited growth, and produced G2/M block and apoptosis. Conclusions: Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E2 insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases. Original Article Mon, 28 Feb 2022 00:00:00 GMT Kate M.Moore, VeraCerqueira, Kenneth G.MacLeod, PeterMullen, Richard L.Hayward, SimonGreen, David J.Harrison, David A.Cameron, Simon P.Langdon, Mon, 28 Feb 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100274 https://www.explorationpub.com/Journals/etat/Article/100275 Messenger RNA (mRNA) has recently made important progress in clinical implementation, offering a promising therapeutic option for infectious disease and cancer. However, the nature of mRNA molecules rendered them poorly bioavailable and unstable in vivo, impeding their further clinical application. Therefore, safe and efficient delivery of mRNA therapeutics to the target site is crucial for their successful translation into the clinical setting. Various vectors have been explored for mRNA delivery. Among them, polyesters and their analogs, a family of biodegradable polymers, have exhibited great potential for mRNA delivery. In this short review, the authors briefly introduce mRNA therapeutics, their therapeutic applications and delivery challenges. The authors then presented the typical examples of polyester materials for mRNA delivery to highlight the current progress and discuss the challenges for the rational design of polyester based mRNA delivery vectors. The authors hope to provide a new insight for the design of biodegradable vectors for nucleic acids delivery, thereby promoting their further clinic translation. Review Fri, 11 Mar 2022 00:00:00 GMT WangChen, YonghuiMa, XiaoxuanLiu, DandanZhu, Fri, 11 Mar 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100275 https://www.explorationpub.com/Journals/etat/Article/100276 The budding yeast Saccharomyces cerevisiae, a favorite model in biology, does not contain any protein of the Bcl-2 family. From initial experiments with two-hybrid systems to the heterologous expression of human Bcl-2 family members, and the characterization of several forms of yeast programmed cell death, it has however always been a powerful tool to gain information on the mechanisms of apoptosis in general and on Bcl-2 family in particular. This is a short survey of 25 years of experiments that have provided, and at times initiated, insights into the molecular mechanisms underlying the function of Bcl-2 family members. Review Sat, 02 Apr 2022 00:00:00 GMT StéphenManon, Sat, 02 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100276 https://www.explorationpub.com/Journals/etat/Article/100277 Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents. These drugs have been extensively studied both in solid and hematologic malignancies, leading to substantial improvement in the therapeutic landscape for several tumors. Despite no ADC have been yet approved for the treatment of gynecological malignancies, some agents have shown promising results and might have the potential to become part of the standard of care. Among them, mirvetuximab soravtansine has shown activity in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent and in combination. Tisotumab vedotin is active in patients with pre-treated cervical cancer, and further investigation is ongoing. The purpose of this review is to summarize the structural and functional characteristics of ADCs and analyze the most recent and promising data regarding the clinical development of ADCs in gynecological malignancies. The available data on the efficacy of the more studied ADCs in ovarian, endometrial, and cervical cancers will be discussed along with toxicities of special interest, the mechanisms of resistance, and future possible drugs combination. Review Tue, 19 Apr 2022 00:00:00 GMT MartaNerone, Maria DelGrande, CristianaSessa, IlariaColombo, Tue, 19 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100277 https://www.explorationpub.com/Journals/etat/Article/100278 The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions. Review Sun, 24 Apr 2022 00:00:00 GMT AglaiaSkolariki, JamieD’Costa, MartinLittle, SimonLord, Sun, 24 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100278 https://www.explorationpub.com/Journals/etat/Article/100279 Improving the survival of patients with cholangiocarcinoma (CCA) has long proved challenging, although the treatment of this disease nowadays is on advancement. The historical invariability of survival outcomes and the limited number of agents known to be effective in the treatment of this disease has increased the number of studies designed to identify genetic targetable hits that can be efficacious for novel therapies. In this respect, the increasing feasibility of molecular profiling starting either from tumor tissue or circulating cell-free DNA (cfDNA) has led to an increased understanding of CCA biology. Intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) display different and typical patterns of actionable genomic alterations, which offer opportunity for therapeutic intervention. This review article will summarize the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease. Review Tue, 26 Apr 2022 00:00:00 GMT MarianeveCarotenuto, AlessandraSacco, LauraForgione, NicolaNormanno, Tue, 26 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100279 https://www.explorationpub.com/Journals/etat/Article/100280 Aim: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer. Methods: A series of in vitro assays, including immunohistochemistry, immunofluorescence, flow cytometry, and western blotting were used to evaluate levels and activity of ZIP7 and ZIP6 in models of TAMR and sensitive (MCF-7) breast cancer. Analyses of these transporters in the clinical setting were performed using publicly available online resources: Gene Expression Profiling Interactive Analysis (GEPIA)2 and Kaplan-Meier Plotter (KmPlot). Results: Both total and activated levels of ZIP7 were significantly elevated in TAMR cells versus responsive MCF-7 cells. This was accompanied by an associated increase in free cytoplasmic zinc leading to amplification of downstream signals. Consistent with our proposed model, activated ZIP6 levels correlated with mitotic cells, which could be efficiently inhibited through use of our anti-ZIP6 monoclonal antibody. Mitotic inhibition translated to impaired proliferation in both models, with TAMR cells displaying increased sensitivity. Analysis of matched tumour and normal breast samples from patients revealed significant increases in both ZIP7 and ZIP6 in tumours, as well as family member ZIP4. Kaplan-Meier analysis revealed that high ZIP7 levels correlated with decreased overall and relapse-free survival (RFS) of patients, including patient groups who had received systemic endocrine therapy or tamoxifen only. In contrast, high ZIP6 levels were significantly linked to improved overall and RFS in all patients, as well as RFS in patients that received systemic endocrine therapy. Conclusions: TAMR cells displayed increased activity of both ZIP7 and ZIP6 transporters compared to anti-hormone responsive cells, suggesting their potential as novel therapeutic targets following development of resistant disease. Original Article Tue, 26 Apr 2022 00:00:00 GMT SamuelJones, GeorgiaFarr, ThirayostNimmanon, SilviaZiliotto, Julia M.W.Gee, Kathryn M.Taylor, Tue, 26 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100280 https://www.explorationpub.com/Journals/etat/Article/100281 Endocrine resistant breast cancer metastasis continues to serve as a significant clinical challenge with high morbidity and mortality for patients. As the number of breast cancer cases continues to rise, the rate of brain metastasis has also increased. For single lesions or a large symptomatic lesion with other smaller lesions, surgical resection is a viable option in non-eloquent regions. Stereotactic radiosurgery is a great option for post-operative therapy or for 10 or fewer small lesions (< 3 cm in size). Whole-brain radiation can be used sparingly for large tumor burdens but should encompass hippocampus sparing techniques. Chemotherapy options have remained relatively limited due to decreased permeability of the blood-brain barrier. Emerging monoclonal antibody treatments have offered initial promise, especially for endocrine resistant breast cancer metastasis. Perspective Wed, 27 Apr 2022 00:00:00 GMT MatthewWillman, JonathanWillman, BrandonLucke-Wold, Wed, 27 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100281 https://www.explorationpub.com/Journals/etat/Article/100282 The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents. Review Thu, 28 Apr 2022 00:00:00 GMT SiddharthMenon, SagunParakh, Andrew M.Scott, Hui K.Gan, Thu, 28 Apr 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100282 https://www.explorationpub.com/Journals/etat/Article/100283 The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed. Review Tue, 24 May 2022 00:00:00 GMT PrasadSulkshane, TanujaTeni, Tue, 24 May 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100283 https://www.explorationpub.com/Journals/etat/Article/100284 The development of endocrine resistance is a common reason for the failure of endocrine therapies in hormone receptor-positive breast cancer. This review provides an overview of the different types of in vitro models that have been developed as tools for studying endocrine resistance. In vitro models include cell lines that have been rendered endocrine-resistant by ex vivo treatment; cell lines with de novo resistance mechanisms, including genetic alterations; three-dimensional (3D) spheroid, co-culture, and mammosphere techniques; and patient-derived organoid models. In each case, the key discoveries, different analysis strategies that are suitable, and strengths and weaknesses are discussed. Certain recently developed methodologies that can be used to further characterize the biological changes involved in endocrine resistance are then emphasized, along with a commentary on the types of research outcomes that using these techniques can support. Finally, a discussion anticipates how these recent developments will shape future trends in the field. We hope this overview will serve as a useful resource for investigators that are interested in understanding and testing hypotheses related to mechanisms of endocrine therapy resistance. Review Thu, 02 Jun 2022 00:00:00 GMT Gary J.Cheng, Euphemia Y.Leung, Dean C.Singleton, Thu, 02 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100284 https://www.explorationpub.com/Journals/etat/Article/100285 Aim: During the coronavirus disease 2019 (COVID-19) pandemic two needs have overlapped: on one hand continuing to provide the best care for patients with lung cancer and preventing the spread of the virus between patients and healthcare professionals on the other hand. Due to the pandemic’s unpredictable duration, physicians had to evaluate the risk/benefit ratio of anti-cancer therapeutic strategy to do the best for their patients and to protect patients themselves, as well as healthcare workers. Methods: Systematic literature research was performed with the aim to assess the available guidelines for the management of lung cancer patients during the COVID-19 pandemic. Thirteen potentially relevant articles were selected and recommendations have been divided into three main categories: dos, don’ts and don’t knows. Results: All guidelines and recommendations highlighted the relevance of being able to delay, if possible and based on risk stratification, and curative interventions. The selected recommendations should be considered adaptable and flexible because they might be contextualized on the basis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prevalence and the availability of diagnostic-therapeutic resources. Conclusions: It remains of fundamental importance to discuss each diagnostic and therapeutic decision with the patient taking into account risks and benefits that might vary from case to case. Systematic Review Fri, 10 Jun 2022 00:00:00 GMT MariangelaTorniai, VeronicaAgostinelli, LucaCantini, CarolinaLiguori, FrancescaMorgese, SilviaRinaldi, LauraScortichini, RossanaBerardi, Fri, 10 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100285 https://www.explorationpub.com/Journals/etat/Article/100286 The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease. Review Mon, 20 Jun 2022 00:00:00 GMT Inês Soaresde Pinho, CatarinaAbreu, InêsGomes, SandraCasimiro, Teresa RaquelPacheco, Rita Teixeirade Sousa, LuísCosta, Mon, 20 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100286 https://www.explorationpub.com/Journals/etat/Article/100287 Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease. Review Wed, 22 Jun 2022 00:00:00 GMT GianlucaArrichiello, ValeriaNacca, FernandoParagliola, Emilio FrancescoGiunta, Wed, 22 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100287 https://www.explorationpub.com/Journals/etat/Article/100288 Aim: Inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitous calcium (Ca2+) channel involved in the regulation of cellular fate and motility. Its modulation by anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) plays an important role in cancer progression. Disrupting this interaction could overcome apoptosis avoidance, one of the hallmarks of cancer, and is, thus, of great interest. Earlier reports have shown the involvement of both the Bcl-2 homology 4 (BH4) and the transmembrane domains (TMDs) of Bcl-2 in regulating IP3R activity, while the Bcl-2 hydrophobic cleft was associated primarily with its anti-apoptotic and IP3R-independent action at the mitochondria (Oncotarget. 2016;7:55704–20. doi: 10.18632/oncotarget.11005). The aim of this study was to investigate how targeting the BH3 hydrophobic cleft of Bcl-2 affects IP3R:Bcl-2 interaction. Methods: Organelle membrane-derived (OMD) patch-clamp and circular dichroism (CD) thermal melting experiments were used to elucidate the effects of the ABT-199 (venetoclax) on the IP3R:Bcl-2 interaction. Molecular dynamics (MD) simulations of free and ABT-199 bound Bcl-2 were used to propose a molecular model of such interaction. Results: It was shown that occlusion of Bcl-2’s hydrophobic cleft by the drug ABT-199 finely modulates IP3R gating in the low open probability (Po) regime, characteristic of the basal IP3R activity in non-excited cells. Complementary MD simulations allowed to propose a model of this modulation, involving an allosteric interaction with the BH4 domain on the opposite side of Bcl-2. Conclusions: Bcl-2 is an important regulator of IP3R activity and, thus of Ca2+ release from internal stores and associated processes, including cellular proliferation and death. The presence of multiple regulatory domains in both proteins suggests a complex interaction. Thus, it was found that the occlusion of the hydrophobic cleft of Bcl-2 by ABT-199 disrupts IP3R activity, leading to Bcl-2 rebinding with smaller affinity and lesser inhibitory effect. MDs simulations of free and ABT-199 bound Bcl-2 propose a molecular model of such disruption, involving an allosteric interaction with the BH4 domain on the opposite side of Bcl-2. Original Article Wed, 29 Jun 2022 00:00:00 GMT GeorgeShapovalov, AbigaëlRitaine, Nadege CharleneEssonghe, Iande Ridder, HristinaIvanova, SpyridoulaKaramanou, AnastassiosEconomou, GeertBultynck, RomanSkryma, NataliaPrevarskaya, Wed, 29 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100288 https://www.explorationpub.com/Journals/etat/Article/100289 Neuroendocrine tumor (NET) is a rare tumor that has been observed in different sites such as lungs and throughout the gastrointestinal tract. Clinical features are usually non-specific and vary considerably depending upon the location of the tumor. Symptoms are similar to those of common conditions such as peptic ulcer disease, gastritis, irritable bowel syndrome, asthma, etc. Thus, an initial diagnosis of a NET usually occurs at an advanced stage. This report describes a case of pancreatic NET (PNET, grade 2) with liver metastasis in a 37-year-old male which was found to be inoperable due to extensive direct involvement of the proximal jejunal branches and superior mesenteric vein. Peptide receptor radionuclide therapy (PRRT) with lutetium-177 dotatate (177Lu-DOTATATE) was administered due to the inoperability of primary PNET. Complete resolution of symptoms occurred with three cycles of PRRT. Case Report Wed, 29 Jun 2022 00:00:00 GMT AmitKumar, ShwetaTanwar, SudhishGupta, RajeshChetiwal, RohitKumar, Wed, 29 Jun 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100289 https://www.explorationpub.com/Journals/etat/Article/100290 Aim: Gene-based immunotherapy against cancer is limited by low gene transfer efficiency. In the literature, interleukin-12 (IL-12) encoding plasmid associated with sonoporation has been shown to enhance antitumoral activity. Moreover, non-viral carriers and high-frequency ultrasound have both been shown to promote immune response activation. Here, IL-12 encoding plasmid, non-viral carrier stimulating the immune response and focused ultrasound were combined in order to improve the antitumoral efficiency. Methods: In order to enhance a gene-based antitumoral immune response, home-made lipids Toll-like receptor 2 (TLR2) agonists and plasmid free of antibiotic resistance version 4 (pFAR4), a mini-plasmid, encoding the IL-12 cytokine were combined with high-intensity focused ultrasound (HIFU). The lipid composition and the combination conditions were selected following in vitro and in vivo preliminary studies. The expression of IL-12 from our plasmid construct was measured in vitro and in vivo. The combination strategy was evaluated in mice bearing colon carcinoma cells (CT26) tumors following their weight, tumor volume, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels in the serum and produced by splenocytes exposed to CT26 tumor cells. Results: Lipid-mediated cell transfection and intratumoral injection into CT26 tumor mice using pFAR4-IL-12 led to the secretion of the IL-12 cytokine into cell supernatant and mice sera, respectively. Conditions of thermal deposition using HIFU were optimized. The plasmid encoding pFAR4-IL-12 or TLR2 agonist alone had no impact on tumor growth compared with control mice, whereas the complete treatment consisting of pFAR4-IL-12, TLR2 lipid agonist, and HIFU limited tumor growth. Moreover, only the complete treatment increased significantly mice survival and provided an abscopal effect on a metastatic CT26 model. Conclusions: The HIFU condition was highly efficient to stop tumor growth. The combined therapy was the most efficient in terms of IL-12 and IFN-γ production and mice survival. The study showed the feasibility and the limits of this combined therapy which has the potential to be improved. Original Article Fri, 01 Jul 2022 00:00:00 GMT Hai DoanDo, CorinneMarie, StéphanieBessoles, HélèneDhotel, JohanneSeguin, BenoitLarrat, Bich-ThuyDoan, DanielScherman, VirginieEscriou, SalimaHacein-Bey-Abina, NathalieMignet, Fri, 01 Jul 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100290 https://www.explorationpub.com/Journals/etat/Article/100291 Aim: To evaluate the local impact of the coronavirus disease 2019 (COVID-19) pandemic on breast cancer (BC) care, with particular attention to the economical and psychological consequences of the possible delay of new diagnoses and treatments. Methods: Three years’ activity (from 2019 to 2021) has been compared. The number of BCs diagnosed from the total amount of mammographic and ultrasound (US) examinations performed in women aged more than 40 years old has been considered. A Pearson’s chi-squared test was performed to verify differences between results. Statistical significance was set at P ≤ 0.01. Results: A statistically significant difference was found in the number of BC diagnosed between screening and ambulatory care patients in both the 2019–2020 (χ2 = 24.93, P < 0.01) and 2019–2021 (χ2 = 29.93, P < 0.01) comparisons. No statistically significant difference was found in the data recorded between 2020 and 2021 (χ2 = 2.35, P > 0.01). By evaluating the specific age groups for each year, a statistically significant difference (P < 0.01) was found in the number of BC diagnosed in screening patients aged 50–69 years old in both 2019–2020 and 2019–2021 comparisons. The percentages of early BC diagnosed in 2019, 2020, and 2021 were 80.9%, 91.7%, and 89.8%, respectively. The adherence rates to screening in 2019, 2020, and 2021 were 67.5%, 45.2%, and 56.9%, respectively. Conclusions: Results showed a reduction of new diagnoses in the screening range during the pandemic in comparison with the previous period. The high percentage of early BC would seem to have prevented worsening outcomes. Nevertheless, women who have not undergone screening could present a more advanced stage disease in the following years. Consequently, the evaluation of possible solutions to guarantee an essential level of care with the purpose to avoid worsening patients’ outcomes and the increase in healthcare costs is mandatory. Original Article Fri, 29 Jul 2022 00:00:00 GMT Daniele UgoTari, RosalindaSantonastaso, FabioPinto, Fri, 29 Jul 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100291 https://www.explorationpub.com/Journals/etat/Article/100292 Compared to humans, plants can synthesize an extremely diverse array of chemical compounds, including phenolic acids, flavonoids, stilbenes, lignans, terpenoids, alkaloids, and many other types of secondary metabolites that have been demonstrated to exert important bioactivities and impacts on the human health. As a result of extensive and sustained efforts, some phytochemicals like vincristine, vinblastine, and paclitaxel have already been approved as anticancer drugs today, while several others are under clinical trials. However, despite this remarkable success, studies on anticancer action of plant-derived products have been and paradoxically are still in some places, mixed up with alternative approaches and thereby considered non-credible, especially in regions where the role of traditional medicine has not been historically so prevalent as in several Asian countries. As a result, only about 10% of higher plants have been explored regarding the potential therapeutic effects of their constituents. Moreover, as one function of secondary metabolites includes the protection of plants against diverse environmental stresses, the content and composition of these phytochemicals might importantly vary between different regional habitats. Therefore, the stereotyped attitudes to plant products as something related to alternative medicine must be changed to identify new lead molecules for novel anticancer drugs. It is possible that plants still harbor an important spectrum of pharmaceutically interesting, but still unidentified, chemical compounds. Perspective Tue, 16 Aug 2022 00:00:00 GMT KatrinSak, Tue, 16 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100292 https://www.explorationpub.com/Journals/etat/Article/100293 With the rapid development of gene therapy technology and the outbreak of coronavirus disease 2019 (COVID-19), messenger RNA (mRNA) therapeutics have attracted more and more attention, and the COVID-19 mRNA vaccine has been approved by the Food and Drug Administration (FDA) for emergency authorization. To improve the delivery efficiency of mRNA in vitro and in vivo, researchers have developed a variety of mRNA carriers and explored different administration routes. This review will systematically introduce the types of mRNA vectors, routes of administration, storage methods, safety of mRNA therapeutics, and the type of diseases that mRNA drugs are applied for. Finally, some suggestions are supplied on the development direction of mRNA therapeutic agents in the future. Review Wed, 31 Aug 2022 00:00:00 GMT HuapanFang, QianChen, Wed, 31 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100293 https://www.explorationpub.com/Journals/etat/Article/100294 Bone metastasis is a frequent complication for cancers and an important reason for the mortality in cancer patients. After surviving in bone, cancer cells can cause severe pain, life-threatening hypercalcemia, pathologic fractures, spinal cord compression, and even death. However, the underlying mechanisms of bone metastasis were not clear. The role of calcium (Ca2+) in cancer cell proliferation, migration, and invasion has been well established. Interestingly, emerging evidence indicates that Ca2+ signaling played a key role in bone metastasis, for it not only promotes cancer progression but also mediates osteoclasts and osteoblasts differentiation. Therefore, Ca2+ signaling has emerged as a novel therapeutical target for cancer bone metastasis treatments. Here, the role of Ca2+ channels and Ca2+-binding proteins including calmodulin and Ca2+-sensing receptor in bone metastasis, and the perspective of anti-cancer bone metastasis therapeutics via targeting the Ca2+ signaling pathway are summarized. Review Wed, 31 Aug 2022 00:00:00 GMT TianyingXie, SitongChen, JiangHao, PengfeiWu, XuelianGu, HaifengWei, ZhenxiLi, JianruXiao, Wed, 31 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100294 https://www.explorationpub.com/Journals/etat/Article/100295 Multiple myeloma (MM) is a blood cancer that derives from plasma cells (PCs), which will accumulate in the bone marrow (BM). Over time, several drugs have been developed to treat this disease that is still uncurable. The therapies used to treat the disease target immune activity, inhibit proteasome activity, and involve the use of monoclonal antibodies. However, MM is a highly heterogeneous disease, in fact, there are several mutations in signaling pathways that are particularly important for MM cell biology and that are possible therapeutic targets. Indeed, some studies suggest that MM is driven by mutations within the rat sarcoma virus (RAS) signaling cascade, which regulates cell survival and proliferation. The RAS/proto-oncogene, serine/threonine kinase (RAF)/mitogen-activated extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is deregulated in several cancers, for which drugs have been developed to inhibit these pathways. In addition to the signaling pathways, the disease implements mechanisms to ensure the survival and consequently a high replicative capacity. This strategy consists in the deregulation of apoptosis. In particular, some cases of MM show overexpression of anti-apoptotic proteins belonging to the B cell lymphoma 2 (BCL-2) family that represent a possible druggable target. Venetoclax is an anti-BCL-2 molecule used in hematological malignancies that may be used in selected MM patients based on their molecular profile. We focused on the possible effects in MM of off-label drugs that are currently used for other cancers with the same molecular characteristics. Their use, combined with the current treatments, could be a good strategy against MM. Review Wed, 31 Aug 2022 00:00:00 GMT VincenzoRaimondi, Nicolas ThomasIannozzi, JessicaBurroughs-Garcìa, DeniseToscani, PaolaStorti, NicolaGiuliani, Wed, 31 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100295 https://www.explorationpub.com/Journals/etat/Article/100296 Endocrine resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. When abnormally regulated, molecular signals responsible for cellular proliferation, as well as ER itself, allow for cellular evasion of ER-dependent treatments. Therefore, pharmacological treatments that target these evasion mechanisms are beneficial for the treatment of endocrine-resistant breast cancers. This review summarizes currently understood molecular signals that contribute to endocrine resistance and their crosstalk that stem from mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase/protein kinase B (PI3K/AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinases 4 and 6 (CDK4/6) and aberrant ER function. Recent clinical trials that target these molecular signals as a treatment strategy for endocrine-resistant breast cancer are also highlighted. Review Wed, 31 Aug 2022 00:00:00 GMT DavidMusheyev, AnyaAlayev, Wed, 31 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100296 https://www.explorationpub.com/Journals/etat/Article/100297 Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells, which are expanded in most cancer patients. MDSCs suppress host immune responses, leading to cancer growth and progression. Several studies demonstrated that there was a relationship between levels of MDSCs and tumorigenesis in colorectal cancer (CRC) patients. MDSCs are now being investigated for their role as possible therapeutic targets in cancer treatment. This review summarizes available studies that investigated MDSC expansion in CRC patients, as well as their role in CRC tumorigenesis, prognosis, and targeting. Based on the available studies, there is a possible relationship between high levels of MDSCs and CRC progression. Additionally, targeting MDSCs in CRC patients selectively represents a significant challenge for the development of targeted treatments. Targeting of MDSCs could be exploited in different ways including MDSC depletion, inhibition of MDSC function and recruitment, and enhancing MDSC differentiation. Overall, MDSCs could be exploited as prognostic biomarkers and potential therapeutic targets in CRC. Review Wed, 31 Aug 2022 00:00:00 GMT Mohammad A.Al-Mterin, EyadElkord, Wed, 31 Aug 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100297 https://www.explorationpub.com/Journals/etat/Article/100298 The dynamic spectrum of microRNA (miRNA) has grown significantly over the years with its identification and exploration in cancer therapeutics and is currently identified as an important resource for innovative strategies due to its functional behavior for gene regulation and modulation of complex biological networks. The progression of cancer is the consequence of uncontrolled, nonsynchronous procedural faults in the biological system. Diversified and variable cellular response of cancerous cells has always raised challenges in effective cancer therapy. miRNAs, a class of non-coding RNAs (ncRNAs), are the natural genetic gift, responsible to preserve the homeostasis of cell to nurture. The unprecedented significance of endogenous miRNAs has exhibited promising therapeutic potential in cancer therapeutics. Currently, miRNA mimic miR-34, and an antimiR aimed against miR-122 has entered the clinical trials for cancer treatments. This review, highlights the recent breakthroughs, challenges, clinical trials, and advanced delivery vehicles in the administration of miRNA therapies for precision oncology. Review Thu, 01 Sep 2022 00:00:00 GMT Chakresh KumarJain, PoornimaSrivastava, Amit KumarPandey, NishaSingh, R SureshKumar, Thu, 01 Sep 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100298 https://www.explorationpub.com/Journals/etat/Article/100299 Head and neck squamous cell carcinomas (HNSCCs) represent the most common epithelial tumors that arise from mucosa of the oral cavity, pharynx, and larynx. The development of HNSCCs is usually associated with tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. Most HNSCCs are diagnosed in advanced states, leading to a worse clinical outcome. Screening tests based on potential biomarkers associated with HNSCCs could improve this scenario. Liquid biopsy has emerged as a promising area of cancer investigation, offering a minimally invasive approach to track circulating biomarkers in body fluids that could potentially contribute to the diagnosis, predict prognosis, and monitor response to treatment. This review will discuss translational studies describing the clinical applications of liquid biopsy in HPV-negative and HPV-positive HNSCCs focused on circulating nucleic acids [cell-free DNA (cfDNA) and cell-free RNA (cfRNA)], circulating tumor cells (CTCs), and extracellular vesicles (EVs), which can be found in plasma, serum, and saliva. Review Thu, 01 Sep 2022 00:00:00 GMT MarianaChantre-Justino, GildaAlves, LucasDelmonico, Thu, 01 Sep 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/100299 https://www.explorationpub.com/Journals/etat/Article/1002100 Aim: Lower grade gliomas [LGGs; World Health Organization (WHO) grades 2 and 3], owing to the heterogeneity of their clinical behavior, present a therapeutic challenge to neurosurgeons. The aim of this study was to explore the N6-methyladenosine (m6A) modification landscape in the LGGs and to develop an m6A-related microRNA (miRNA) risk model to provide new perspectives for the treatment and prognostic assessment of LGGs. Methods: Messenger RNA (mRNA) and miRNA expression data of LGGs were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. An m6A-related miRNA risk model was constructed via least absolute shrinkage and selection operator (LASSO), univariate, and multivariate Cox regression analysis. Next, Kaplan-Meier analysis, principal-component analysis (PCA), functional enrichment analysis, immune infiltrate analysis, dynamic nomogram, and drug sensitivity prediction were used to evaluate this risk model. Results: Firstly, six m6A-related miRNAs with independent prognostic value were selected based on clinical information and used to construct a risk model. Subsequently, compared with low-risk group, LGGs in the high-risk group had a higher m6A writer and reader scores, but a lower eraser score. Moreover, LGGs in the high-risk group had a significantly worse clinical prognosis than those in the low-risk group. Simultaneously, this risk model outperformed other clinicopathological variables in the prognosis prediction of LGGs. Immune infiltrate analysis revealed that the proportion of M2 macrophages, regulatory T (Treg) cells, and the expression levels of exhausted immune response markers were significantly higher in the high-risk group than in the low-risk group. Finally, this study constructed an easy-to-use and free dynamic nomogram to help clinicians use this risk model to aid in diagnosis and prognosis assessment. Conclusions: This study developed a m6A-related risk model and uncovered two different m6A modification landscapes in LGGs. Moreover, this risk model may provide guidance and help in clinical prognosis assessment and immunotherapy response prediction for LGGs. Original Article Fri, 30 Sep 2022 00:00:00 GMT FengYuan, YingshuaiWang, XiangmingCai, ChaonanDu, JunhaoZhu, ChaoTang, JinYang, ChiyuanMa, Fri, 30 Sep 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002100 https://www.explorationpub.com/Journals/etat/Article/1002101 Solute carrier family 7 member 11 (SLC7A11; also known as xCT), a key component of the cystine/glutamate antiporter, is essential for the maintenance of cellular redox status and the regulation of tumor-associated ferroptosis. Accumulating evidence has demonstrated that xCT overexpression, resulting from different oncogenic and tumor suppressor signaling, promotes tumor progression and multidrug resistance partially via suppressing ferroptosis. In addition, recent studies have highlighted the role of xCT in regulating the metabolic flexibility in cancer cells. In this review, the xCT activities in intracellular redox balance and in ferroptotic cell death have been summarized. Moreover, the role of xCT in promoting tumor development, drug resistance, and nutrient dependency in cancer cells has been explored. Finally, different therapeutic strategies, xCT-based, for anti-cancer treatments have been discussed. Commentary Tue, 25 Oct 2022 00:00:00 GMT DanielaCriscuolo, FrancescoMorra, AngelaCeletti, Tue, 25 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002101 https://www.explorationpub.com/Journals/etat/Article/1002102 Aim: Diagnostic laboratories are progressively introducing next-generation sequencing (NGS) technologies in the routine workflow to meet the increasing clinical need for comprehensive molecular characterization in cancer patients for diagnosis and precision medicine, including fusion-transcripts detection. Nevertheless, the low quality of messenger RNA (mRNA) extracted from formalin-fixed paraffin-embedded (FFPE) samples may affect the transition from traditional single-gene testing approaches [like fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or polymerase chain reaction (PCR)] to NGS. The present study is aimed at assessing the overall accuracy of RNA fusion transcripts detection by NGS analysis in FFPE samples in real-world diagnostics. Methods: Herein, NGS data from 190 soft tissue tumors (STTs) and carcinoma cases, discussed in the context of the institutional Molecular Tumor Board, are reported and analyzed by FusionPlex© Solid tumor kit through the manufacturer’s pipeline and by two well-known fast and accurate open-source tools [Arriba (ARR) and spliced transcripts alignment to reference (STAR)-fusion (SFU)]. Results: The combination of FusionPlex© Solid tumor with ArcherDX® Analysis suite (ADx) analysis package has been proven to be sensitive and specific in STT samples, while partial loss of sensitivity has been found in carcinoma specimens. Conclusions: Albeit ARR and SFU showed lower sensitivity, the use of additional fusion-detection tools can contribute to reinforcing or extending the output obtained by ADx, particularly in the case of low-quality input data. Overall, our results sustain the clinical use of NGS for the detection of fusion transcripts in FFPE material. Original Article Thu, 27 Oct 2022 00:00:00 GMT IolandaCapone, FabioBozzi, Gian PaoloDagrada, PaoloVerderio, ElenaConca, AdeleBusico, Maria AdeleTesti, ValentinaMonti, MatteoDuca, ClaudiaProto, SilviaDamian, AlbertaPiccolo, FedericaPerrone, ElenaTamborini, AndreaDevecchi, PaolaCollini, DanieleLorenzini, AndreaVingiani, LucaAgnelli, GiancarloPruneri, Thu, 27 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002102 https://www.explorationpub.com/Journals/etat/Article/1002103 Cancer-associated fibroblasts (CAFs) are highly heterogeneous players that shape the tumor microenvironment and influence tumor progression, metastasis formation, and response to conventional therapies. During the past years, some CAFs subsets have also been involved in the modulation of immune cell functions, affecting the efficacy of both innate and adaptive anti-tumor immune responses. Consequently, the implication of these stromal cells in the response to immunotherapeutic strategies raised major concerns. In this review, current knowledge of CAFs origins and heterogeneity in the tumor stroma, as well as their effects on several immune cell populations that explain their immunosuppressive capabilities are summarized. The current development of therapeutic strategies for targeting this population and their implication in the field of cancer immunotherapy is also highlighted. Review Thu, 27 Oct 2022 00:00:00 GMT JeromeThiery, Thu, 27 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002103 https://www.explorationpub.com/Journals/etat/Article/1002104 Recently, technological advances in the detection and biological characterization of circulating tumor DNA (ctDNA) have enabled the implementation of liquid biopsy testing into clinical practice. Methods for analysis of liquid biopsies have rapidly evolved over the past few years and have continued to advance, thus providing details about tumor biological characteristics such as tumor progression, metastasis, tumor heterogeneity, genomic mutation profile, clonal evolution, etc. In tandem with technological advances, the implementation of liquid biopsy in routine clinical settings has proceeded. In 2016, the Food and Drug Administration (FDA) approved the first ctDNA liquid biopsy test to detect epidermal growth factor receptor (EGFR) gene mutations in patients with non-small-cell lung cancer (NSCLC) as a companion diagnostic for molecular targeted drug of EGFR-tyrosine kinase inhibitor (TKI, EGFR-TKI). More recently, multigene panel assays of liquid biopsy have been approved as companion diagnostics and have been used in routine clinical settings. The estimation of blood tumor mutation burden (bTMB) to predict the efficacy of immune checkpoint inhibitor (ICI) treatment can be one of the promising approaches to liquid biopsy. The next stage of implementation of liquid biopsy for routine clinical settings is for monitoring of ctDNA after surgical treatment to predict prognosis and to detect disease relapse earlier than conventional imaging diagnosis. Its clinical utility is under assessment in several clinical trials. This review introduces recent advances in liquid biopsy methodology, the development of biomarkers, and its clinical utility in the treatment of NSCLC patients. Review Mon, 31 Oct 2022 00:00:00 GMT YoshiharuSato, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002104 https://www.explorationpub.com/Journals/etat/Article/1002105 The uncontrolled and metastatic nature of cancer makes it worse and more unpredictable. Hence, many therapy and medication are used to control and treat cancer. However, apart from this, many medications cause various side effects. In America, nearly 8% of patients admitted to the hospital are due to side effects. Cancer is more seen in people residing in developed countries related of their lifestyle. There are various phytoconstituents molecules in which resveratrol (RSV) is the best-fitted molecule for cancer due to its significantly less adverse effect on the body. RSV inhibits the initiation and progression of cell proliferation due to the modulation of various pathways like the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. RSV downgraded cell cycle-regulated proteins like cyclin E, cyclin D1, and proliferating cell nuclear antigen (PCNA) and induced the release of cytochrome c from the mitochondria, causing apoptosis or programmed cell death (PCD). A great benefit comes with some challenges, hence, RSV does suffer from poor solubility in water i.e. 0.05 mg/mL. It suffers from poor bioavailability due to being highly metabolized by the liver and intestine. Surprisingly, RSV metabolites also induce the metabolism of RSV. Hence, significantly less amount of RSV presented in the urine in the unchanged form. Due to some challenges like poor bioavailability, less aqueous solubility, and retention time in the body, researchers concluded to make the nanocarriers for better delivery. Adopting the technique of nano-formulations, increased topical penetration by up to 21%, improved nano-encapsulation and consequently improved bioavailability and permeability by many folds. Hence, the present review describes the complete profile of RSV and its nano-formulations for improving anti-cancer activity along with a patent survey. Review Mon, 31 Oct 2022 00:00:00 GMT AkshayKumar, Balak DasKurmi, AmrinderSingh, DilpreetSingh, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002105 https://www.explorationpub.com/Journals/etat/Article/1002106 Steroid use is a widely accepted practice for both the treatment and prevention of tumor-induced edema, but there are many unknowns regarding their current clinical utility with modern anti-tumor therapies. This decreases edema and relieves the symptomatic mass effect. There are clearly understood benefits and commonly accepted complications of methylprednisolone (MP) use, but the topic is recently controversial. With immunotherapy advancing, a robust immune response is crucial for full therapeutic efficacy. The immunosuppression of MP may interfere with future and current therapeutics relying on the integrity of the patient’s immune system. This further emphasizes the need for alternative agents to effectively treat tumor-induced cerebral edema. This review highlights the current clinical utility of steroids to treat brain tumor-related edema and the underlying pathophysiology. It also reviews details regarding different steroid formulations and dosing. Research available regarding concurrent steroid use with immunotherapy is detailed next, followed by alternatives to steroids and barriers to their adoption. Finally, this paper discusses pre-clinical findings and emerging treatments aimed to augment or replace steroid use. Review Mon, 31 Oct 2022 00:00:00 GMT MatthewGoldman, BrandonLucke-Wold, MeleineMartinez-Sosa, JasonKatz, YusufMehkri, JeffValisno, StephanQuintin, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002106 https://www.explorationpub.com/Journals/etat/Article/1002107 In this era of cancer immunotherapy, the response rates of immune checkpoint blockers (ICBs) are still too low and the adverse events may also be significant. Of the ways of patching up such deficits, chemotherapy (ChT), especially if metronomic, seems promising, especially as immunity induced by immunogenic cell death (ICD) may be preserved. However, side effects, e.g., lymphocytopenia and interstitial pneumonitis cannot be ignored; eventually, resistance may also ensue. Vascular endothelial growth factors (VEGFs), being potent angiogenic factors, promote cancer cells’ purposeful angiogenesis rendering an extremely resistant tumor microenvironment (TME). This highly evasive and extremely resilient TME actually demands multi-agent, multi-target agents as currently in use through traditional Chinese medicine (TCM). With a good track record of 3,000 years, TCM is favored by mainland Chinese cancer patients. Although TCM had been criticized as unscientific and imprecise, recently, artificial intelligence (AI) technologies serve to elucidate the sound scientific basis and validity of TCM. Several TCM preparations having anti-VEGF actions are found; others suppress immune checkpoints. Especially, these herbs’ multi-prong approach appears to be more effective than Western medicine’s primarily monotherapy approach if one wishes to eradicate the very resistant TME. A “bonus” point is that some autoimmune-related adverse side effects of ICBs may also be reduced by TCM. Nevertheless, as the TCM experience is mostly anecdotal, robust clinical trials are mandatory. Moreover, other TCM problems, e.g., herbal batch variations and consistency and uniformity of herbal prescriptions are outstanding. Invariably, TCM prescriptions have daily variations as the practice of “syndrome differentiation” is hailed. Despite experienced TCM practitioners would refuse to give up their time-honored traditional practice, the multi-prong approach is still very attractive for the undue resilience of TME, let alone its good safety profile, ready availability, and eminent affordability. Although the passage is dark, light is now appearing at the end of the tunnel. Review Mon, 31 Oct 2022 00:00:00 GMT Shiu YingTsao, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002107 https://www.explorationpub.com/Journals/etat/Article/1002108 Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME. Review Mon, 31 Oct 2022 00:00:00 GMT Maria TeresaPalano, MatteoGallazzi, MartinaCucchiara, FedericoDehò, PaoloCapogrosso, AntoninoBruno, LorenzoMortara, Mon, 31 Oct 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002108 https://www.explorationpub.com/Journals/etat/Article/1002109 Onosma (O.) is a genus of perennial flowering plants in the family Boraginaceae with approximately 250 species widely dispersed in temperate, tropical, and subtropical areas. It is traditionally used to treat rheumatism, fever, asthma, stomach irritation, and inflammatory ailments. The bioactive constituents present in the genus O. include benzoquinones, naphthazarins, alkaloids, phenolic, naphthoquinones, and flavonoids whereas shikonins and onosmins are the most significant. The review compiled contemporary research on O. L., including its distribution, morphology, traditional applications, phytochemistry, ethnopharmacology, and toxicology. This review also highlights a few critical challenges and possible future directions for O. L. research. Modern research has demonstrated a wide range of pharmacological effects of different species of O. L., including anti-diabetic, anticancer, anti-inflammatory, and cardiovascular protective. However, the studies on the O. genus are still not fully explored, therefore, researchers need to discover novel products with their toxicity studies, molecular mechanism, and associated side effects. Future exploration of potent constituents from this genus and clinical trials are required to explore its pharmacological importance. Review Tue, 01 Nov 2022 00:00:00 GMT AjayKumar, ShivaniAttri, SandeepKaur, Hardeep SinghTuli, Reena V.Saini, Adesh KumarSaini, ManojKumar, SatwinderjeetKaur, Tue, 01 Nov 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002109 https://www.explorationpub.com/Journals/etat/Article/1002110 Aim: Head and neck squamous cell cancer (HNSCC) is the ninth most common tumor worldwide. Neck lymph node (LN) status is the major indicator of prognosis in all head and neck cancers, and the early detection of LN involvement is crucial in terms of therapy and prognosis. Diffusion-weighted imaging (DWI) is a non- invasive imaging technique used in magnetic resonance imaging (MRI) to characterize tissues based on the displacement motion of water molecules. This review aims to provide an overview of the current literature concerning quantitative diffusion imaging for LN staging in patients with HNSCC. Methods: This systematic review performed a literature search on the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) for all relevant, peer-reviewed literature on the subject following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) criteria, using the keywords: DWI, MRI, head and neck, staging, lymph node. Results: After excluding reviews, meta-analyses, case reports, and bibliometric studies, 18 relevant papers out of the 567 retrieved were selected for analysis. Conclusions: DWI improves the diagnosis, treatment planning, treatment response evaluation, and overall management of patients affected by HNSCC. More robust data to clarify the role of apparent diffusion coefficient (ADC) and DWI parameters are needed to develop models for prognosis and prediction in HNSCC cancer using MRI. Systematic Review Tue, 13 Dec 2022 00:00:00 GMT Maria PaolaBelfiore, ValerioNardone, IdaD’Onofrio, Antonio Alessandro HelliotSalvia, EmmaD’Ippolito, LuigiGallo, ValentinaCaliendo, GianlucaGatta, MorenaFasano, RobertaGrassi, AntonioAngrisani, CesareGuida, AlfonsoReginelli, SalvatoreCappabianca, Tue, 13 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002110 https://www.explorationpub.com/Journals/etat/Article/1002111 Major advances in cancer treatment have emerged with the introduction of immunotherapies using blocking antibodies that target T-cell inhibitory receptors, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), known as immune checkpoints. However, most cancer patients do not respond to immune checkpoint blockade (ICB) therapies, suggesting the development of resistance mechanisms associated with either an insufficient number of preexisting tumor-specific T-cell precursors and/or inappropriate T-cell reactivation. To broaden clinical benefit, anti-PD-1/PD-1 ligand (PD-L1) neutralizing antibodies have been combined with therapeutic cancer vaccines based on non-mutant and/or mutant tumor antigens, to stimulate and expand tumor-specific T lymphocytes. Although these combination treatments achieve the expected goal in some patients, relapse linked to alterations in antigen presentation machinery (APM) of cancer cells often occurs leading to tumor escape from CD8 T-cell immunity. Remarkably, an alternative antigenic peptide repertoire, referred to as T-cell epitopes associated with impaired peptide processing (TEIPP), arises on these malignant cells with altered APM. TEIPP are derived from ubiquitous non-mutant self-proteins and represent a unique resource to target immune-edited tumors that have acquired resistance to cytotoxic T lymphocytes (CTLs) related to defects in transporter associated with antigen processing (TAP) and possibly also to ICB. The present review discusses tumor-associated antigens (TAAs) and mutant neoantigens and their use as targets in peptide- and RNA-based therapeutic cancer vaccines. Finally, this paper highlights TEIPP as a promising immunogenic non-mutant neoantigen candidates for active cancer immunotherapy and combination with TAA and mutant neoantigens. Combining these polyepitope cancer vaccines with ICB would broaden T-cell specificity and reinvigorate exhausted antitumor CTL, resulting in the eradication of all types of neoplastic cells, including immune-escaped subtypes. Review Thu, 22 Dec 2022 00:00:00 GMT Mohamad OmarAshi, FathiaMami-Chouaib, StéphanieCorgnac, Thu, 22 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002111 https://www.explorationpub.com/Journals/etat/Article/1002220 Cancer immunotherapy has emerged as a groundbreaking field, offering promising and transformative tools for oncological research and treatment. However, it faces several limitations, including variations in cancer types, dependence on the tumor microenvironments (TMEs), immune cell exhaustion, and adverse reactions. Magnetic nanoparticles, particularly magnetite nanoparticles (MNPs), with established pharmacodynamics and pharmacokinetics for clinical use, hold great promise in this context and are now being explored for therapeutic aims. Numerous preclinical studies have illustrated their efficacy in enhancing immunotherapy through various strategies, such as modulating leukocyte functions, creating favorable TMEs for cytotoxic T lymphocytes, combining with monoclonal antibodies, and stimulating the immune response via magnetic hyperthermia (MHT) treatment (Front Immunol. 2021;12:701485. doi: 10.3389/fimmu.2021.701485). However, the current clinical trials of MNPs are mostly for diagnostic aims and as a tool for generating hyperthermia for tumor ablation. With concerns about the adverse effects of MNPs in the in vivo systems, clinical translation and clinical study of MNP-boosted immunotherapy remains limited. The lack of extensive clinical investigations poses a current barrier to patient application. Urgent efforts are needed to ascertain both the efficacy of MNP-enhanced immunotherapy and its safety profile in combination therapy. This article reviews the roles, potential, and challenges of using MNPs in advancing cancer immunotherapy. The application of MNPs in boosting immunotherapy, and its perspective role in research and development is also discussed. Review Wed, 24 Apr 2024 00:00:00 GMT PhoomipatJungcharoen, KunakornThivakorakot, NachayadaThientanukij, NatkamonKosachunhanun, ChayanitthaVichapattana, JutatipPanaampon, CharupongSaengboonmee, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002220 https://www.explorationpub.com/Journals/etat/Article/1002112 Antibody-drug conjugates (ADCs) are a recent, revolutionary approach for malignancies treatment, designed to provide superior efficacy and specific targeting of tumor cells, compared to systemic cytotoxic chemotherapy. Their structure combines highly potent anti-cancer drugs (payloads or warheads) and monoclonal antibodies (Abs), specific for a tumor-associated antigen, via a chemical linker. Because the sensitive targeting capabilities of monoclonal Abs allow the direct delivery of cytotoxic payloads to tumor cells, these agents leave healthy cells unharmed, reducing toxicity. Different ADCs have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of a wide range of malignant conditions, both as monotherapy and in combination with chemotherapy, including for lymphoma patients. Over 100 ADCs are under preclinical and clinical investigation worldwide. This paper it provides an overview of approved and promising ADCs in clinical development for the treatment of lymphoma. Each component of the ADC design, their mechanism of action, and the highlights of their clinical development progress are discussed. Review Tue, 27 Dec 2022 00:00:00 GMT MariliaBarreca, NoémieLang, ChiaraTarantelli, FilippoSpriano, PaolaBarraja, FrancescoBertoni, Tue, 27 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002112 https://www.explorationpub.com/Journals/etat/Article/1002113 The advent of artificial intelligence (AI) represents a real game changer in today’s landscape of breast cancer imaging. Several innovative AI-based tools have been developed and validated in recent years that promise to accelerate the goal of real patient-tailored management. Numerous studies confirm that proper integration of AI into existing clinical workflows could bring significant benefits to women, radiologists, and healthcare systems. The AI-based approach has proved particularly useful for developing new risk prediction models that integrate multi-data streams for planning individualized screening protocols. Furthermore, AI models could help radiologists in the pre-screening and lesion detection phase, increasing diagnostic accuracy, while reducing workload and complications related to overdiagnosis. Radiomics and radiogenomics approaches could extrapolate the so-called imaging signature of the tumor to plan a targeted treatment. The main challenges to the development of AI tools are the huge amounts of high-quality data required to train and validate these models and the need for a multidisciplinary team with solid machine-learning skills. The purpose of this article is to present a summary of the most important AI applications in breast cancer imaging, analyzing possible challenges and new perspectives related to the widespread adoption of these new tools. Review Tue, 27 Dec 2022 00:00:00 GMT MaurizioCè, ElenaCaloro, Maria E.Pellegrino, MariachiaraBasile, AdrianaSorce, DeborahFazzini, GiancarloOliva, MichaelaCellina, Tue, 27 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002113 https://www.explorationpub.com/Journals/etat/Article/1002114 Among the malignant tumors in the central nervous system (CNS), glioma is the most challenging tumor to the public society, which accounts for the majority of intracranial malignant tumors with impaired brain function. In general, conventional therapies are still unable to provide an effective cure. However, novel immunotherapies have changed the treatment scene giving patients a greater potential to attain long term survival, improved quality of life. Having shown favorable results in solid tumors, those therapies are now at a cancer research hotspot, which could even shrink the growth of glioma cells without causing severe complications. However, it is important to recognize that the therapy may be occasionally associated with noteworthy adverse action called immune-related adverse events (IRAEs) which have emerged as a potential limitation of the therapy. Multiple classes of mediators have been developed to enhance the ability of immune system to target malignant tumors including glioma but may also be associated with the IRAEs. In addition, it is probable that it would take long time after the therapy to exhibit severe immune-related disorders. Gut microbiota could play an integral role in optimal immune development and/or appropriate function for the cancer therapy, which is a vital component of the multidirectional communication between immune system, brain, and gut, also known as gut-brain-immune axis. Here, we show the potential effects of the gut-brain-immune axis based on an “engram theory” for the innovative treatment of IRAEs. Perspective Tue, 27 Dec 2022 00:00:00 GMT SayuriYoshikawa, KurumiTaniguchi, HarukaSawamura, YukaIkeda, AiTsuji, SatoruMatsuda, Tue, 27 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002114 https://www.explorationpub.com/Journals/etat/Article/1002115 Aim: Recent progress in cancer immunotherapy has shown its promise and prompted researchers to develop novel therapeutic strategies. Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating adaptive anti-tumor immunity, therefore a promising target for cancer treatment. Here, anti-tumor activities of DC-targeting chemokines were explored in murine colorectal tumor models. Methods: The correlation of chemokine messenger RNA (mRNA) expression with DC markers was analyzed using The Cancer Genome Atlas (TCGA) dataset. Murine colorectal tumor cell lines (CT26 and MC38) stably overexpressing mouse C-C motif chemokine ligand 3 (CCL3), CCL19, CCL21, and X-C motif chemokine ligand 1 (XCL1) were established by lentiviral transduction. The effect of chemokines on tumor cell proliferation/survival was evaluated in vitro by cell counting kit-8 (CCK-8) assay and colony formation assay. Syngeneic subcutaneous tumor models were used to study the effects of these chemokines on tumor growth. Ki-67 expression in tumors was examined by immunohistochemistry. Immune cells in the tumor microenvironment (TME) and lymph nodes were analyzed by flow cytometry. Results: Expression of the four chemokines was positively correlated with the two DC markers [integrin alpha X (ITGAX) and CLEC9A] in human colorectal tumor samples. Tumoral overexpression of DC-targeting chemokines had little or no effect on tumor cell proliferation/survival in vitro while significantly suppressing tumor growth in vivo. Fluorescence-activated cell sorting (FACS) analysis showed that CCL19, CCL21, and XCL1 boosted the ratios of DCs and T cells in CD45+ leukocytes while CCL3 increased the percentage of CD45+ leukocytes in total cells in MC38 tumor. XCL1 had an additional positive effect on antigen uptake by DCs in the TME and antigen transfer to tumor-draining lymph nodes. Conclusions: CCL3, CCL19, CCL21, and XCL1 exhibited potent anti-tumor activities in vivo, although they might differentially regulate immune cells in the TME and antigen transfer to lymph nodes. Original Article Tue, 27 Dec 2022 00:00:00 GMT PengkunYuan, YunyiZhou, ZhixueWang, LimingGui, BinMa, Tue, 27 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002115 https://www.explorationpub.com/Journals/etat/Article/1002116 The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate de novo cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the de novo cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy. Commentary Wed, 28 Dec 2022 00:00:00 GMT DanilaCoradini, Wed, 28 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002116 https://www.explorationpub.com/Journals/etat/Article/1002117 Aim: Functional screening of new pharmaceutical compounds requires clinically relevant models to monitor essential cellular and immune responses during cancer progression, with or without treatment. Beyond survival, the emergence of resistant tumor cell clones should also be considered, including specific properties related to plasticity, such as invasiveness, stemness, escape from programmed cell death, and immune response. Numerous pathways are involved in these processes. Defining the relevant ones in the context of a specific tumor type will be key to designing an appropriate combination of inhibitors. However, the diversity and potential redundancy of these pathways remain a challenge for therapy. Methods: A new microfluidic device developed by Okomera was dedicated to the screening of drug treatment for breast cancer. This microchip includes 150 droplet-trapping microwells, offering multi-chip settings and multiple treatment choices. Results: After validating the system with established cell lines and a panel of drugs used clinically at Gustave Roussy, preclinical experiments were initiated including patient-derived xenograft (PDX) and primary tumor cells-derived tumoroids with the collaboration of Gustave Roussy clinicians. Tumor-isolated lymphocytes were also added to the tumoroids, using secondary droplets in proof-of-concept experiments. Conclusions: These results show the relevance of the methodology for screening large numbers of drugs, a wide range of doses, and multiple drug combinations. This methodology will be used for two purposes: 1) new drug screening from the compound library, using the high throughput potential of the chip; and 2) pre-clinical assay for a two-weeks response for personalized medicine, allowing evaluation of drug combinations to flag an optimized treatment with potential clinical application. Original Article Thu, 29 Dec 2022 00:00:00 GMT FloraDoffe, LaylaFuoco, JudithMichels, SandraJernström, RaphaelTomasi, PierreSavagner, Thu, 29 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002117 https://www.explorationpub.com/Journals/etat/Article/1002118 Glioblastoma multiforme (GBM) is known as the most aggressive and prevalent brain tumor with a high mortality rate. It is reported in people who are as young as 10 years old to as old as over 70 years old, exhibiting inter and intra tumor heterogeneity. There are several genomic and proteomic investigations that have been performed to find the unexplored potential targets of the drug against GBM. Therefore, certain effective targets have been taken to further validate the studies embarking on the robustness in the field of medicinal chemistry followed by testing in clinical trials. Also, The Cancer Genome Atlas (TCGA) project has identified certain overexpressed targets involved in the pathogenesis of GBM in three major pathways, i.e., tumor protein 53 (p53), retinoblastoma (RB), and receptor tyrosine kinase (RTK)/rat sarcoma virus (Ras)/phosphoinositide 3-kinase (PI3K) pathways. This review focuses on the compilation of recent developments in the fight against GBM thus, directing future research into the elucidation of pathogenesis and potential cure for GBM. Also, it highlights the potential biomarkers that have undergone extensive research and have promising prognostic and predictive values. Additionally, this manuscript analyses the advent of gene therapy and immunotherapy, unlocking the way to consider treatment approaches other than, or in addition to, conventional chemo-radiation therapies. This review study encompasses all the relevant research studies associated with the pathophysiology, occurrence, diagnostic tools, and therapeutic intervention for GBM. It highlights the evolution of various therapeutic perspectives against GBM from the most conventional form of radiotherapy to the recent advancement of gene/cell/immune therapy. Further, the review focuses on various targeted therapies for GBM including chemotherapy sensitization, radiotherapy, nanoparticles based, immunotherapy, cell therapy, and gene therapy which would offer a comprehensive account for exploring several facets related to GBM prognostics. Review Fri, 30 Dec 2022 00:00:00 GMT ManishaSingh, DivyaJindal, VinayakAgarwal, DeepanshiPathak, MansiSharma, PranavPancham, ShaliniMani, Rachana, Fri, 30 Dec 2022 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002118 https://www.explorationpub.com/Journals/etat/Article/1002119 Aim: The process of biomarker discovery is being accelerated with the application of artificial intelligence (AI), including machine learning. Biomarkers of diseases are useful because they are indicators of pathogenesis or measures of responses to therapeutic treatments, and therefore, play a key role in new drug development. Proteins are among the candidates for biomarkers of rectal cancer, which need to be explored using state-of-the-art AI to be utilized for prediction, prognosis, and therapeutic treatment. This paper aims to investigate the predictive power of Ras homolog family member B (RhoB) protein in rectal cancer. Methods: This study introduces the integration of pretrained convolutional neural networks and support vector machines (SVMs) for classifying biopsy samples of immunohistochemical expression of protein RhoB in rectal-cancer patients to validate its biologic measure in biopsy. Features of the immunohistochemical expression images were extracted by the pretrained networks and used for binary classification by the SVMs into two groups of less and more than 5-year survival rates. Results: The fusion of neural search architecture network (NASNet)-Large for deep-layer feature extraction and classifier using SVMs provided the best average classification performance with a total accuracy = 85%, prediction of survival rate of more than 5 years = 90%, and prediction of survival rate of less than 5 years = 75%. Conclusions: The finding obtained from the use of AI reported in this study suggest that RhoB expression on rectal-cancer biopsy can be potentially used as a biomarker for predicting survival outcomes in rectal-cancer patients, which can be informative for clinical decision making if the patient would be recommended for preoperative therapy. Original Article Tue, 07 Feb 2023 00:00:00 GMT Tuan D.Pham, VinayakumarRavi, BinLuo, ChuanwenFan, Xiao-FengSun, Tue, 07 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002119 https://www.explorationpub.com/Journals/etat/Article/1002120 Cancer-associated fibroblasts (CAFs) are a major point of interest in modern oncology. Their interest resides in their ability to favor tumor growth without carrying genetic mutations. From a translational standpoint, they are potential therapeutic targets, particularly for hard-to-treat solid cancers. CAFs can be defined as non-tumor cells within the tumor microenvironment that have the morphological traits of fibroblasts, are negative for lineage-specific markers (e.g., leukocyte, endothelium), and enhance tumor progression in a multi-pronged manner. Two often-mentioned aspects of CAF biology are their ability to alter the mechanics and architecture of the tumor microenvironment, and also to drive local immunosuppression. These two aspects are the specific focus of this work, which also contains a brief summary of novel therapeutic interventions under study to normalize or eliminate CAFs from the tumor microenvironment. Perspective Tue, 21 Feb 2023 00:00:00 GMT Vanessa C.Talayero, MiguelVicente-Manzanares, Tue, 21 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002120 https://www.explorationpub.com/Journals/etat/Article/1002121 Glioblastoma is the most common and malignant primary brain tumor. Despite a century of research efforts, the survival of patients has not significantly improved. Currently, diagnosis is based on neuroimaging techniques followed by histopathological and molecular analysis of resected or biopsied tissue. A recent paradigm shift in diagnostics ranks the molecular analysis of tissue samples as the new gold standard over classical histopathology, thus correlating better with the biological behavior of glioblastoma and clinical prediction, especially when a tumor lacks the typical hallmarks for glioblastoma. Liquid biopsy aims to detect and quantify tumor-derived content, such as nucleic acids (DNA/RNA), circulating tumor cells (CTCs), or extracellular vesicles (EVs) in biofluids, mainly blood, cerebrospinal fluid (CSF), or urine. Liquid biopsy has the potential to overcome the limitations of both neuroimaging and tissue-based methods to identify early recurrence and to differentiate tumor progression from pseudoprogression, without the risks of repeated surgical biopsies. This review highlights the origins and time-frame of liquid biopsy in glioblastoma and points to recent developments, limitations, and challenges of adding liquid biopsy to support the clinical management of glioblastoma patients. Review Sat, 25 Feb 2023 00:00:00 GMT Robert H.Eibl, MarkusSchneemann, Sat, 25 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002121 https://www.explorationpub.com/Journals/etat/Article/1002122 Aim: Triple negative breast cancer (TNBC) is difficult to treat since it lacks all the three most commonly targeted hormone receptors. Patients afflicted with TNBC are treated with platinum core chemotherapeutics, such as cisplatin. Despite the initial effective anticancer effects of cisplatin, TNBC attenuates its effect and develops resistance eventually, which results in tumor reoccurrence. Hence, there is a critical demand for effective, alternative, and natural ways to treat TNBC. Towards this, a promising technique for inhibiting TNBC cell proliferation involves promoting the production of reactive oxygen species (ROS), which triggers pro-apoptotic caspases 9 and 3. Resveratrol (RESV), an active bio compound found in naturally available fruits, such as grapes, is utilized in this research for that. In addition, electrochemotherapy (ECT), which involves the application of electrical pulses (EP), was utilized to enhance the uptake of RESV. Methods: MDA-MB-231, human TNBC cells were treated with/out RESV, and eight 600–1,000 V/cm, 100 μs pulses at 1 Hz. The cells were characterized by using various assays, including viability assay, and ROS assay. Results: A TNBC cell viability of as low as 20% was obtained at 24 h (it was 13% at 60 h), demonstrating the potential of this novel treatment. ROS production was the highest in the combination of EP at 1,000 V/cm along with RESV at 100 μmol/L. Conclusions: Results indicate that RESV has the potential as an anti-TNBC agent and that EP + RESV can significantly enhance the cell death to reduce MDA-MB-231 cell viability by increasing ROS production and triggering apoptosis. Original Article Tue, 28 Feb 2023 00:00:00 GMT PragatheiswarGiri, Ignacio G.Camarillo, RajiSundararajan, Tue, 28 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002122 https://www.explorationpub.com/Journals/etat/Article/1002123 Aim: This study shows how important it is to coordinate research on Ficus deltoidea Jack (FD) so that results from different sources can be compared directly and a scientific conclusion can be made. Methods: The author looked for research papers on Ficus (F.) deltoidea on Google Scholar, Science Direct, Google.com, Wiley, PubMed, Hindawi, Springer, and other related databases. This analysis excludes data that cannot be trusted, thesis papers, and review articles about F. deltoidea. Results: In traditional medicine, the plant’s leaves and syconia are used to cure a wide variety of ailments, including itchiness, diarrhoea, cancer, sexual dysfunction, age-related issues, malaria, cancer, anxiety, pain, constipation, fever, diabetes, tooth pain, and tooth decay. In vitro and in vivo studies showed the effectiveness of the leaves against cancer cell lines. Conclusions: Based on the existing research on the health benefits of FD, it is critical to focus on its more active constituents and their identification, determination, further development, and, most importantly, standardization of the leaves for the management and treatment of cancer and its related cases. More research is needed before it can be considered a promising herbal source of novel medication candidates for treating various disorders. Systematic Review Tue, 28 Feb 2023 00:00:00 GMT Mahmoud DogaraAbdulrahman, Tue, 28 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002123 https://www.explorationpub.com/Journals/etat/Article/1002124 Macrophages, as ubiquitous and functionally diverse immune cells, play a central role in innate immunity and initiate adaptive immunity. Especially, tumor-associated macrophages (TAMs) are crucial contributors to the tumorigenesis and development of cancer. Thus, macrophages are emerging potential targets for cancer treatment. Among the numerous targeted therapeutic options, gene therapy is one of the most potential therapeutic strategies via directly and specifically regulating biological functions of macrophages at the gene level for cancer treatment. This short review briefly introduces the characteristics of macrophage populations, the functions of TAM in the occurrence, and the progress of cancer. It also summarized some representative examples to highlight the current progress in TAM-targeted gene therapy. The review hopes to provide new insights into macrophage-targeted gene therapy for precision cancer therapy. Review Tue, 28 Feb 2023 00:00:00 GMT YuanzhengHuang, ZhihuiWang, JunniGong, DandanZhu, WangChen, FangzhouLi, Xing-JieLiang, XiaoxuanLiu, Tue, 28 Feb 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002124 https://www.explorationpub.com/Journals/etat/Article/1002125 Liquid biopsy is a diagnostic repeatable test, which in last years has emerged as a powerful tool for profiling cancer genomes in real-time with minimal invasiveness and tailoring oncological decision-making. It analyzes different blood-circulating biomarkers and circulating tumor DNA (ctDNA) is the preferred one. Nevertheless, tissue biopsy remains the gold standard for molecular evaluation of solid tumors whereas liquid biopsy is a complementary tool in many different clinical settings, such as treatment selection, monitoring treatment response, cancer clonal evolution, prognostic evaluation, as well as the detection of early disease and minimal residual disease (MRD). A wide number of technologies have been developed with the aim of increasing their sensitivity and specificity with acceptable costs. Moreover, several preclinical and clinical studies have been conducted to better understand liquid biopsy clinical utility. Anyway, several issues are still a limitation of its use such as false positive and negative results, results interpretation, and standardization of the panel tests. Although there has been rapid development of the research in these fields and recent advances in the clinical setting, many clinical trials and studies are still needed to make liquid biopsy an instrument of clinical routine. This review provides an overview of the current and future clinical applications and opening questions of liquid biopsy in different oncological settings, with particular attention to ctDNA liquid biopsy. Review Wed, 01 Mar 2023 00:00:00 GMT VincenzaCaputo, FortunatoCiardiello, Carminia Maria DellaCorte, GiuliaMartini, TeresaTroiani, StefaniaNapolitano, Wed, 01 Mar 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002125 https://www.explorationpub.com/Journals/etat/Article/1002126 Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB. Review Wed, 01 Mar 2023 00:00:00 GMT ZixuanZhou, BingxinZhu, QingmingMeng, TongZhang, YihaoWu, RutongYu, ShangfengGao, Wed, 01 Mar 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002126 https://www.explorationpub.com/Journals/etat/Article/1002127 Artificial intelligence (AI) algorithms have been applied in abundant medical tasks with high accuracy and efficiency. Physicians can improve their diagnostic efficiency with the assistance of AI techniques for improving the subsequent personalized treatment and surveillance. AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events with working principles of machine learning and deep learning. AI algorithms with sufficient graphic processing unit power have been demonstrated to provide timely diagnostic references based on preliminary training of large amounts of clinical and imaging data. The sample size issue is an inevitable challenge for pediatric oncology considering its low morbidity and individual heterogeneity. However, this problem may be solved in the near future considering the exponential advancements of AI algorithms technically to decrease the dependence of AI operation on the amount of data sets and the efficiency of computing power. For instance, it could be a feasible solution by shifting convolutional neural networks (CNNs) from adults and sharing CNN algorithms across multiple institutions besides original data. The present review provides important insights into emerging AI applications for the diagnosis of pediatric oncology by systematically overviewing of up-to-date literature. Review Wed, 01 Mar 2023 00:00:00 GMT YuhanYang, YimaoZhang, YuanLi, Wed, 01 Mar 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002127 https://www.explorationpub.com/Journals/etat/Article/1002128 The Raf kinase inhibitor protein (RKIP) has been reported to be underexpressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/AKT pathway, is either mutated, underexpressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. The transcriptional and posttranscriptional regulations of RKIP and PTEN expressions and their roles in resistance were reviewed. The underlying mechanism of the interrelationship between the signaling expressions of RKIP and PTEN in cancer is not clear. Several pathways are regulated by RKIP and PTEN and the transcriptional and post-transcriptional regulations of RKIP and PTEN is significantly altered in cancers. In addition, RKIP and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In addition, molecular and bioinformatic data revealed crosstalk signaling networks that regulate the expressions of both RKIP and PTEN. These crosstalks involved the mitogen-activated protein kinase (MAPK)/PI3K pathways and the dysregulated nuclear factor-kappaB (NF-κB)/Snail/Yin Yang 1 (YY1)/RKIP/PTEN loop in many cancers. Furthermore, further bioinformatic analyses were performed to investigate the correlations (positive or negative) and the prognostic significance of the expressions of RKIP or PTEN in 31 different human cancers. These analyses were not uniform and only revealed that there was a positive correlation between the expression of RKIP and PTEN only in few cancers. These findings demonstrated the existence of signaling cross-talks between RKIP and PTEN and both regulate resistance. Targeting either RKIP or PTEN (alone or in combination with other therapies) may be sufficient to therapeutically inhibit tumor growth and reverse the tumor resistance to cytotoxic therapies. Review Fri, 21 Apr 2023 00:00:00 GMT MatthewMoghaddam, SilviaVivarelli, LucaFalzone, MassimoLibra, BenjaminBonavida, Fri, 21 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002128 https://www.explorationpub.com/Journals/etat/Article/1002130 Esophageal squamous cell carcinoma (ESCC) is the second leading cause of cancer-related deaths in Iran, often diagnosed in advanced stages with a poor prognosis. Growth and differentiation factor 3 (GDF3) is a member of the transforming growth factor-beta (TGF-β) superfamily. It acts as an inhibitor of bone morphogenetic proteins (BMPs) signaling pathway associated with pluripotent embryonic and cancer stem cells (CSCs) characteristics. Since its expression in ESCC has not yet been evaluated, the clinicopathological relevance of GDF3 expression was elucidated in ESCC patients. Expression of GDF3 in tumor tissues from 40 ESCC patients was compared to the related margin normal tissues by relatively comparative real-time polymerase chain reaction (PCR). Glyceraldehydes 3-phosphate dehydrogenase (GAPDH) was used as the endogenous control. Likewise, the function of GDF3 in the differentiation and development of embryonic stem cells (ESCs) was also reviewed. GDF3 was significantly overexpressed in 17.5% of tumors and a significant correlation between GDF3 expression and the depth of tumor invasion was observed (P = 0.032). The results suggest that GDF3 expression is likely to have substantial roles in the progression and invasiveness behavior of ESCC. Having considered the importance of CSC markers identification and their exploitation in targeted cancer therapy, GDF3 may be introduced as a promising therapeutic target to inhibit the invasion of tumor cells in ESCC. Letter to the Editor Mon, 24 Apr 2023 00:00:00 GMT Sara TahbazzadehMoghaddam, Mohammad MahdiForghanifard, Mon, 24 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002130 https://www.explorationpub.com/Journals/etat/Article/1002129 Tannins are secondary metabolites that belong to the family of polyphenolic compounds and have gained a huge interest among researchers due to their versatile therapeutic potential. After lignin, these are the second most abundant polyphenols found in almost every plant part like stem, bark, fruit, seed, leaves, etc. Depending upon their structural composition, these polyphenols can be divided into two distinct groups, namely condensed tannins and hydrolysable tannins. Hydrolysable tannins can be further divided into two types: gallotannins and ellagitannins. Gallotannins are formed by the esterification of D-glucose hydroxyl groups with gallic acid. The gallolyl moieties are bound by a depside bond. The current review focuses mainly on the anti-carcinogenic potential of recently discovered gallotannins, ginnalin A, and hamamelitannin (HAM). Both of these gallotannins possess two galloyl moieties linked to a core monosaccharide having anti-oxidant, anti-inflammatory, and anti-carcinogenic abilities. Ginnalin A is found in plants of the genus Acer whereas HAM is present in witch hazel plants. The biosynthetic pathway of ginnalin A along with the mechanism of the anti-cancer therapeutic potential of ginnalin A and HAM has been discussed. This review will certainly help researchers to work further on the chemo-therapeutic abilities of these two unique gallotannins. Review Fri, 21 Apr 2023 00:00:00 GMT Rippin, VikasBeniwal, AjaySharma, Bikram JitSingh, SeemaRamniwas, KatrinSak, SatishKumar, Anil K.Sharma, Fri, 21 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002129 https://www.explorationpub.com/Journals/etat/Article/1002131 Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts of the plant, Plectranthus vettiveroides (P. vettiveroides), and to analyze the molecular mechanism of the anticancer activity. Methods: The leaf extracts were prepared by polarity-graded serial extraction of the dried leaf powder. The cytotoxic effect of the extracts was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The most active ethyl acetate extract was subjected to bioactivity-guided fractionation by column chromatography, which yielded a cytotoxic fraction designated as the P. vettiveroides fraction (PVF). The anticancer property of PVF was confirmed further by clonogenic assay. The mechanism of PVF-induced cell death was analyzed by flow cytometry and fluorescence microscopy. Additionally, the effects of PVF on apoptotic and cell survival pathways were analyzed using western immunoblot analysis. Results: A bioactive fraction PVF, was isolated from the ethyl acetate leaf extract. PVF showed significant anticancer activity against colon cancer cells, whilst normal cells were comparatively less affected. PVF induced strong apoptotic stimuli in colorectal carcinoma cell line HCT116, involving both extrinsic and intrinsic pathways. Investigation into the molecular mechanism of anticancer activity of PVF in HCT116 cells revealed that the fraction activates the pro-apoptotic pathway via tumor suppressor protein 53 (p53) and inhibits the anti-apoptotic pathway by regulating phosphatidylinositol 3-kinase (PI3K) signaling. Conclusions: The findings of this study demonstrate, with mechanism-based evidence, the chemotherapeutic potential of a bioactive fraction PVF, derived from the leaves of the medicinal plant P. vettiveroides against colon cancer. Original Article Tue, 25 Apr 2023 00:00:00 GMT Faisal M.Athikkavil, Sreekumar U.Aiswarya, RemyaJohny, MeghnaSudhesh, Amrutha A.Nisthul, Ravi S.Lankalapalli, Ruby J.Anto, Smitha V.Bava, Tue, 25 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002131 https://www.explorationpub.com/Journals/etat/Article/1002133 Neuroendocrine tumours (NETs) are a rare type of tumours that arise from the neuroendocrine cells which are distributed throughout the body. Of all the gastrointestinal tumours only 1–2% account for NETs. They have an extremely low incidence of 0.17% arising in the intrahepatic bile duct epithelium. Majority of hepatic NETs occur as a result of metastases from the primary NETs. Most cases of primary hepatic NET (PHNET) present as a solid nodular mass. However, predominantly cystic PHNET is extremely rare which mimics other cystic space-occupying lesions clinically and radiologically as seen in this case. Case Report Wed, 26 Apr 2023 00:00:00 GMT MangeshLondhe, SakshiGarg, SushamaGurwale, CharusheelaGore, Wed, 26 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002133 https://www.explorationpub.com/Journals/etat/Article/1002132 It is now well-acknowledged that microbiota has a profound influence on both human health and illness. The gut microbiota has recently come to light as a crucial element that influences cancer through a variety of mechanisms. The connections between the microbiome and cancer therapy are further highlighted by a number of preclinical and clinical evidence, suggesting that these complicated interactions may vary by cancer type, treatment, or even by tumor stage. The paradoxical relationship between gut microbiota and cancer therapies is that in some cancers, the gut microbiota may be necessary to maintain therapeutic efficacy, whereas, in other cancers, gut microbiota depletion significantly increases efficacy. Actually, mounting research has shown that the gut microbiota plays a crucial role in regulating the host immune response and boosting the efficacy of anticancer medications like chemotherapy and immunotherapy. Therefore, gut microbiota modulation, which aims to restore gut microbial balance, is a viable technique for cancer prevention and therapy given the expanding understanding of how the gut microbiome regulates treatment response and contributes to carcinogenesis. This review will provide an outline of the gut microbiota’s role in health and disease, along with a summary of the most recent research on how it may influence the effectiveness of various anticancer medicines and affect the growth of cancer. This study will next cover the newly developed microbiota-targeting strategies including prebiotics, probiotics, and fecal microbiota transplantation (FMT) to enhance anticancer therapy effectiveness, given its significance. Review Wed, 26 Apr 2023 00:00:00 GMT SoumayaKouidhi, OumaimaZidi, ZeinebBelkhiria, HendaRais, AidaAyadi, FarhatBen Ayed, AmorMosbah, AmeurCherif, Amel Ben AmmarEl Gaaied, Wed, 26 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002132 https://www.explorationpub.com/Journals/etat/Article/1002135 Aim: In countries where access to mammography equipment and skilled personnel is limited, most breast cancer (BC) cases are detected in locally advanced stages. Infrared breast thermography is recognized as an adjunctive technique for the detection of BC due to its advantages such as safety (by not emitting ionizing radiation nor applying any stress to the breast), portability, and low cost. Improved by advanced computational analytics techniques, infrared thermography could be a valuable complementary screening technique to detect BC at early stages. In this work, an infrared-artificial intelligence (AI) software was developed and evaluated to help physicians to identify potential BC cases. Methods: Several AI algorithms were developed and evaluated, which were learned from a proprietary database of 2,700 patients, with BC cases that were confirmed through mammography, ultrasound, and biopsy. Following by evaluation of the algorithms, the best AI algorithm (infrared-AI software) was submitted to a clinic validation process in which its ability to detect BC was compared to mammography evaluations in a double-blind test. Results: The infrared-AI software demonstrated efficiency values of 94.87% sensitivity, 72.26% specificity, 30.08% positive predictive value (PPV), and 99.12% negative predictive value (NPV), whereas the reference mammography evaluation reached 100% sensitivity, 97.10% specificity, 81.25% PPV, and 100% NPV. Conclusions: The infrared-AI software here developed shows high BC sensitivity (94.87%) and high NPV (99.12%). Therefore, it is proposed as a complementary screening tool for BC. Original Article Thu, 27 Apr 2023 00:00:00 GMT EnriqueMartín-Del-Campo-Mena, Pedro A.Sánchez-Méndez, EvaRuvalcaba-Limon, Federico M.Lazcano-Ramírez, AndrésHernández-Santiago, Jorge A.Juárez-Aburto, Kictzia Y.Larios-Cruz, L. EnriqueHernández-Gómez, J. AndreiMerino-González, YessicaGonzález-Mejía, Thu, 27 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002135 https://www.explorationpub.com/Journals/etat/Article/1002134 Aim: One in eight fatalities globally are considered cancer-related. The need for cancer therapy is growing. Natural products continue to play a role in drug development, as up to 50% of authorized drugs in the last 30 years have been isolated from natural sources. Methods: Anticancer, antioxidant, antibacterial, antifungal, antiviral, analgesic, anti-inflammatory, and other actions have all been reported in research papers using plants from the Syzygium genus in the treatment and prevention of disease. Results: Results from the anticancer test showed that the genus, especially Syzygium aqueum, Syzygium samarangense, and Syzygium cumini had significant promise as an anticancer agent in vitro against several cancer cell lines. Numerous factors, including phytochemical composition, increased apoptotic activity, decreased cell proliferation, stopped angiogenesis, and reduced inflammation. Conclusions: These results, despite preliminary, show promise for further purification and investigation of bioactive compounds and extracts within the genus Syzygium for their anticancer properties. Systematic Review Thu, 27 Apr 2023 00:00:00 GMT Mahmoud DogaraAbdulrahman, Harmand A.Hama, Thu, 27 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002134 https://www.explorationpub.com/Journals/etat/Article/1002338 Cancer immunotherapy has revolutionized oncology by harnessing the immune system to target tumor cells. Cancer vaccines that trigger immune responses specific to tumors are becoming more and more popular among new approaches. Nevertheless, traditional tumour-associated antigens are susceptible to immune tolerance and frequently show low immunogenicity. The revolutionary potential of cryptic and non-canonical antigens as new targets for precision immunotherapy is examined in this review. Due to their enhanced tumor selectivity and ability to evade central tolerance, these unconventional antigens present encouraging options for vaccine development. This review examines the mechanisms underlying their antigen production, advanced technologies for their discovery, and various vaccine platforms, highlighting their potential to drive the next generation of cancer vaccines. Review Thu, 25 Sep 2025 00:00:00 GMT Anu ShibiAnilkumar, Sheena MariamThomas, RamakrishnanVeerabathiran, Thu, 25 Sep 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002338 https://www.explorationpub.com/Journals/etat/Article/1002136 A clinical case of a 61-year-old female diagnosed with stage IV right colon adenocarcinoma (unresectable liver and multiple lymph node metastases at the time of diagnosis), Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type, proficient mismatch repair (pMMR), in whom a complete response to the third-line of systemic treatment with trifluridine/tipiracil (TAS-102) was obtained. The complete response has been maintained for more than 2 years after its suspension. Case Report Thu, 27 Apr 2023 00:00:00 GMT CeliaLara-Morga, MagdaPalka-Kotlowska, SaraCustodio-Cabello, VilmaPacheco-Barcia, LuisCabezón-Gutiérrez, Thu, 27 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002136 https://www.explorationpub.com/Journals/etat/Article/1002137 Transforming growth factor-β (TGF-β) signaling is an important pathway for promoting the pathogenesis of inflammatory diseases, including cancer. The roles of TGF-β signaling are heterogeneous and versatile in cancer development and progression, both anticancer and protumoral actions are reported. Interestingly, increasing evidence suggests that TGF-β enhances disease progression and drug resistance via immune-modulatory actions in the tumor microenvironment (TME) of solid tumors. A better understanding of its regulatory mechanisms in the TME at the molecular level can facilitate the development of precision medicine to block the protumoral actions of TGF-β in the TME. Here, the latest information about the regulatory mechanisms and translational research of TGF-β signaling in the TME for therapeutic development had been summarized. Review Fri, 28 Apr 2023 00:00:00 GMT Max Kam-KwanChan, Emily Lok-YiuChan, Zoey ZeyuanJi, Alex Siu-WingChan, ChunjieLi, Kam-TongLeung, Ka-FaiTo, Patrick Ming-KuenTang, Fri, 28 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002137 https://www.explorationpub.com/Journals/etat/Article/1002138 Oncologic emergencies are a wide spectrum of oncologic conditions caused directly by malignancies or their treatment. Oncologic emergencies may be classified according to the underlying physiopathology in metabolic, hematologic, and structural conditions. In the latter, radiologists have a pivotal role, through an accurate diagnosis useful to provide optimal patient care. Structural conditions may involve the central nervous system, thorax, or abdomen, and emergency radiologists have to know the characteristics imaging findings of each one of them. The number of oncologic emergencies is growing due to the increased incidence of malignancies in the general population and also to the improved survival of these patients thanks to the advances in cancer treatment. Artificial intelligence (AI) could be a solution to assist emergency radiologists with this rapidly increasing workload. To our knowledge, AI applications in the setting of the oncologic emergency are mostly underexplored, probably due to the relatively low number of oncologic emergencies and the difficulty in training algorithms. However, cancer emergencies are defined by the cause and not by a specific pattern of radiological symptoms and signs. Therefore, it can be expected that AI algorithms developed for the detection of these emergencies in the non-oncological field can be transferred to the clinical setting of oncologic emergency. In this review, a craniocaudal approach was followed and central nervous system, thoracic, and abdominal oncologic emergencies have been addressed regarding the AI applications reported in literature. Among the central nervous system emergencies, AI applications have been reported for brain herniation and spinal cord compression. In the thoracic district the addressed emergencies were pulmonary embolism, cardiac tamponade and pneumothorax. Pneumothorax was the most frequently described application for AI, to improve sensibility and to reduce the time-to-diagnosis. Finally, regarding abdominal emergencies, AI applications for abdominal hemorrhage, intestinal obstruction, intestinal perforation, and intestinal intussusception have been described. Review Fri, 28 Apr 2023 00:00:00 GMT Salvatore ClaudioFanni, GiuseppeGreco, SaraRossi, GayaneAghakhanyan, SalvatoreMasala, MarianoScaglione, MicheleTonerini, EmanueleNeri, Fri, 28 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002138 https://www.explorationpub.com/Journals/etat/Article/1002139 Aim: Coagulation is frequently activated in cancer patients and has been correlated with an unfavorable prognosis. To evaluate whether a putative release of tissue factor (TF) by circulating tumor cells (CTCs) represents a target to impair the dissemination of small cell lung cancer (SCLC), the expression of relevant proteins in a panel of permanent SCLC and SCLC CTC cell lines that have been established at the Medical University of Vienna. Methods: Five CTC and SCLC lines were analyzed using a TF enzyme-linked immunosorbent assay (ELISA) tests, RNA sequencing, and western blot arrays covering 55 angiogenic mediators. Furthermore, the influence of topotecan and epirubicin as well as hypoxia-like conditions on the expression of these mediators was investigated. Results: The results demonstrate that the SCLC CTC cell lines express no significant amounts of active TF but thrombospondin-1 (TSP-1), urokinase-type plasminogen activator receptor (uPAR), vascular endothelial-derived growth factor (VEGF) and angiopoietin-2 in two cases. The major difference between the SCLC and SCLC CTC cell lines found was the loss of the expression of angiogenin in the blood-derived CTC lines. Topotecan and epirubicin decreased the expression of VEGF, whereas hypoxia-like conditions upregulated VEGF. Conclusions: Active TF capable of triggering coagulation seems not to be expressed in SCLC CTC cell lines in significant levels and, thus, CTC-derived TF seems dispensable for dissemination. Nevertheless, all CTC lines form large spheroids, termed tumorospheres, which may become trapped in clots of the microvasculature and extravasate in this supportive microenvironment. The contribution of clotting to the protection and dissemination of CTCs in SCLC may be different from other solid tumors such as breast cancer. Original Article Fri, 28 Apr 2023 00:00:00 GMT BarbaraRath, AdelinaPlangger, LukasKlameth, MaximilianHochmair, ErnstUlsperger, BramBoeckx, ChristophNeumayer, GerhardHamilton, Fri, 28 Apr 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002139 https://www.explorationpub.com/Journals/etat/Article/1002212 Cancer is the leading cause of death globally superseded only by cardiovascular diseases, and novel strategies to overcome therapeutic resistance against existing cancer treatments are urgently required. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with potent immunosuppressive capacity against well-established anti-tumour effectors such as natural killer cells (NK cells) and T cells thereby promoting cancer initiation and progression. Critically, MDSCs are readily identified in almost all tumour types and human cancer patients, and numerous studies in the past decade have recognised their role in contributing to therapeutic resistance against all four pillars of modern cancer treatment, namely surgery, chemotherapy, radiotherapy and immunotherapy. MDSCs suppress anti-tumour immunity through a plethora of mechanisms including the well-characterised arginase 1 (Arg1), inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS)-mediated pathways, along with several other more recently discovered. MDSCs are largely absent in healthy homeostatic states and predominantly exist in pathological conditions, making them attractive therapeutic targets. However, the lack of specific markers identified for MDSCs to date greatly hindered therapeutic development, and currently there are no clinically approved drugs that specifically target MDSCs. Methods to deplete MDSCs clinically and inhibit their immunosuppressive function will be crucial in advancing cancer treatment and to overcome treatment resistance. This review provides a detailed overview of the current understandings behind the mechanisms of MDSC-mediated suppression of anti-tumour immunity, and discusses potential strategies to target MDSC immunosuppressive mechanisms to overcome therapeutic resistance. Review Wed, 28 Feb 2024 00:00:00 GMT EricJou, NatashaChaudhury, FizzaNasim, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002212 https://www.explorationpub.com/Journals/etat/Article/1002140 Cancer serum biomarkers are valuable or even indispensable for cancer diagnostics and/or monitoring and, currently, many cancer serum markers are routinely used in the clinic. Most of those markers are glycoproteins, carrying cancer-specific glycan structures that can provide extra-information for cancer monitoring. Nonetheless, in the majority of cases, this differential feature is not exploited and the corresponding analytical assays detect only the protein amount, disregarding the analysis of the aberrant glycoform. Two exceptions to this trend are the biomarkers α-fetoprotein (AFP) and cancer antigen 19-9 (CA19-9), which are clinically monitored for their cancer-related glycan changes, and only the AFP assay includes quantification of both the protein amount and the altered glycoform. This narrative review demonstrates, through several examples, the advantages of the combined quantification of protein cancer biomarkers and the respective glycoform analysis, which enable to yield the maximum information and overcome the weaknesses of each individual analysis. This strategy allows to achieve higher sensitivity and specificity in the detection of cancer, enhancing the diagnostic power of biomarker-based cancer detection tests. Review Thu, 29 Jun 2023 00:00:00 GMT Maria Luísa S.Silva, Thu, 29 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002140 https://www.explorationpub.com/Journals/etat/Article/1002141 Aim: 177Lu-Dotatate (Lu-177), a form of peptide receptor radionuclide therapy (PRRT), was approved by Food and Drug Administration (FDA) for the treatment of somatostatin-receptor-positive neuroendocrine tumors (NETs) in 2018. Clinical trials prior to the FDA approval of Lu-177 showed favorable outcomes but there is limited published real world outcomes data. This study aims to describe and analyze real world outcomes of patients with NET who received Lu-177. Methods: After obtaining institutional review board approval, retrospective evaluation was performed to analyze the efficacy of Lu-177 for somatostatin receptor-positive gastro-entero-pancreatic NETs (GEP-NETs) patients at the University of Kansas Cancer Center between June 2018 and September 2021. This study aims to determine the response rate to the treatment of the entire cohort and subgroups. Results: A total of 65 patients received Lu-177 of which 58 completed treatment. The 58 patients had a median age of 61.5 years, 24 females and 34 males, 86% Caucasian and 12% black. The origins of NETs were primarily small bowel (n = 24) and pancreatic (n = 14). Pathology showed grades 1 (n = 21), 2 (n = 25), and 3 (n = 4) and were primarily well-differentiated tumors (n = 4). Among the cohort, 52 patients had imaging to assess response with 14 (26.9%) patients with partial response (PR), 31 (59.6%) with stable disease (SD), and 7 (13.5%) with progressive disease (PD). In a subset analysis, patients with non-functional disease (n = 29) had higher rates of PR 42.3% (compared to 11.5%, P = 0.0147) and higher disease control rate of 96% (compared to 78%, P = 0.042) than patients with functional disease (n = 29). Patients with non-functional disease had a lower PD of 3.85% (compared to 23%, P = 0.0147) than those with functional disease. Conclusions: This real world outcomes analysis of NETs treated with Lu-177 shows improved PR when compared to the initial clinical trials and is promising for patients. In addition, patients with non-functional tumors were found to have a statistically significant improved response rate which has not been described in the literature before. If these study findings are validated in a larger cohort they may guide patient selection for Lu-177 therapy in the future. Original Article Thu, 29 Jun 2023 00:00:00 GMT StijnHentzen, KathanMehta, Raed Moh’d TaiseerAl-Rajabi, AnwaarSaeed, Joaquina CelebreBaranda, Stephen K.Williamson, WeijingSun, AnupKasi, Thu, 29 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002141 https://www.explorationpub.com/Journals/etat/Article/1002142 Rectal cancer (RC) is one of the most common tumours worldwide in both males and females, with significant morbidity and mortality rates, and it accounts for approximately one-third of colorectal cancers (CRCs). Magnetic resonance imaging (MRI) has been demonstrated to be accurate in evaluating the tumour location and stage, mucin content, invasion depth, lymph node (LN) metastasis, extramural vascular invasion (EMVI), and involvement of the mesorectal fascia (MRF). However, these features alone remain insufficient to precisely guide treatment decisions. Therefore, new imaging biomarkers are necessary to define tumour characteristics for staging and restaging patients with RC. During the last decades, RC evaluation via MRI-based radiomics and artificial intelligence (AI) tools has been a research hotspot. The aim of this review was to summarise the achievement of MRI-based radiomics and AI for the evaluation of staging, response to therapy, genotyping, prediction of high-risk factors, and prognosis in the field of RC. Moreover, future challenges and limitations of these tools that need to be solved to favour the transition from academic research to the clinical setting will be discussed. Review Fri, 30 Jun 2023 00:00:00 GMT GiuseppeDi Costanzo, RaffaeleAscione, AndreaPonsiglione, Anna GiacomaTucci, SerenaDell’Aversana, FrancescaIasiello, EnricoCavaglià, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002142 https://www.explorationpub.com/Journals/etat/Article/1002143 Aim: Recently, a tumor cell-platelet interaction was identified in different tumor entities, resulting in a transfer of tumor-derived RNA into platelets, named further “tumor-educated platelets (TEP)”. The present pilot study aims to investigate whether such a tumor-platelet transfer of RNA occurs also in patients suffering from head and neck squamous cell carcinoma (HNSCC). Methods: Sequencing analysis of RNA derived from platelets of tumor patients (TPs) and healthy donors (HDs) were performed. Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for verification of differentially expressed genes in platelets from TPs and HDs in a second cohort of patients and HDs. Data were analyzed by applying bioinformatic tools. Results: Sequencing of RNA derived from the tumor as well as from platelets of TPs and HDs revealed 426 significantly differentially existing RNA, at which 406 RNA were more and 20 RNA less abundant in platelets from TPs in comparison to that of HDs. In TPs’ platelets, abundantly existing RNA coding for 49 genes were detected, characteristically expressed in epithelial cells and RNA, the products of which are involved in tumor progression. Applying bioinformatic tools and verification on a second TP/HD cohort, collagen type I alpha 1 chain (COL1A1) and zinc finger protein 750 (ZNF750) were identified as the strongest potentially platelet-RNA-sequencing (RNA-seq)-based biomarkers for HNSCC. Conclusions: These results indicate a transfer of tumor-derived messenger RNA (mRNA) into platelets of HNSCC patients. Therefore, analyses of a patient’s platelet RNA could be an efficient option for liquid biopsy in order to diagnose HNSCC or to monitor tumorigenesis as well as therapeutic responses at any time and in real time. Original Article Fri, 30 Jun 2023 00:00:00 GMT Lisa T.Huber, Johann M.Kraus, JasminEzić, AminWanli, MarcoGroth, SimonLaban, Thomas K.Hoffmann, BarbaraWollenberg, Hans A.Kestler, CorneliaBrunner, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002143 https://www.explorationpub.com/Journals/etat/Article/1002144 Aim: Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere with the enzyme activity of KDAC8. These compounds have been identified under equilibrium or near equilibrium conditions for inhibitor binding to the target enzyme. This study aims for the classification of KDAC8 inhibitors according to the mode of action and identification of most promising lead compounds for drug development. Methods: A continuous enzyme activity assay is used to monitor inhibition kinetics. Results: A high-throughput continuous KDAC8 activity assay is developed that provides additional mechanistic information about enzyme inhibition enabling the classification of KDAC8 inhibitors according to their mode of action. Fast reversible inhibitors act as a molecular chaperone and are capable to rescue the enzyme activity of misfolded KDAC8, while covalent inactivators and slow dissociating inhibitors do not preserve KDAC8 activity. Conclusions: The application of continuous KDAC8 activity assay reveals additional information about the mode of interaction with inhibitors, which can be used to classify KDAC8 inhibitors according to their mode of action. The approach is compatible with the high-throughput screening of compound libraries. Fast reversible inhibitors of KDAC8 act as molecular chaperones and recover enzyme activity from misfolded protein conformations. In contrast, slow-binding inhibitors and covalent inactivators of KDAC8 are not capable to recover enzyme activity. Original Article Fri, 30 Jun 2023 00:00:00 GMT MarkusSchweipert, AnujaAmurthavasan, Franz-JosefMeyer-Almes, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002144 https://www.explorationpub.com/Journals/etat/Article/1002145 Immunotherapy strategies targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are revolutionizing oncology. However, its effectiveness is limited in part due to the loss of effector cytotoxic T lymphocytes. Interestingly, supplementation of vitamin D could abolish the repressive effect of programmed cell death-ligand 1 (PD-L1) on CD8+ T cells, which might prevent the lymphocytopenia. In addition, vitamin D signaling could contribute to the differentiation of T-regulatory (Treg) cells associated with the expression of Treg markers such as forkhead box P3 (FOXP3) and CTLA-4. Furthermore, vitamin D may be associated with the stimulation of innate immunity. Peroxisome proliferator-activated receptor (PPAR) and estrogen receptor (ESR) signaling, and even the signaling from phosphoinositide-3 kinase (PI3K)/AKT pathway could have inhibitory roles in carcinogenesis possibly via the modulation of immune checkpoint molecules. In some cases, certain small molecules including vitamin D could be a novel therapeutic modality with a promising potential for the better performance of immune checkpoint blockade cancer therapies. Perspective Fri, 30 Jun 2023 00:00:00 GMT AiTsuji, SayuriYoshikawa, SaeMorikawa, YukaIkeda, KurumiTaniguchi, HarukaSawamura, TomokoAsai, SatoruMatsuda, Fri, 30 Jun 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002145 https://www.explorationpub.com/Journals/etat/Article/1002146 Cancer remains the second leading cause of death worldwide despite modern breakthroughs in medicine, and novel treatments are urgently needed. The revolutionary success of immune checkpoint inhibitors in the past decade serves as proof of concept that the immune system can be effectively harnessed to treat cancer. Cytokines are small signalling proteins with critical roles in orchestrating the immune response and have become an attractive target for immunotherapy. Type 1 immune cytokines, including interferon γ (IFNγ), interleukin-12 (IL-12), and tumour necrosis factor α (TNFα), have been shown to have largely tumour suppressive roles in part through orchestrating anti-tumour immune responses mediated by natural killer (NK) cells, CD8+ T cells and T helper 1 (Th1) cells. Conversely, type 2 immunity involving group 2 innate lymphoid cells (ILC2s) and Th2 cells are involved in tissue regeneration and wound repair and are traditionally thought to have pro-tumoural effects. However, it is found that the classical type 2 immune cytokines IL-4, IL-5, IL-9, and IL-13 may have conflicting roles in cancer. Similarly, type 2 immunity-related cytokines IL-25 and IL-33 with recently characterised roles in cancer may either promote or suppress tumorigenesis in a context-dependent manner. Furthermore, type 1 cytokines IFNγ and TNFα have also been found to have pro-tumoural effects under certain circumstances, further complicating the overall picture. Therefore, the dichotomy of type 1 and type 2 cytokines inhibiting and promoting tumours respectively is not concrete, and attempts of utilising these for cancer immunotherapy must take into account all available evidence. This review provides an overview summarising the current understanding of type 1 and type 2 cytokines in tumour immunity and discusses the prospects of harnessing these for immunotherapy in light of previous and ongoing clinical trials. Review Sat, 01 Jul 2023 00:00:00 GMT EricJou, Sat, 01 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002146 https://www.explorationpub.com/Journals/etat/Article/1002148 Transmission of a malignancy from a donor’s organ to the recipient of the graft is a rare event, though it is a severe complication that can result in a poor outcome. Usually, immunosuppressive therapy is discontinued and the allograft is removed. However, treatment of patients with the disseminated cancers implies that after the graft removal and cessation of the immunosuppression, radiotherapy, chemotherapy, or immunotherapy with alpha-interferon (INF-α) or interleukin-2 (IL-2) are required. The case report presents a clinical case of a transmitted kidney graft with multiple metastases (MTS) in a 31-year-old woman with the spontaneous regression of the metastatic cancer after transplantectomy and cancellation of the immunosuppressive therapy. Obviously, the determining factor is the recognition of the tumor by the effectors of the antitumor immunity due to the human leukocyte antigen (HLA) mismatch between the donor and the recipient. Therefore, cancellation of the immunosuppressive therapy in cases of transferal of a malignancy with a transplanted organ allows the effectors of the immune system to distinguish the tumor as a foreign tissue and effectively eliminate this neoplasm. Case Report Sat, 01 Jul 2023 00:00:00 GMT Mikhail V.Kiselevskiy, Elena G.Gromova, Nikolay A.Kozlov, Svetlana D.Bezhanova, Irina Zh.Shubina, Sat, 01 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002148 https://www.explorationpub.com/Journals/etat/Article/1002147 Soft tissue sarcomas (STSs) are rare, heterogeneous, and very often asymptomatic diseases. Their diagnosis is fundamental, as is the identification of the degree of malignancy, which may be high, medium, or low. The Italian Medical Oncology Association and European Society of Medical Oncology (ESMO) guidelines recommend magnetic resonance imaging (MRI) because the clinical examination is typically ineffective. The diagnosis of these rare diseases with artificial intelligence (AI) techniques presents reduced datasets and therefore less robust methods. However, the combination of AI techniques with radiomics may be a new angle in diagnosing rare diseases such as STSs. Results obtained are promising within the literature, not only for the performance but also for the explicability of the data. In fact, one can make tumor classification, site localization, and prediction of the risk of developing metastasis. Thanks to the synergy between computer scientists and radiologists, linking numerical features to radiological evidence with excellent performance could be a new step forward for the diagnosis of rare diseases. Review Sat, 01 Jul 2023 00:00:00 GMT RaffaeleNatella, GiuliaVarriano, Maria ChiaraBrunese, MarcelloZappia, MichelaBruno, MicheleGallo, FlavioFazioli, IginoSimonetti, VincenzaGranata, LucaBrunese, AntonellaSantone, Sat, 01 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002147 https://www.explorationpub.com/Journals/etat/Article/1002149 Hepatocellular carcinoma (HCC) is a complex process that plays an important role in its progression. Abnormal glucose metabolism in HCC cells can meet the nutrients required for the occurrence and development of liver cancer, better adapt to changes in the surrounding microenvironment, and escape the attack of the immune system on the tumor. There is a close relationship between reprogramming of glucose metabolism and immune escape. This article reviews the current status and progress of glucose metabolism reprogramming in promoting immune escape in liver cancer, aiming to provide new strategies for clinical immunotherapy of liver cancer. Review Sat, 01 Jul 2023 00:00:00 GMT QiuyueZhang, JinchenLiu, HaifengLin, BoLin, MingyueZhu, MengsenLi, Sat, 01 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002149 https://www.explorationpub.com/Journals/etat/Article/1002150 The treatment of central nervous system (CNS) tumors is complicated by high rates of recurrence and treatment resistance that contribute to high morbidity and mortality (Nat Rev Neurol. 2022;18:221–36. doi: 10.1038/s41582-022-00621-0). One of the challenges of treating these tumors is the limited permeability of the blood brain barrier (BBB). Early pharmacologic treatments worked to overcome the BBB by targeting vulnerabilities in the tumor cell replication process directly through alkylating agents like temozolomide. However, as advancements have been made options have expanded to include immunologic targets through the use of monoclonal antibodies. In the future, treatment will likely continue to focus on the use of immunotherapies, as well as emerging technology like the use of low-intensity focused ultrasound (LIFU). Ultimately, this paper serves as an introductory overview of current therapeutic options for post-resection primary brain tumors, as well as a look towards future work and emerging treatment options. Review Sat, 01 Jul 2023 00:00:00 GMT MeaghanMcGovern, MichaelaScanlon, AmandaStanton, BrandonLucke-Wold, Sat, 01 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002150 https://www.explorationpub.com/Journals/etat/Article/1002151 In the past few years, artificial intelligence (AI) has been increasingly used to create tools that can enhance workflow in medicine. In particular, neuro-oncology has benefited from the use of AI and especially machine learning (ML) and radiogenomics, which are subfields of AI. ML can be used to develop algorithms that dynamically learn from available medical data in order to automatically do specific tasks. On the other hand, radiogenomics can identify relationships between tumor genetics and imaging features, thus possibly giving new insights into the pathophysiology of tumors. Therefore, ML and radiogenomics could help treatment tailoring, which is crucial in personalized neuro-oncology. The aim of this review is to illustrate current and possible future applications of ML and radiomics in neuro-oncology. Review Wed, 19 Jul 2023 00:00:00 GMT TeresaPerillo, Marcode Giorgi, Umberto MariaPapace, AntoniettaSerino, RenatoCuocolo, AndreaManto, Wed, 19 Jul 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002151 https://www.explorationpub.com/Journals/etat/Article/1002152 Hepatocellular carcinoma (HCC) constitutes an extremely malignant form of primary liver cancer. Intricate connections linking to the immune system might be associated with the pathogenesis of HCC. Meanwhile, immunotherapy with immune checkpoint inhibitors has been established to be a favorable therapeutic possibility for advanced HCC. Although curative opportunities for advanced HCC are restricted, the immune checkpoint immunotherapy has developed as the main choice for treating HCC. However, patients with metabolic-associated fatty liver disease (MAFLD)-linked HCC might be less likely to benefit from the immunotherapy alone. The limitation of the effect of the immunotherapy might be owing to the impaired T cell activation in MAFLD patients, which could be well explained by a dysfunctional gut-liver axis. Gut microbiota and their metabolites including several bile acids could contribute to modulating the responses of the immune checkpoint immunotherapy. Roles of gut microbiota in the development of cancers have expected great interest in the latest studies. Here, an interplay between the gut and liver has been presented, which might suggest to affect the efficacy of immune checkpoint immunotherapy against HCC. Perspective Thu, 24 Aug 2023 00:00:00 GMT SayuriYoshikawa, KurumiTaniguchi, HarukaSawamura, YukaIkeda, TomokoAsai, AiTsuji, SatoruMatsuda, Thu, 24 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002152 https://www.explorationpub.com/Journals/etat/Article/1002153 Cancer is a fatal disease and the second most cause of death worldwide. Treatment of cancer is a complex process and requires a multi-modality-based approach. Cancer detection and treatment starts with screening/diagnosis and continues till the patient is alive. Screening/diagnosis of the disease is the beginning of cancer management and continued with the staging of the disease, planning and delivery of treatment, treatment monitoring, and ongoing monitoring and follow-up. Imaging plays an important role in all stages of cancer management. Conventional oncology practice considers that all patients are similar in a disease type, whereas biomarkers subgroup the patients in a disease type which leads to the development of precision oncology. The utilization of the radiomic process has facilitated the advancement of diverse imaging biomarkers that find application in precision oncology. The role of imaging biomarkers and artificial intelligence (AI) in oncology has been investigated by many researchers in the past. The existing literature is suggestive of the increasing role of imaging biomarkers and AI in oncology. However, the stability of radiomic features has also been questioned. The radiomic community has recognized that the instability of radiomic features poses a danger to the global generalization of radiomic-based prediction models. In order to establish radiomic-based imaging biomarkers in oncology, the robustness of radiomic features needs to be established on a priority basis. This is because radiomic models developed in one institution frequently perform poorly in other institutions, most likely due to radiomic feature instability. To generalize radiomic-based prediction models in oncology, a number of initiatives, including Quantitative Imaging Network (QIN), Quantitative Imaging Biomarkers Alliance (QIBA), and Image Biomarker Standardisation Initiative (IBSI), have been launched to stabilize the radiomic features. Review Thu, 24 Aug 2023 00:00:00 GMT Ashish KumarJha, SnehaMithun, Umeshkumar B.Sherkhane, PoojDwivedi, SendersPuts, BicheOsong, AlbertoTraverso, NilenduPurandare, LeonardWee, VenkateshRangarajan, AndreDekker, Thu, 24 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002153 https://www.explorationpub.com/Journals/etat/Article/1002154 Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher’s interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed. Review Thu, 24 Aug 2023 00:00:00 GMT Rui CaetanoOliveira, JoãoGama, JoséCasanova, Thu, 24 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002154 https://www.explorationpub.com/Journals/etat/Article/1002155 Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins’ anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential “hallmark of cancer” required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation. Review Tue, 29 Aug 2023 00:00:00 GMT Ashley J.Hoskin, Amy K.Holt, Danny N.Legge, Tracey J.Collard, Ann C.Williams, Emma E.Vincent, Tue, 29 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002155 https://www.explorationpub.com/Journals/etat/Article/1002156 Epidermal growth factor receptor (EGFR) is one of the most well-studied oncogenes with roles in proliferation, growth, metastasis, and therapeutic resistance. This intense study has led to the development of a range of targeted therapeutics including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and nanobodies. These drugs are excellent at blocking the activation and kinase function of wild-type EGFR (wtEGFR) and several common EGFR mutants. These drugs have significantly improved outcomes for patients with cancers including head and neck, glioblastoma, colorectal, and non-small cell lung cancer (NSCLC). However, therapeutic resistance is often seen, resulting from acquired mutations or activation of compensatory signaling pathways. Additionally, these therapies are ineffective in tumors where EGFR is found predominantly in the nucleus, as can be found in triple negative breast cancer (TNBC). In TNBC, EGFR is subjected to alternative trafficking which drives the nuclear localization of the receptor. In the nucleus, EGFR interacts with several proteins to activate transcription, DNA repair, migration, and chemoresistance. Nuclear EGFR (nEGFR) correlates with metastatic disease and worse patient prognosis yet targeting its nuclear localization has proved difficult. This review provides an overview of current EGFR-targeted therapies and novel peptide-based therapies that block nEGFR, as well as their clinical applications and potential for use in oncology. Review Wed, 30 Aug 2023 00:00:00 GMT BenjaminAtwell, PavaniChalasani, JoyceSchroeder, Wed, 30 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002156 https://www.explorationpub.com/Journals/etat/Article/1002157 Cancer stem-like cells (CSCs) identified by self-renewal ability and tumor-initiating potential are responsible for tumor recurrence and metastasis in many cancers. Conventional chemotherapy fails to eradicate CSCs that hold a state of dormancy and possess multi-drug resistance. Spurred by the progress of nanotechnology for drug delivery and biomedical applications, nanomedicine has been increasingly developed to tackle stemness-associated chemotherapeutic resistance for cancer therapy. This review focuses on advances in nanomedicine-mediated therapeutic strategies to overcome chemoresistance by specifically targeting CSCs, the combination of chemotherapeutics with chemopotentiators, and programmable controlled drug release. Perspectives from materials and formulations at the nano-scales are specifically surveyed. Future opportunities and challenges are also discussed. Review Thu, 31 Aug 2023 00:00:00 GMT HuayuLiu, MingqiLiu, YananZhao, RanMo, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002157 https://www.explorationpub.com/Journals/etat/Article/1002158 Aim: The aim of this study was to investigate the feasibility of developing a deep learning (DL) algorithm for classifying brain metastases from non-small cell lung cancer (NSCLC) into epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement groups and to compare the accuracy with classification based on semantic features on imaging. Methods: Data set of 117 patients was analysed from 2014 to 2018 out of which 33 patients were EGFR positive, 43 patients were ALK positive and 41 patients were negative for either mutation. Convolutional neural network (CNN) architecture efficient net was used to study the accuracy of classification using T1 weighted (T1W) magnetic resonance imaging (MRI) sequence, T2 weighted (T2W) MRI sequence, T1W post contrast (T1post) MRI sequence, fluid attenuated inversion recovery (FLAIR) MRI sequences. The dataset was divided into 80% training and 20% testing. The associations between mutation status and semantic features, specifically sex, smoking history, EGFR mutation and ALK rearrangement status, extracranial metastasis, performance status and imaging variables of brain metastasis were analysed using descriptive analysis [chi-square test (χ2)], univariate and multivariate logistic regression analysis assuming 95% confidence interval (CI). Results: In this study of 117 patients, the analysis by semantic method showed 79.2% of the patients belonged to ALK positive were non-smokers as compared to double negative groups (P = 0.03). There was a 10-fold increase in ALK positivity as compared to EGFR positivity in ring enhancing lesions patients (P = 0.015) and there was also a 6.4-fold increase in ALK positivity as compared to double negative groups in meningeal involvement patients (P = 0.004). Using CNN Efficient Net DL model, the study achieved 76% accuracy in classifying ALK rearrangement and EGFR mutations without manual segmentation of metastatic lesions. Analysis of the manually segmented dataset resulted in improved accuracy of 89% through this model. Conclusions: Both semantic features and DL model showed comparable accuracy in classifying EGFR mutation and ALK rearrangement. Both methods can be clinically used to predict mutation status while biopsy or genetic testing is undertaken. Original Article Thu, 31 Aug 2023 00:00:00 GMT AbhishekMahajan, GurukrishnaB, ShwetaWadhwa, UjjwalAgarwal, UjjwalBaid, SanjayTalbar, Amit KumarJanu, VijayPatil, VanitaNoronha, NaveenMummudi, AnilTibdewal, JPAgarwal, SubashYadav, RajivKumar Kaushal, AmeyaPuranik, NilenduPurandare, KumarPrabhash, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002158 https://www.explorationpub.com/Journals/etat/Article/1002159 Aim: Early diagnosis of paediatric brain tumors significantly improves the outcome. The aim is to study magnetic resonance imaging (MRI) features of paediatric brain tumors and to develop an automated segmentation (AS) tool which could segment and classify tumors using deep learning methods and compare with radiologist assessment. Methods: This study included 94 cases, of which 75 were diagnosed cases of ependymoma, medulloblastoma, brainstem glioma, and pilocytic astrocytoma and 19 were normal MRI brain cases. The data was randomized into training data, 64 cases; test data, 21 cases and validation data, 9 cases to devise a deep learning algorithm to segment the paediatric brain tumor. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the deep learning model were compared with radiologist’s findings. Performance evaluation of AS was done based on Dice score and Hausdorff95 distance. Results: Analysis of MRI semantic features was done with necrosis and haemorrhage as predicting features for ependymoma, diffusion restriction and cystic changes were predictors for medulloblastoma. The accuracy of detecting abnormalities was 90%, with a specificity of 100%. Further segmentation of the tumor into enhancing and non-enhancing components was done. The segmentation results for whole tumor (WT), enhancing tumor (ET), and non-enhancing tumor (NET) have been analyzed by Dice score and Hausdorff95 distance. The accuracy of prediction of all MRI features was compared with experienced radiologist’s findings. Substantial agreement observed between the classification by model and the radiologist’s given classification [K-0.695 (K is Cohen’s kappa score for interrater reliability)]. Conclusions: The deep learning model had very high accuracy and specificity for predicting the magnetic resonance (MR) characteristics and close to 80% accuracy in predicting tumor type. This model can serve as a potential tool to make a timely and accurate diagnosis for radiologists not trained in neuroradiology. Original Article Thu, 31 Aug 2023 00:00:00 GMT AbhishekMahajan, MayurBurrewar, UjjwalAgarwal, BharadwajKss, ApparaoMlv, AmritaGuha, ArpitaSahu, AmitChoudhari, VivekPawar, VivekPunia, SridharEpari, AyushiSahay, TejpalGupta, GirishChinnaswamy, PrakashShetty, AliasgarMoiyadi, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002159 https://www.explorationpub.com/Journals/etat/Article/1002322 Transforming growth factor-β (TGF-β) is a multifunctional molecule with a dual role in carcinogenesis. Recent studies have demonstrated its various effects on cancer-related processes. However, the identification of TGF-β and TGF-β signaling pathway regulators in extracellular vesicles (EVs) appears promising for targeting them to control cancer progression associated with drug resistance. Exosomal TGF-β has been shown to be implicated in cancer cell phenotypic plasticity, a dynamic feature of cancer cells, and an evasive process hampering treatment efficacy. Additionally, EVs can influence the metastatic cascade through mechanisms, including their effects on the immune system and their binding to extracellular matrix (ECM) proteins. These processes collaborate to provide a supportive microenvironment for the development and growth of metastatic tumors. A deeper understanding of the mechanisms by which EVs facilitate TGF-β-mediated intercellular communication may have practical implications for better controlling oncological disorders and providing new methods for cancer diagnostics and treatment, including approaches targeting EVs. Review Fri, 06 Jun 2025 00:00:00 GMT TatianaRuksha, NadezhdaPalkina, Fri, 06 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002322 https://www.explorationpub.com/Journals/etat/Article/1002160 Precision oncology is a rapidly evolving field that uses advanced technologies to deliver personalized cancer care based on a patient’s unique genetic and clinical profile. The use of artificial intelligence (AI) in precision oncology has shown great potential to improve diagnosis, treatment planning, and treatment outcomes. However, the integration of AI in precision oncology also raises important ethical considerations related to patient privacy, autonomy, and protection from bias. In this opinion paper, an overview is provided of previous studies that have explored the use of AI in precision oncology and the ethical considerations associated with this technology. The conclusions of these studies are compared, and the importance of approaching the use of AI in precision oncology with caution is emphasized. It is stressed that patient privacy, autonomy, and protection from bias should be made central to the development and use of AI in precision oncology. Clear guidelines and regulations must be established to ensure that AI is used ethically and for the benefit of patients. The use of AI in precision oncology has the potential to revolutionize cancer care, but it should be ensured that it striked a balance between advancements in technology and ethical considerations. In conclusion, the use of AI in precision oncology is a promising development that has the potential to improve cancer outcomes. However, ethical considerations related to patient privacy, autonomy, and protection from bias must be central to the development and use of AI in precision oncology. Perspective Thu, 31 Aug 2023 00:00:00 GMT BaharehFarasati Far, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002160 https://www.explorationpub.com/Journals/etat/Article/1002161 One of the major causes of death on the globe is cancer. The fourth most frequent malignancy in women worldwide is cervical cancer. Several cancer patients are remaining incurable due to the emergence of medication resistance, despite notable advances in cancer research over the previous few decades. The importance of natural sources as possible therapeutic candidates may be significant. Anthraquinones are one of the many chemical families of natural products, and they stand out for their wide range of structural variations, notable biological activity, and low toxicity. A natural substance called emodin, an anthraquinone derivative, is present in the roots and rhizomes of several plants. This substance has demonstrated antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative properties. It is also capable of preventing cancer spread and can reverse cancer cells’ multidrug resistance. Emodin, a broad-spectrum inhibitor of cancer cells, have anticancer properties in many different types of biological pathways. These molecular mechanisms in cancer cells include the suppression of cell growth and proliferation, deterioration of the cell cycle arrest, the start of apoptosis, antimetastasis, and antiangiogenic impact. Therefore, the aim of the present review summarised the antiproliferative and anticarcinogenic qualities of cervical cancer of emodin. Review Thu, 31 Aug 2023 00:00:00 GMT Priyanka S.Lande, Vaibhav S.Adhao, Jaya P.Ambhore, Kiran P.Gaikwad, Chanchal S.Chandak, Leena P.Joge, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002161 https://www.explorationpub.com/Journals/etat/Article/1002163 Aim: AT-rich interaction domain 1A (ARID1A) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients. Methods: Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A+. Results: Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A+ population was higher compared to ARID1A– population (6 vs. 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), catenin beta 1 (CTNNB1), and lysine methyltransferase 2D (MLL2) mutations were enriched in ARID1A+ population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A2+) were all gynecological cancers (83% endometrioid endometrial cancers). Conclusions: This analysis provides clinical and molecular details about the phenotypes of ARID1A+ cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor. Original Article Thu, 31 Aug 2023 00:00:00 GMT RosaFalcone, MarcoFiletti, PasqualeLombardi, ValeriaAltamura, FrancescoParoni Sterbini, GiovanniScambia, GennaroDaniele, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002163 https://www.explorationpub.com/Journals/etat/Article/1002162 Interferon (IFN)-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (UBL) protein family that can modify specific proteins via a catalytic process called ISGylation. This posttranslational modification can modulate the stability of the ISGylated proteins and protein-protein interactions. Some proteins modified by ISG15 have been identified in malignant neoplasms, suggesting the functional relevance of ISGylation in cancer. This review discusses the ISGylated proteins reported in malignant neoplasms that suggest the potential of ISG15 as a biomarker and therapeutic target in cancer. Review Thu, 31 Aug 2023 00:00:00 GMT Angeles C.Tecalco-Cruz, JesúsZepeda-Cervantes, Thu, 31 Aug 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002162 https://www.explorationpub.com/Journals/etat/Article/1002167 Aim: DNA damage involves in the carcinogenesis of some cancer and may act as a target for therapeutic intervention of cancers. However, it is unclear whether aflatoxin B1 (AFB1)-DNA adducts (ADAs), an important kind of DNA damage caused by AFB1, affect the efficiency of post-operative adjuvant transarterial chemoembolization (po-TACE) treatment improving hepatocellular carcinoma (HCC) survival. Methods: A hospital-based retrospective study, including 318 patients with Barcelona Clinic Liver Cancer (BCLC)-C stage HCC from high AFB1 exposure areas, to investigate the potential effects of ADAs in the tissues with HCC on po-TACE treatment. The amount of ADAs in the cancerous tissues was tested by competitive enzyme-linked immunosorbent assay (c-ELISA). Results: Among these patients with HCC, the average amount of ADAs was 3.00 µmol/mol ± 1.51 µmol/mol DNA in their tissues with cancer. For these patients, increasing amount of ADAs was significantly associated with poorer overall survival (OS) and tumor reoccurrence-free survival (RFS), with corresponding death risk (DR) of 3.69 (2.78–4.91) and tumor recurrence risk (TRR) of 2.95 (2.24–3.88). The po-TACE therapy can efficiently improve their prognosis [DR = 0.59 (0.46–0.76), TRR = 0.63 (0.49–0.82)]. Interestingly, this improving role was more noticeable among these patients with high ADAs [DR = 0.36 (0.24–0.53), TRR = 0.40 (0.28–0.59)], but not among those with low ADAs (P > 0.05). Conclusions: These results suggest that increasing ADAs in the cancerous tissues may be beneficial for po-TACE in ameliorating the survival of patients with HCC. Original Article Fri, 01 Sep 2023 00:00:00 GMT LiyanHuang, QinqinLong, QunyingSu, XiaoyingZhu, XidaiLong, Fri, 01 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002167 https://www.explorationpub.com/Journals/etat/Article/1002164 Aim: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer. Methods: Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol. Results: All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase. Conclusions: Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity. Original Article Fri, 01 Sep 2023 00:00:00 GMT ZahraAzhar, Richard P.Grose, AfsheenRaza, ZohaibRaza, Fri, 01 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002164 https://www.explorationpub.com/Journals/etat/Article/1002165 Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC). Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context. Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors. Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations. Original Article Fri, 01 Sep 2023 00:00:00 GMT MelissaBersanelli, LetiziaGnetti, Francesco PaoloPilato, ElenaVarotti, FedericoQuaini, NicolettaCampanini, ElenaRapacchi, RobertaCamisa, PaoloCarbognani, Enrico MariaSilini, MicheleRusca, FrancescoLeonardi, UmbertoMaestroni, MimmaRizzo, MatteoBrunelli, SebastianoButi, LucaAmpollini, Fri, 01 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002165 https://www.explorationpub.com/Journals/etat/Article/1002166 Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression—most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors. Review Fri, 01 Sep 2023 00:00:00 GMT Diaaeldin I.Abdallah, Elvin D.de Araujo, Naman H.Patel, Lina S.Hasan, RichardMoriggl, Oliver H.Krämer, Patrick T.Gunning, Fri, 01 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002166 https://www.explorationpub.com/Journals/etat/Article/1002168 Aim: From the start of the pandemic, several aspects of healthcare policies changed, not least the clinical trials management from recruiting capabilities to the protocol compliance in terms of schedule of procedures, follow-up visits, staff constraints and monitoring. This study aims to assess the impact of the COronaVIrusDisease-2019 (COVID-19) pandemic in the conduction of clinical trials at the site of clinical oncology, Ancona (Italy), to identify the strengths and weaknesses upfront the past emergency, and to select better strategies for future similar situations. Methods: Data from February to July of the years 2019, 2020 and 2021 were collected and three practical parameters of the trial unit were investigated: milestones, performance, and impact. Results: The trials mean numbers were 18, 24, and 23, in 2019, 2020, and 2021 respectively. The pre-Site Initiation Visit (PRE-SIV) rate grew from 66.6% in 2019 to 95.5% in 2021 with a deflection in 2020. Protocol deviations were 40 in the period February-July 2019, in the same period of 2020 the number of deviations increased due to COVID related ones, then there was a significant total decrease in February-July 2021. In 2020 and 2021, all the investigator meetings were online. Conclusions: The growing number of remote Site Initiation Visit (SIV) and meetings over the last 3 years suggests the feasibility of the on-line processes. The significant reduction in protocol deviations during 2021 is probably due to an under check of data during a pandemic. But that is also a possible key indicator of the coping strategy made out by clinical oncology to guarantee the continuity of care in clinical trials and to offer new opportunities of cancer care in a bad scenario such as a pandemic one. Original Article Thu, 07 Sep 2023 00:00:00 GMT ZelmiraBallatore, AmaliaGoudas, FrancescoBozzi, AlessandraLucarelli, MichelaBurattini, GiuliaRicci, FrancescoSavino, RossanaBerardi, Thu, 07 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002168 https://www.explorationpub.com/Journals/etat/Article/1002169 Malignant tumors of the external auditory canal (EAC) are rare neoplasms that appear in the head and neck area. A common feature of these malignancies is their rarity, as well as their delayed diagnosis due to the appearance of non-specific symptoms that mimic various benign otologic conditions. The reported histological types of cancer of the external ear are: squamous cell carcinoma, basal cell carcinoma, malignant melanoma, Merkel cell carcinoma, angiosarcoma, adnexal carcinoma (including ceruminous adenocarcinoma and adenoid cystic carcinoma), and lymphoma (Lancet Oncol. 2005;6:411–20. doi: 10.1016/S1470-2045(05)70208-4). Several therapeutic interventions have been proposed, primarily orientated towards the cure of the patient, placing the surgical excision of the lesions at the tip of the spear. Subsequently and depending on the clinical stage and the pathological characteristics of the tumor, radiation, chemotherapy, a combination thereof, or some form of palliative treatment for particularly advanced cases, may be recommended. The aim of all the above-mentioned approaches is the complete resection of the mass with negative surgical margins along with lymph node dissection, the elimination of any residual disease or metastasis, and the improvement of survival. The anatomical complexity of the region will always remain a demanding challenge. Nevertheless, advances in the fields of ear microsurgery, imaging, radiation, molecular biology, and genomics have led to remarkable outcomes compared to the past, with a view to the patient’s quality of life. Large, well-organized, and prospective studies with the participation of multiple centers in contrast to existing retrospective studies with a limited number of patients will help to establish universally accepted guidelines. The exploration of the molecular and genetic background of these cancers in conjunction with the search for new biomarkers and target molecules seems promising for providing upgraded and more personalized treatment modalities for the future. Review Thu, 21 Sep 2023 00:00:00 GMT PinelopiSamara, MichaelAthanasopoulos, AnastasiosGoulioumis, IoannisAthanasopoulos, Thu, 21 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002169 https://www.explorationpub.com/Journals/etat/Article/1002171 Despite consistent progress in prompt diagnosis and curative therapies in the last decade, lung cancer (LC) continues to threaten mankind, accounting for nearly twice the casualties compared to prostate, breast, and other cancers. Statistics associate ~25% of 2021 cancer-related deaths with LC, more than 80% of which are explicitly caused by tobacco smoking. Prevailing as small and non-small cell pathologies, with respective occurring frequency of nearly 15% and 80–85%, non-small cell LCs (NSCLCs) are prominently distinguished into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes. Since the first use of epidermal growth factor receptor (EGFR) inhibitor gefitinib for NSCLC treatment in 2002, immense progress has been made for targeted therapies with the next generation of drugs spanning across the chronological generations of small molecule inhibitors. The last two years have overseen the clinical approval of more than 10 therapeutic agents as first-line NSCLC medications. However, uncertain mutational aberrations as well as systemic resistant responses, and abysmal overall survival curtail the combating efficacies. Of late, immune checkpoint inhibitors (ICIs) against various molecules including programmed cell death-1 (PD-1) and its ligand (PD-L1) have been demonstrated as reliable LC treatment targets. Keeping these aspects in mind, this review article discusses the success of NSCLC chemo and immunotherapies with their characteristic effectiveness and future perspectives. Review Wed, 11 Oct 2023 00:00:00 GMT ParthMalik, RumaRani, RaghuSolanki, Vishal HaribhaiPatel, Tapan KumarMukherjee, Wed, 11 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002171 https://www.explorationpub.com/Journals/etat/Article/1002172 Aim: Sarcopenia and skeletal muscle density (SMD) have been shown to be both predictive and prognostic marker in oncology. Advanced lung cancer inflammation index (ALI) has been shown to predict overall survival (OS) in small cell lung cancer (SCLC). Computed tomography (CT) enables skeletal muscle to be quantified, whereas body mass index (BMI) cannot accurately reflect body composition. The purpose was to evaluate the prognostic value of modified ALI (mALI) using CT-determined third lumbar vertebra (L3) muscle index beyond original ALI and see the interaction between sarcopenia, SMD, neutrophil-lymphocyte ratio (NLR), ALI and mALI at baseline and post 4 cycles of chemotherapy and their effects on OS and progress free survival (PFS) in patients with advanced non-SCLC (NSCLC). Methods: This retrospective study consisted of a total of 285 advanced NSCLC patients. The morphometric parameters such as SMD, skeletal muscle index (SMI) and fat-free mass (FFM) were measured by CT at the L3 vertebra. ALI was defined as BMI × serum albumin/NLR and mALI was defined as SMI × serum albumin/NLR. Results: Sarcopenia was observed in over 70% of patients across all BMI categories. Patients having sarcopenia suffered from a higher incidence of chemotherapeutic drug toxicities but this was not found to be statistically significant. Concordance was seen between ALI and mALI in the pre-treatment setting and this was statistically significant. A significant proportion of patients with poor ALI (90.9%), poor pre-chemotherapy mALI (91.3%) and poor post-chemotherapy mALI (89%) had poor NLR and each of them was statistically significant. Conclusions: In both univariate and multivariate analyses, this study demonstrated the statistical significance of sarcopenia, SMD, and mALI as predictive factors for OS. Additionally, sarcopenia and SMD were also found to be statistically significant factors in predicting PFS. These biomarkers could potentially help triage patients for active nutritional intervention for better outcomes. Original Article Wed, 11 Oct 2023 00:00:00 GMT AbhishekMahajan, DevendraGoyal, UjjwalAgarwal, VijayPatil, ShreyaShukla, VanitaNoronha, AmitJoshi, NandiniMenon, KumarPrabhash, Wed, 11 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002172 https://www.explorationpub.com/Journals/etat/Article/1002170 From attributing mutations to cancers with the advent of cutting-edge genetic technology in recent decades, to re-searching the age-old theory of intrinsic metabolic shift of cancers (Warburg’s glycolysis), the quest for a precise panacea for mainly the metastatic cancers, remains incessant. This review delineates the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway driven intricate oncogenic cues, budding from the metabolic (glycolytic) reliance of tumour cells, branching into metastatic emergence of malignancies. Strong AGE-RAGE concomitance in metastasis, chemo-resistance and cancer resurgence adversely incite disease progression and patient mortality. At the conjunction of metabolic and metastatic shift of cancers, are the “glycolytically” generated AGEs and AGE-activated RAGE, instigating aberrant molecular pathways, culminating in aggressive malignancies. AGEs as by-products of metabolic insurgence, modify the metabolome, epigenome and microbiome, besides coercing the inter-, intra- and extra-cellular micro-milieu conducive for oncogenic events like epithelial-mesenchymal transition (EMT). AGE-RAGE synergistically elicit ATP surge for surplus energy, autophagy for apoptotic evasion and chemo-resistance, insulin-like growth factor 1 (IGF-1) for meta-inflammation and angiogenesis, high mobility group box-1 (HMGB1) for immune tolerance, S100 proteins for metastasis, and p53 protein attenuation for tumour suppression. AGEs are pronouncedly reported in invasive forms of breast, prostate, colon and pancreatic cancers, higher in patients with cancer than healthy counterparts, and higher in advanced stage than localized phase. Hence, the investigation of person-specific presence of AGEs, soluble RAGE and AGE-activated RAGE can be advocated as impending bio-markers for diagnostic, prognostic and therapeutic purposes, to predict cancer risk in patients with diabetes, obesity, metabolic syndrome as well as general population, to monitor prognosis and metastasis in patients with cancer, and to reckon complications in cancer survivors. Furthermore, clinical reports of exogenous (dietary) and endogenous (internally formed) AGEs in cancer patients, and contemporary clinical trials involving AGE-RAGE axis in cancer are underlined with theranostic implications. Review Thu, 28 Sep 2023 00:00:00 GMT GowriPalanissami, Solomon F.D.Paul, Thu, 28 Sep 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002170 https://www.explorationpub.com/Journals/etat/Article/1002173 Breast cancer (BC) is a leading cause of cancer-related deaths in women worldwide where the process of metastasis is a major contributor to the mortality associated with this disease. Metastasis suppressor genes are a group of genes that play a crucial role in preventing or inhibiting the spread of cancer cells. They suppress the metastasis process by inhibiting colonization and by inducing dormancy. These genes function by regulating various cellular processes in the tumor microenvironment (TME), such as cell adhesion, invasion, migration, and angiogenesis. Dysregulation of metastasis suppressor genes can lead to the acquisition of an invasive and metastatic phenotype and lead to poor prognostic outcomes. The components of the TME generally play a necessary in the metastasis progression of tumor cells. This review has identified and elaborated on the role of a few metastatic suppressors associated with the TME that have been shown to inhibit metastasis in BC by different mechanisms, such as blocking certain cell signaling molecules involved in cancer cell migration, invasion, enhancing immune surveillance of cancer cells, and promoting the formation of a protective extracellular matrix (ECM). Understanding the interaction of metastatic suppressor genes and the components of TME has important implications for the development of novel therapeutic strategies to target the metastatic cascade. Targeting these genes or their downstream signaling pathways offers a promising approach to inhibiting the spread of cancer cells and improves patient outcomes. Review Thu, 12 Oct 2023 00:00:00 GMT Sathammai SathappaSupuramanian, SidDsa, SitaramHarihar, Thu, 12 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002173 https://www.explorationpub.com/Journals/etat/Article/1002174 Aim: Artificial intelligence (AI) is a new field of science in which computers will provide decisions-supporting tools to help doctors make difficult clinical choices. Recent AI applications in otolaryngology include head and neck oncology, rhinology, neurotology, and laryngology. The aim of this systematic review is to describe the potential uses of AI in head and neck oncology with a special focus on the surgical field. Methods: The authors performed a systematic review, in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, in the main medical databases, including PubMed, Scopus, and Cochrane Library, considering all original studies published until February 2023 about the role of AI in head and neck cancer surgery. The search strategy included a combination of the following terms: “artificial intelligence” or “machine learning” and “head and neck cancer”. Results: Overall, 303 papers were identified and after duplicate removal (12 papers) and excluding papers not written in English (1 paper) and off-topic (4 papers), papers were assessed for eligibility; finally, only 12 papers were included. Three main fields of clinical interest were identified: the most widely investigated included the role of AI in surgical margins assessment (7 papers); the second most frequently evaluated topic was complications assessment (4 papers); finally, only one paper dealt with the indication of salvage laryngectomy after primary radiotherapy. Conclusions: The authors report the first systematic review in the literature concerning the role of AI in head and neck cancer surgery. An increasing influx of AI applications to clinical problems in otolaryngology is expected, so specialists should be increasingly prepared to manage the constant changes. It will always remain critical for clinicians to use their skills and knowledge to critically evaluate the additional information provided by AI and make the final decisions on each patient. Systematic Review Wed, 25 Oct 2023 00:00:00 GMT AntonellaLoperfido, AlessandraCelebrini, AndreaMarzetti, GianlucaBellocchi, Wed, 25 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002174 https://www.explorationpub.com/Journals/etat/Article/1002175 Renal cell carcinoma (RCC) is one of the most life-threatening urinary malignancies displaying poor response to radiotherapy and chemotherapy. Although in the recent past there have been tremendous advancements in using targeted therapies for RCC, despite that it remains the most lethal urogenital cancer with a 5-year survival rate of roughly 76%. Timely diagnosis is still the key to prevent the progression of RCC into metastatic stages as well as to treat it. But due to the lack of definitive and specific diagnostic biomarkers for RCC and its asymptomatic nature in its early stages, it becomes very difficult to diagnose it. Reliable and distinct molecular markers can not only refine the diagnosis but also classifies the tumors into thier sub-types which can escort subsequent management and possible treatment for patients. Potential biomarkers can permit a greater degree of stratification of patients affected by RCC and help tailor novel targeted therapies. The review summarizes the most promising epigenetic [DNA methylation, microRNA (miRNA; miR), and long noncoding RNA (lncRNA)] and protein biomarkers that have been known to be specifically involved in diagnosis, cancer progression, and metastasis of RCC, thereby highlighting their utilization as non-invasive molecular markers in RCC. Also, the rationale and development of novel molecular targeted drugs and immunotherapy drugs [such as tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs)] as potential RCC therapeutics along with the proposed implication of these biomarkers in predicting response to targeted therapies will be discussed. Review Wed, 25 Oct 2023 00:00:00 GMT ShrutiGupta, Shamsher SinghKanwar, Wed, 25 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002175 https://www.explorationpub.com/Journals/etat/Article/1002176 A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications. Review Wed, 25 Oct 2023 00:00:00 GMT GeorgeAnderson, Wed, 25 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002176 https://www.explorationpub.com/Journals/etat/Article/1002177 The present coronavirus disease 2019 (COVID-19) pandemic scenario has posed a difficulty for cancer treatment. Even under ideal conditions, malignancies like small cell lung cancer (SCLC) are challenging to treat because of their fast development and early metastases. The treatment of these patients must not be jeopardized, and they must be protected as much as possible from the continuous spread of the COVID-19 infection. Initially identified in December 2019 in Wuhan, China, the contagious coronavirus illness 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finding inhibitors against the druggable targets of SARS-CoV-2 has been a significant focus of research efforts across the globe. The primary motivation for using molecular modeling tools against SARS-CoV-2 was to identify candidates for use as therapeutic targets from a pharmacological database. In the published study, scientists used a combination of medication repurposing and virtual drug screening methodologies to target many structures of SARS-CoV-2. This virus plays an essential part in the maturation and replication of other viruses. In addition, the total binding free energy and molecular dynamics (MD) modeling findings showed that the dynamics of various medications and substances were stable; some of them have been tested experimentally against SARS-CoV-2. Different virtual screening (VS) methods have been discussed as potential means by which the evaluated medications that show strong binding to the active site might be repurposed for use against SARS-CoV-2. Review Thu, 26 Oct 2023 00:00:00 GMT BabakSokouti, Thu, 26 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002177 https://www.explorationpub.com/Journals/etat/Article/1002178 Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5–6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment. Review Thu, 26 Oct 2023 00:00:00 GMT GerhardHamilton, SandraStickler, BarbaraRath, Thu, 26 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002178 https://www.explorationpub.com/Journals/etat/Article/1002179 Aim: Changes in strategies in the coronavirus disease 2019 (COVID-19) crisis and the imposing of restrictions have isolated many vulnerable patients including those with hepatocellular carcinoma (HCC) from routine medical care. This study investigated how the COVID-19 pandemic is affecting the diagnosis and treatment of HCC. Methods: An extensive search was conducted in the PubMed, Scopus, and Web of Science databases by using the appropriate keywords: COVID-19, hepatocellular carcinoma, hepatocellular cancer, and MeSH. Studies in English related to the purpose of the study were included in the analysis, and review studies, case reports, letters to editors, comments, and reports were excluded. The quality of the studies was assessed by the “Adapted Newcastle-Ottawa Quality Assessment Scales” checklist. The Endnote X7 software has been used for managing items. Results: The final qualitative analysis consisted of 27 articles. During the COVID-19 crisis, HCC diagnosis decreased from 20% to 34.13% compared to pre-crisis. The impact of the COVID-19 pandemic on HCC treatment encompasses a wide range of aspects. Generally, delays in treatment for patients with HCC ranged from more than one month for 21.5% of patients in France, to two months for 26% of patients in Italy, up to 30% in Austria, and 66.7% in Asia-Pacific countries. Conclusions: According to the findings, developing and implementing appropriate diagnostic and therapeutic strategies and developing low-cost and high-precision screening programs among high-risk populations seem to be effective in reducing the impact of the COVID-19 pandemic on HCC management. Systematic Review Thu, 26 Oct 2023 00:00:00 GMT AfroozMazidimoradi, SamaneSabet Birjandi, HamidSalehiniya, Thu, 26 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002179 https://www.explorationpub.com/Journals/etat/Article/1002180 Aim: This study aimed to establish a learning system using an artificial neural network (ANN) to predict the effects of vitamin D supplementation on the serum levels of vitamin D, inflammatory factors, and total antioxidant capacity (TAC) in women with breast cancer. Methods: The data set of the current project was created from women with breast cancer who were referred to the Shafa State Hospital of Patients with Cancers in Ahvaz city, Iran. Modeling was implemented using the data set at the serum levels of vitamin D, tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β), and TAC, before and after vitamin D3 supplement therapy. A prediction ANN model was designed to detect the effects of vitamin D3 supplementation on the serum level changes of vitamin D, inflammatory factors and TAC. Results: The results showed that the ANN model could predict the effect of vitamin D3 supplementation on the serum level changes of vitamin D, TNF-α, TGF-β1, and TAC with an accuracy average of 85%, 40%, 89.5%, and 88.1%, respectively. Conclusions: According to the findings of the study, the ANN method could accurately predict the effect of vitamin D3 supplementation on the serum levels of vitamin D, TNF-α, TGF-β1, and TAC. The results showed that the proposed ANN method can help specialists to improve the treatment process more confidently in terms of time and accuracy of predicting the influence of vitamin D supplementation on the factors affecting the progression of breast cancer (https://www.irct.ir/ identifier: IRCT2015090623924N1). Original Article Mon, 30 Oct 2023 00:00:00 GMT MarziehTahmasebi, MasoudVeissi, Seyed AhmadHosseini, AmirJamshidnezhad, Mon, 30 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002180 https://www.explorationpub.com/Journals/etat/Article/1002181 Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico. Review Tue, 31 Oct 2023 00:00:00 GMT ChristosLadias, PavlosPapakotoulas, MariaPapaioannou, Nikolaos A.Papanikolaou, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002181 https://www.explorationpub.com/Journals/etat/Article/1002182 Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality. Review Tue, 31 Oct 2023 00:00:00 GMT AbrahamsOcanto, XabierMielgo-Rubio, JavierLuna Tirado, NuriaLinares Mesa, MartaLópez Valcárcel, SaraPedraza, Victoria VeraBarragan, Patricia ValenciaNieto, Juan ZafraMartín, FelipeCouñago, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002182 https://www.explorationpub.com/Journals/etat/Article/1002183 Aim: Coronavirus disease 2019 (COVID-19) became pandemic on 11th March 2020 and it deeply stressed the healthcare system. Cancer patients represent a vulnerable population, so many recommendations have been approved to ensure optimal management. Clinical research was notably impacted by COVID too. This review aims to analyze the challenges occurred during a pandemic for the management of enrolled patients (enrollment, use of telemedicine visits, study procedures) and for the clinical trials system (from feasibility to selection visit, site initiation visit, monitorings, use of e-signature, deviations and discontinuations). Methods: The studies included in the present review were selected from PubMed/Google Scholar/ScienceDirect databases. Results: During the first phase of pandemic many clinical trials were suspended in accrual and, as the pandemic progressed, recommendations were established to guarantee the safety and the continuity of care of enrolled patients. In addition, lot of new strategies was found during the pandemic to reduce the negative consequences on clinical trial performance and to guarantee new opportunities of care in the respect of good clinical practice (GCP) in a bad scenario. Conclusions: Among all modifiers, investigators would prefer to maintain the positive ones such as pragmatic and simplified trial designs and protocols, reducing in-person visits when not necessary and to minimizing sponsor and contract research organizations (CROs) visits. Systematic Review Tue, 31 Oct 2023 00:00:00 GMT VeronicaAgostinelli, ZelmiraBallatore, GiuliaRicci, AlessandraLucarelli, MichelaBurattini, LorenzoMariotti, ClaudiaCatani, ValentinaTarantino, RossanaBerardi, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002183 https://www.explorationpub.com/Journals/etat/Article/1002184 Aim: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival. Methods: Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient. Results: Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival. Conclusions: A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects. Original Article Tue, 31 Oct 2023 00:00:00 GMT LeviArnold, Juan PinedaGomez, MichaelBarry, MarrionYap, LauraJackson, ThucLy, DavidStanding, Subhash B.Padhye, BernhardBiersack, ShrikantAnant, Sufi MaryThomas, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002184 https://www.explorationpub.com/Journals/etat/Article/1002185 Many human cancers carry missense mutations in or deletions of the tumor protein 53 (TP53) tumor suppressor gene. TP53’s product, p53 regulates many biological processes, including cell metabolism. Cholesterol is a key lipid needed for the maintenance of membrane function and tissue homeostasis while also serving as a precursor for steroid hormone and bile acid synthesis. An over-abundance of cholesterol can lead to its esterification and storage as cholesterol esters. The recent study has shown that the loss of p53 leads to excessive cholesterol ester biosynthesis, which promotes hepatocellular carcinoma in mice. Blocking cholesterol esterification improves treatment outcomes, particularly for liver cancers with p53 deletions/mutations that originate in a background of non-alcoholic fatty liver disease. Perspective Tue, 31 Oct 2023 00:00:00 GMT YoujunLi, MichaelKarin, Edward V.Prochownik, Tue, 31 Oct 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002185 https://www.explorationpub.com/Journals/etat/Article/1002186 On Feb 2, 2022, Nature published the paper titled “Decade-long leukemia remissions with the persistence of CD4+ CAR T-cells” (Nature. 2022;602:503–9. doi: 10.1038/s41586-021-04390-6). According to the results presented, it could be argued that “chimeric antigen receptor (CAR) T-cells can actually cure patients with chronic lymphocytic leukemia (CLL)”. CAR T-cells remained detectable more than ten years after infusion, and immunoglobulin heavy chain (IGH) rearrangement deep sequencing showed persistent deep molecular remission for both patients (no CLL clonotypes were detectable six months after CAR T-cell infusion and onwards). However, the existing actual disease status of both patients remained unclear, as it was unknown: (1) if CAR T-cells killed all leukemia cells during the initial anti-leukemic response phase, that is, soon after CAR T-cell infusion into both patients; (2) if few CLL cells survived, but persistent CAR T-cells had been able to destroy any leukemia cells before they reach detectable levels. In the first case, both patients could be considered definitely cured; in the second not and their decade-prolonged deep remission could be a consequence of the cytotoxic activity of the functionally active CD4+ CAR T-cells. The first version appears to be stronger and the supporting arguments have been included in a comprehensive commentary article. A new therapeutic intervention may emerge with the potential to fully improve the quality of life of both patients and in addition, ongoing research into CAR T-cells may turn in a new, more effective direction. Commentary Wed, 01 Nov 2023 00:00:00 GMT DimitriosBouzianas, StellaBouziana, Wed, 01 Nov 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002186 https://www.explorationpub.com/Journals/etat/Article/1002187 Aim: This article is based on our previous research, which was presented as a post at the Congress Aiom 2022 Congress and published in Tumori Journal as Conference Abstract (Tumori J. 2022;108:1–194. doi: 10.1177/03008916221114500). In this paper, a comprehensive presentation of all the achieved results is provided. Several tyrosine kinase inhibitors (TKIs) have been investigated to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, direct comparisons between these TKIs are lacking, with many only being compared to crizotinib. To address this gap, a network meta-analysis was conducted to compare the efficacy and safety of various first-line systemic therapies for ALK-positive NSCLC. Methods: A thorough search of PubMed, Embase, and Cochrane Library was performed to identify randomized controlled trials (RCTs) published between January 01, 2000 and April 01, 2022, and included trials that investigated upfront treatments for this molecular subgroup and reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher (grade ≥ 3 AEs). Results: The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Second and third-generation TKIs significantly prolonged PFS compared to crizotinib, with lorlatinib having the highest probability of yielding the most favorable PFS, followed by alectinib (300 mg or 600 mg). However, only alectinib has been shown to significantly prolong OS compared to crizotinib to date. Lorlatinib appears superior in reducing the risk of central nervous system (CNS) progression, followed by alectinib 600 mg. Ceritinib had the highest rate of AEs, followed by lorlatinib and brigatinib. Conclusions: Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile. Meta-Analysis Fri, 01 Dec 2023 00:00:00 GMT MarcoFiletti, PasqualeLombardi, RosaFalcone, RaffaeleGiusti, DianaGiannarelli, AntonellaCarcagnì, ValeriaAltamura, GiovanniScambia, GennaroDaniele, Fri, 01 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002187 https://www.explorationpub.com/Journals/etat/Article/1002188 Aim: The present study aims to generate chimeric mouse single-chain variable fragment (scFv) and immunoglobulin G1 (IgG1) crystallizable fragment (Fc) antibody against disialoganglioside (GD2) for the treatment of neuroblastoma (NB). The generated scFv-IgG Fc antibody, lacking first constant domain of heavy chain (CH1), is of a smaller size than the natural antibody and has anti-tumor activity. Methods: Vector for scFv-IgG Fc antibody was constructed and scFv-IgG Fc antibody was expressed in human embryonic kidney 293T (HEK293T) cell line. Purification of scFv-IgG Fc antibody from the culture supernatant of transfected HEK293T cells was performed by Protein G affinity chromatography. The structure and binding activity of scFv-IgG Fc antibody were verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting (WB), and immunofluorescence techniques. Anti-tumor activities by antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were determined. Results: Using plasmid fusion-human IgG1-Fc2 tag vector (pFUSE-hIgG1-Fc2), a plasmid vector encoding chimeric mouse scFv and hIgG1 Fc antibody against GD2 was successfully constructed. This vector was transfected into human HEK293T cells to produce scFv-IgG Fc antibody. The transfected HEK293T cells could produce chimeric scFv-IgG Fc antibody against GD2, which lacks the IgG heavy chain CH1 domain but carries CH2 and CH3 domains. The chimeric antibodies could be purified from the culture supernatant of the transfected HEK293T culture in the presence of zeocin drug. The produced GD2 scFv-IgG Fc antibodies, which are smaller in size than the intact antibody, could trigger the killing of GD2 expressed NB cell line SH-SY5Y by ADCC and ADCP mechanisms. Conclusions: The results indicate that chimeric scFv-hIgG Fc antibody, lacking heavy chain CH1 domain, could mediate antibody induced anti-tumor activities. The small size of this type of chimeric antibody may be employed as anti-GD2 antibody for NB therapy. Original Article Wed, 06 Dec 2023 00:00:00 GMT WitidaLaopajon, NuchjiraTakheaw, KamonpornKotemul, SupansaPata, SuradejHongeng, WatcharaKasinrerk, Wed, 06 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002188 https://www.explorationpub.com/Journals/etat/Article/1002189 Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs. The efficacy of this approach is explained by the ability of bevacizumab to eliminate immature blood vessels thus normalizing intratumoral blood flow and improving the delivery of cytotoxic or targeted agents. This report describes four cases of heavily pretreated patients with metastatic HER2-positive breast cancer, who had no meaningful treatment options left, and who received single-agent bevacizumab as an empirical last-resort therapy. Three of these patients had severe complaints, and they demonstrated striking symptomatic relief within the first day of this treatment. In addition to the observed “Lazarus response”, which was likely attributed to the bevacizumab-driven resolution of edema, some evidence of a direct antitumor effect was observed. These data may call for the reconsideration of bevacizumab monotherapy in patients with HER2-associated breast cancer, and perhaps in some other categories of cancer patients. Case Report Wed, 06 Dec 2023 00:00:00 GMT Alexey V.Emshanov, Denis V.Nesterov, Tatyana N.Sokolova, Priscilla S.Amankwah, Evgeny N.Imyanitov, Wed, 06 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002189 https://www.explorationpub.com/Journals/etat/Article/1002190 Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity. Review Mon, 11 Dec 2023 00:00:00 GMT ZhengwangGuo, ShuyanHan, Mon, 11 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002190 https://www.explorationpub.com/Journals/etat/Article/1002191 Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown impressive results in EGFR mutant lung cancer (LC) patients in terms of disease control rate with a positive impact on overall survival. Nevertheless, after months of treatment with targeted therapy, progression inevitably occurs. Some patients develop oligoprogression and local treatment is required for optimal disease control while maintaining EGFR-TKIs. This work features a clinical case of a patient harboring an EGFR mutant LC undergoing oligoprogression to EGFR-TKIs, first into the brain and afterward to the primary tumor, requiring local ablative strategies, including primary tumor resection three years after the start of osimertinib. Currently, the patient is still alive and continues with a complete response upon EGFR-TKIs maintenance. Hence, oligoprogression, even in driven oncogenic tumors, represents a distinct biological entity and potential curative disease that deserves particular consideration in multidisciplinary tumor boards. In this case, tumor primary resection after three years of the initial diagnosis represents a paradigm shift in the treatment of EGFR mutant patients. Case Report Wed, 13 Dec 2023 00:00:00 GMT SviatoslavChekhun, AssumpcióLopez-Paradís, AintzaneUrbizu, TeresaMorán, AnabelMañes, MarcCucurull, CarlosMartínez-Barenys, IrisTeruel, GloriaMoragas, EnricCarcereny, Ana MariaMuñoz Mármol, MariaSaigí, Wed, 13 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002191 https://www.explorationpub.com/Journals/etat/Article/1002192 Aim: It is important to identify anti-cancer compounds that can inhibit specific molecular targets to eradicate androgen-receptor negative (ARneg), androgen-independent (AI) prostate cancer, which is an aggressive form of prostate cancer with limited treatment options. The goal of this study was to selectively target prostate cancer cells that have high levels of oncogenic protein Receptor tyrosine kinase-like orphan receptor 1 (ROR1) by using strictinin, a small molecule ROR1 inhibitor. Methods: The methods performed in this study include western blots, methyl thiazolyl tetrazolium (MTT) proliferation assays, phosphatidylserine apoptosis assays, apoptosis flow cytometry (Annexin V, caspase 3/7), migration scratch assays, Boyden chamber invasion assays, and cell cycle flow cytometry. Results: Strictinin was most lethal against PC3 [half-maximal drug inhibitory concentration (IC50) of 277.2 µmol/L], an ARneg-AI cell type that expresses the highest levels of ROR1. Strictinin inhibited ROR1 expression, downstream phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-glycogen synthase kinase 3beta (GSK3β) pro-survival signaling, and epithelial-to-mesenchymal transition markers in PC3 cells. Additionally, strictinin decreased PC3 cell migration and invasion, while increasing S-phase cell cycle arrest. In ARneg-AI DU145 cells, strictinin inhibited ROR1 expression and modulated downstream AKT-GSK3β signaling. Furthermore, strictinin exhibited anti-migratory, anti-invasive, but minimal pro-apoptotic effects in DU145 cells likely due to DU145 having less ROR1 expression in comparison to PC3 cells. Throughout the study, strictinin minimally impacted the phenotype of normal prostatic epithelial cells RWPE-1 (IC50 of 658.5 µmol/L). Strictinin was further identified as synergistic with docetaxel [combination index (CI) = 0.311] and the combination therapy was found to reduce the IC50 of strictinin to 38.71 µmol/L in PC3 cells. Conclusions: ROR1 is an emerging molecular target that can be utilized for treating prostate cancer. The data from this study establishes strictinin as a potential therapeutic agent that targets ARneg-AI prostate cancer with elevated ROR1 expression to reduce the migration, invasion, cell cycle progression, and survival of prostate cancer. Original Article Thu, 21 Dec 2023 00:00:00 GMT VigneshSivaganesh, BelaPeethambaran, Thu, 21 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002192 https://www.explorationpub.com/Journals/etat/Article/1002193 Aim: In response to DNA damage the serine/threonine-specific protein kinase checkpoint kinase 1 (CHK1) is activated allowing cells to enter S phase (S) and G2 phase (G2) cell-cycle arrest. CHK1 inhibitors are expected to prevent cells from entering such arrest, thereby enhancing DNA damage-induced cytotoxicity. In contrast, normal cells with intact ataxia–telangiectasia mutated (ATM), CHK2 and tumour suppressor protein 53 (P53) signalling are still able to enter cell-cycle arrest using the functioning G1/S checkpoint, thereby being rescued from enhanced cytotoxicity. The main objective of this work is to investigate the in vitro effects of the novel CHK1 inhibitor SRA737 on pairs of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines, all with genetic aberrations rendering them susceptible to replication stress but of differing tumour protein 53 (TP53) gene status, focusing on DNA damage induction and the subsequent effects on cell proliferation and viability. Methods: NSCLC cell lines H23 [TP53 mutant (MUT)] and A549 [TP53 wild-type (WT)] and CRC cell lines HT29 (TP53 MUT) and HCT116 (TP53 WT) were incubated with differing micromolar concentrations of SRA737 for 24 h and then analysed using alkaline comet and phosphorylated H2A.X variant histone (γH2AX)-foci assays to assess mostly DNA single strand break and double strand break damage, respectively. Cell-counting/trypan blue staining was also performed to assess cell proliferation/viability. Results: Clear concentration-dependent increases in comet formation and γH2AX-foci/cell were noted for the TP53 MUT cells with no or lower increases being noted in the corresponding TP53 WT cells. Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. Conclusions: This study’s data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress. Original Article Thu, 21 Dec 2023 00:00:00 GMT Ali JNDuabil, Christian RCooper, EsraaAldujaily, Sarah ERHalford, SandraHirschberg, Sidath DKatugampola, George DDJones, Thu, 21 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002193 https://www.explorationpub.com/Journals/etat/Article/1002194 A generalized therapeutic strategy for various disease conditions, including cancer, is to deplete or inactivate harmful protein targets. Various forms of protein or gene silencing molecules, e.g., small molecule inhibitors, RNA interference (RNAi), and microRNAs (miRNAs) have been used against druggable targets. Over the past few years, targeted protein degradation (TPD) approaches have been developed for direct degradation of candidate proteins. Among the TPD approaches, proteolysis targeting chimeras (PROTACs) have emerged as one of the most promising approaches for the selective elimination of proteins via the ubiquitin-proteasome system. Other than PROTACs, TPD methods with potential therapeutic use include intrabody-mediated protein knockdown and tripartite motif-21 (TRIM-21) mediated TRIM-Away. In this review, protein knockdown approaches, their modes of action, and their advantages over conventional gene knockdown approaches are summarized. In cancers, disease-associated protein functions are often executed by specific post-translational modifications (PTMs). The role of TRIM-Away is highlighted in the direct knockdown of PTM forms of target proteins. Moreover, the application challenges and the prospective clinical use of TPD approaches in various diseases are also discussed. Review Tue, 26 Dec 2023 00:00:00 GMT MansiJoshi, PranayDey, AbhijitDe, Tue, 26 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002194 https://www.explorationpub.com/Journals/etat/Article/1002195 Breast cancer (BC) is the second most diagnosed cancer in 2018 with around 2.3 million cases globally in 2020. In March 2020 and after its worldwide spread, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) outbreak, a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, a pandemic. During this time, cancer patients were heavily impacted and their treatment plans were changed due to measures to fight the disease and solutions had to be found to maintain their follow-up and management from a distance. Some cancer groups worldwide have recommended then the use of telemedicine for oncology patients to ensure the continuity of medical care during the pandemic. This method was considered effective and clinicians worldwide continued using telehealth even after the cessation of worldwide restrictions. To this end, current up-to-date data on the use of telemedicine in BC patient after the COVID-19 outbreak are summarized in this narrative review. Review Wed, 27 Dec 2023 00:00:00 GMT JeanZeghondy, ElieRassy, PietroLapidari, RolandEid, BarbaraPistilli, Wed, 27 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002195 https://www.explorationpub.com/Journals/etat/Article/1002196 Cells need to adapt their activities to extra- and intracellular signalling cues. To translate a received extracellular signal, cells have specific receptors that transmit the signal to downstream proteins so that it can reach the nucleus to initiate or repress gene transcription. Post-translational modifications (PTMs) of proteins are reversible or irreversible chemical modifications that help to further modulate protein activity. The most commonly observed PTMs are the phosphorylation of serine, threonine, and tyrosine residues, followed by acetylation, glycosylation, and amidation. In addition to PTMs that involve the modification of a certain amino acid (phosphorylation, hydrophobic groups for membrane localisation, or chemical groups like acylation), or the conjugation of peptides (SUMOylation, NEDDylation), structural changes such as the formation of disulphide bridge, protein cleavage or splicing can also be classified as PTMs. Recently, it was discovered that metabolites from the tricarboxylic acid (TCA) cycle are not only intermediates that support cellular metabolism but can also modify lysine residues. This has been shown for acetate, succinate, and lactate, among others. Due to the importance of mitochondria for the overall fitness of organisms, the regulatory function of such PTMs is critical for protection from aging, neurodegeneration, or cardiovascular disease. Cancer cells and activated immune cells display a phenotype of accelerated metabolic activity known as the Warburg effect. This metabolic state is characterised by enhanced glycolysis, the use of the pentose phosphate pathway as well as a disruption of the TCA cycle, ultimately causing the accumulation of metabolites like citrate, succinate, and malate. Succinate can then serve as a signalling molecule by directly interacting with proteins, by binding to its G protein-coupled receptor 91 (GPR91) and by post-translationally modifying proteins through succinylation of lysine residues, respectively. This review is focus on the process of protein succinylation and its importance in health and disease. Review Wed, 27 Dec 2023 00:00:00 GMT Katharina F.Kubatzky, YueGao, DayoungYu, Wed, 27 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002196 https://www.explorationpub.com/Journals/etat/Article/1002197 Irrespective of men and women, colorectal cancer (CRC), is the third most common cancer in the population with more than 1.85 million cases annually. Fewer than 20% of patients only survive beyond five years from diagnosis. CRC is a highly preventable disease if diagnosed at the early stage of malignancy. Several screening methods like endoscopy (like colonoscopy; gold standard), imaging examination [computed tomographic colonography (CTC)], guaiac-based fecal occult blood (gFOBT), immunochemical test from faeces, and stool DNA test are available with different levels of sensitivity and specificity. The available screening methods are associated with certain drawbacks like invasiveness, cost, or sensitivity. In recent years, computer-aided systems-based screening, diagnosis, and treatment have been very promising in the early-stage detection and diagnosis of CRC cases. Artificial intelligence (AI) is an enormously in-demand, cost-effective technology, that uses various tools machine learning (ML), and deep learning (DL) to screen, diagnose, and stage, and has great potential to treat CRC. Moreover, different ML algorithms and neural networks [artificial neural network (ANN), k-nearest neighbors (KNN), and support vector machines (SVMs)] have been deployed to predict precise and personalized treatment options. This review examines and summarizes different ML and DL models used for therapeutic intervention in CRC cancer along with the gap and challenges for AI. Review Wed, 27 Dec 2023 00:00:00 GMT KritiDas, MaanviPaltani, Pankaj KumarTripathi, RajnishKumar, SaniyaVerma, SubodhKumar, Chakresh KumarJain, Wed, 27 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002197 https://www.explorationpub.com/Journals/etat/Article/1002198 Pembrolizumab combined with chemotherapy has been established as the preferred first-line therapy for treating metastatic triple-negative breast cancer (mTNBC) with programmed cell death ligand-1 (PD-L1)-positive disease since its approval for that indication. However, the optimal sequencing of therapy remains an unanswered question for a subset of mTNBC patients who harbor germline breast cancer gene 1/2 (BRCA1/2; gBRCA1/2) mutation. This article aims to offer insights into the optimal therapy sequencing for mTNBC patients with gBRCA1/2 mutations and its impact on clinical decision-making. The perspective offered is based on the best currently available data and propose a practical algorithm to guide the management of this subgroup in the frontline setting. Perspective Thu, 28 Dec 2023 00:00:00 GMT SabahAlaklabi, Arya MariamRoy, Lubna N.Chaudhary, ShipraGandhi, Thu, 28 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002198 https://www.explorationpub.com/Journals/etat/Article/1002199 Cholangiocarcinoma (CCA) is a highly aggressive type of adenocarcinoma distinguished by its invasiveness. Depending on specific anatomical positioning within the biliary tree, CCA can be categorized into intrahepatic CCA (ICCA), perihilar CCA (pCCA) and distal CCA (dCCA). In recent years, there has been a significant increase in the global prevalence of CCA. Unfortunately, many CCA patients are diagnosed at an advanced stage, which makes surgical resection impossible. Although systemic chemotherapy is frequently used as the primary treatment for advanced or recurrent CCA, its effectiveness is relatively low. Therefore, immunotherapy has emerged as a promising avenue for advancing cancer treatment research. CCA exhibits a complex immune environment within the stromal tumor microenvironment (TME), comprising a multifaceted immune landscape and a tumor-reactive stroma. A deeper understanding of this complex TME is indispensable for identifying potential therapeutic targets. Thus, targeting tumor immune microenvironment holds promise as an effective therapeutic strategy. Review Thu, 28 Dec 2023 00:00:00 GMT ChaoqunLi, LeiBie, MuhuaChen, JieerYing, Thu, 28 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002199 https://www.explorationpub.com/Journals/etat/Article/1002200 Aim: While the traditional use of Cola rostrata in treating illnesses and diseases has not been reported, the presence of cytotoxic principles has been reported in phylogenetically and biogeographically related species within the Cola genus. This study, therefore, evaluated the cytotoxic potential of extracts of the plant, and the associated cellular and molecular mechanisms. Methods: Activity-based fractionation of the extracts was carried out and cytotoxicity was assessed in the human cervical cancer cell line, HeLa, and the transformed human lung cell line, MRC5-SV2, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay complemented with brightfield imaging. The 2ʼ,7ʼ-dichlorofluorescein diacetate (DCFDA) assay was used to assess induction of cellular reactive oxygen species (ROS), while flow cytometry of 5,5ʼ,6,6ʼ-tetrachloro-1,1ʼ,3,3ʼ-tetraethyl-imidacarbocyanine iodide (JC-1)-stained cells assessed the loss of mitochondrial membrane potential (∆ΨM). Gas chromatography-mass spectrometry (GC-MS) analysis was carried out on an active fraction. Results: Extracts of the fruit epicarp and leaf were cytotoxic against the cell lines. Half-maximal inhibitory concentration (IC50) values for the 48 h cytotoxicity of the ethanol extract of the epicarp against HeLa and MRC5-SV2 cells were 48.0 μg/mL ± 12.1 μg/mL and 40.4 μg/mL ± 7.2 μg/mL, respectively, while fractions from second-level partitioning of the hexane fraction of the leaf extract elicited cytotoxicity with IC50 values ranging from 12.8 μg/mL ± 1.0 μg/mL to 39.6 μg/mL ± 7.2 μg/mL in both cell lines, following 48 h treatment. GC-MS revealed the presence of seventeen compounds in a hexane fraction of the leaf extract, including even- and odd-chain fatty acids, the most abundant of which were n-hexadecanoic acid, decanoic acid 10-(2-hexylcyclopropyl); and octadecanoic acid. The mechanisms of cytotoxicity of most active fractions involved generation of ROS and mitochondrial membrane depolarisation. Conclusions: The findings show that C. rostrata is rich in cytotoxic phytochemicals which could be isolated for developing new anti-cancer agents. Original Article Fri, 29 Dec 2023 00:00:00 GMT Babatunde E.Ajayi, BolaOboh, Joseph B.Minari, Darren W.Sexton, Satyajit D.Sarker, Amos A.Fatokun, Fri, 29 Dec 2023 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002200 https://www.explorationpub.com/Journals/etat/Article/1002201 Aim: Breast cancer (BC) is the most common cancer in women worldwide, where adiposity has been linked to BC morbidity. In general, obese premenopausal women diagnosed with triple-negative BC (TNBC) tend to have larger tumours with more metastases, particularly to the bone marrow, and worse prognosis. Previous work using a 3-dimensional (3D) co-culture system consisting of TNBC cells, adipocytes and the laminin-rich extracellular matrix (ECM) trademarked as Matrigel, demonstrated that adipocytes and adipocyte-derived conditioned media (CM) caused a partial mesenchymal-to-epithelial transition (MET). Given that MET has been associated with secondary tumour formation, this study sought to identify molecular mediators responsible for this phenotypic change. Methods: Adipocytes were cultured with and without Matrigel, where semi-quantitative proteomics was used to identify proteins whose presence in the CM was induced or enhanced by Matrigel, which were referred to as adipocyte-secreted ECM-induced proteins (AEPs). The AEPs identified were assessed for association with prognosis in published proteomic datasets and prior literature. Of these, 4 were evaluated by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), followed by a functional and MET marker analysis of 1 AEP on MDA-MB-231 cells grown on Matrigel or as monolayers. Results: The 4 AEPs showed a positive correlation between protein expression and poor prognosis. RT-qPCR analysis reported no significant change in AEPs mRNA expression. However, lysyl oxidase (LOX) was increased in CM of ECM-exposed adipocytes. Recombinant LOX (rLOX) caused the mesenchymal MDA-MB-231 TNBC cells to form less branched 3D structures and reduced the expression of vimentin. Conclusions: The data suggest that adipocyte-secreted LOX changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumour formation, particularly at sites high in adipocytes such as the bone marrow. Future efforts should focus on determining whether targeting LOX could reduce BC metastasis in obese individuals. Original Article Tue, 16 Jan 2024 00:00:00 GMT Cassidy M.Van Stiphout, GrantKelly, Nikitha K.Pallegar, EmanElbakry, Ana ValeriaVilchis-Celis, Sherri L.Christian, Alicia M.Viloria-Petit, Tue, 16 Jan 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002201 https://www.explorationpub.com/Journals/etat/Article/1002202 Pancreatic cancer remains a serious and deadly disease, impacting people globally. There remain prominent gaps in the current understanding of the disease, specifically regarding the role of the signal transducer and activator of transcription (STAT) family of proteins in pancreatic tumors. STAT proteins, particularly STAT3, play important roles in pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent histotype. The role of STAT3 across a continuum of molecular processes, such as PDAC tumorigenesis and progression, immune escape, drug resistance and stemness, and modulation of the tumor microenvironment (TME), are only a tip of the iceberg. In some ways, the role of STAT3 in PDAC may hold greater importance than that of oncogenic Kirsten rat sarcoma virus (KRAS). This makes STAT3 a highly attractive target for developing targeted therapies for the treatment of pancreatic cancer. In this review, the current knowledge of STAT3 in pancreatic cancer has been summarized, particularly relating to STAT3 activation in cancer cells, cells of the TME, and the state of targeting STAT3 in pre-clinical and clinical trials of PDAC. Review Wed, 17 Jan 2024 00:00:00 GMT ZacharyHamel, SierraSanchez, DavidStanding, ShrikantAnant, Wed, 17 Jan 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002202 https://www.explorationpub.com/Journals/etat/Article/1002203 Colorectal cancer (CRC) is a multifaceted disease influenced by the interplay of genetic and environmental factors. The clinical heterogeneity of CRC cannot be attributed exclusively to genetic diversity and environmental exposures, and epigenetic markers, especially DNA methylation, play a critical role as key molecular markers of cancer. This review compiles a comprehensive body of evidence underscoring the significant involvement of DNA methylation modifications in the pathogenesis of CRC. Moreover, this review explores the potential utility of DNA methylation in cancer diagnosis, prognostics, assessment of disease activity, and prediction of drug responses. Recognizing the impact of DNA methylation will enhance the ability to identify distinct CRC subtypes, paving the way for personalized treatment strategies and advancing precision medicine in the management of CRC. Review Mon, 29 Jan 2024 00:00:00 GMT JingxinYe, JianfengZhang, WeifengDing, Mon, 29 Jan 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002203 https://www.explorationpub.com/Journals/etat/Article/1002204 Aim: Triple-negative breast cancer (TNBC) is a very aggressive subset of breast cancer, with limited treatment options, due to the lack of three commonly targeted receptors, which merits the need for novel treatments for TNBC. Towards this need, the use of metformin (Met), the most widely used type-2 diabetes drug worldwide, was explored as a repurposed anticancer agent. Cancer being a metabolic disease, the modulation of two crucial metabolites, glucose, and reactive oxygen species (ROS), is studied in MDA-MB-231 TNBC cells, using Met in the presence of electrical pulses (EP) to enhance the drug efficacy. Methods: MDA-MB-231, human TNBC cells were treated with Met in the presence of EP, with various concentrations Met of 1 mmol/L, 2.5 mmol/L, 5 mmol/L, and 10 mmol/L. EP of 500 V/cm, 800 V/cm, and 1,000 V/cm (with a pulse width of 100 µs at 1 s intervals) were applied to TNBC and the impact of these two treatments was studied. Various assays, including cell viability, microscopic inspection, glucose, ROS, and wound healing assay, were performed to characterize the response of the cells to the combination treatment. Results: Combining 1,000 V/cm with 5 mmol/L Met yielded cell viability as low as 42.6% at 24 h. The glucose level was reduced by 5.60-fold and the ROS levels were increased by 9.56-fold compared to the control, leading to apoptotic cell death. Conclusions: The results indicate the enhanced anticancer effect of Met in the presence of electric pulses. The cell growth is inhibited by suppressing glucose levels and elevated ROS. This shows a synergistic interplay between electroporation, Met, glucose, and ROS metabolic alterations. The results show promises for combinational therapy in TNBC patients. Original Article Mon, 19 Feb 2024 00:00:00 GMT PraveenSahu, Ignacio G.Camarillo, RajiSundararajan, Mon, 19 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002204 https://www.explorationpub.com/Journals/etat/Article/1002299 Pancreatic cancer is a challenging disease with limited treatment options and a high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features and mutational status represent important obstacles in the improvement of survival outcomes. Up to now, first-line therapy did achieve a median overall survival of less than 12 months and this discouraging data lead clinicians all over the world to focus their efforts on various fields of investigation: 1) sequential cycling of different systemic therapy in order to overcome mechanisms of resistance; 2) discovery of new predictive bio-markers, in order to target specific patient population; 3) combination treatment, in order to modulate the tumor microenvironment of pancreatic cancer; 4) new modalities of the delivery of drugs in order to pass the physical barrier of desmoplasia and tumor stroma. This review shows future directions of treatment strategies in advanced pancreatic cancer through a deep analysis of these recent macro areas of research. Review Tue, 18 Mar 2025 00:00:00 GMT VittoreCereda, Mario RosarioD’Andrea, Tue, 18 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002299 https://www.explorationpub.com/Journals/etat/Article/1002205 Aim: To investigate magnetic resonance imaging (MRI)-based peritumoral texture features as prognostic indicators of survival in patients with colorectal liver metastasis (CRLM). Methods: From 2007–2015, forty-eight patients who underwent MRI within 3 months prior to initiating treatment for CRLM were identified. Clinicobiological prognostic variables were obtained from electronic medical records. Ninety-four metastatic hepatic lesions were identified on T1-weighted post-contrast images and volumetrically segmented. A total of 112 radiomic features (shape, first-order, texture) were derived from a 10 mm region surrounding each segmented tumor. A random forest model was applied, and performance was tested by receiver operating characteristic (ROC). Kaplan-Meier analysis was utilized to generate the survival curves. Results: Forty-eight patients (male:female = 23:25, age 55.3 years ± 18 years) were included in the study. The median lesion size was 25.73 mm (range 8.5–103.8 mm). Microsatellite instability was low in 40.4% (38/94) of tumors, with Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation detected in 68 out of 94 (72%) tumors. The mean survival was 35 months ± 21 months, and local disease progression was observed in 35.5% of patients. Univariate regression analysis identified 42 texture features [8 first order, 5 gray level dependence matrix (GLDM), 5 gray level run time length matrix (GLRLM), 5 gray level size zone matrix (GLSZM), 2 neighboring gray tone difference matrix (NGTDM), and 17 gray level co-occurrence matrix (GLCM)] independently associated with metastatic disease progression (P < 0.03). The random forest model achieved an area under the curve (AUC) of 0.88. Conclusions: MRI-based peritumoral heterogeneity features may serve as predictive biomarkers for metastatic disease progression and patient survival in CRLM. Original Article Mon, 19 Feb 2024 00:00:00 GMT AzadehTabari, BrianD’Amore, JaniceNoh, Michael S.Gee, DaniaDaye, Mon, 19 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002205 https://www.explorationpub.com/Journals/etat/Article/1002206 Lung cancer remains the most common cause of cancer death across the world. Non-small-cell lung cancer (NSCLC) represents the most frequent type of lung cancer and is frequently diagnosed at an advanced stage. Stage III NSCLC, which encompasses 30% of cases, refers to a state between localized and metastatic disease, and is associated with poor prognosis. As highlighted in this review, stage III represents a heterogenous group, whose complex management includes multimodal treatment, discussed below, and requires discussion in multidisciplinary teams. The goal of this approach is a maximalist attitude in these patients with locally advanced and non-metastatic disease. However, many issues remain under debate including the optimal sequences of treatment between different treatment modalities, patient selection particularly for surgery, the duration of perioperative treatments and the identification of biomarkers to determine which patients might benefit of specific treatment like immunotherapy and targeted therapies. This review describes the current landscape of management of stage III NSCLC, discussing the critical issue of resectability, and highlighting the recent advancements in the field, particularly the incorporation of immune-checkpoint inhibitors (ICIs) and targeted therapies in this setting. Mini Review Mon, 19 Feb 2024 00:00:00 GMT FloryaneKim, MaximeBorgeaud, AlfredoAddeo, AlexFriedlaender, Mon, 19 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002206 https://www.explorationpub.com/Journals/etat/Article/1002207 Monoclonal antibodies (mAbs) are an effective drug for targeted immunotherapy in several cancer types. However, so far, no antibody has been successfully developed for certain types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy. T-ALL patients who are treated with chemotherapeutic drugs frequently relapse and become drug resistant. Therefore, antibody-based therapy is promising for T-ALL treatment. To successfully develop an antibody-based therapy for T-ALL, antibodies that induce death in malignant T cells but not in nonmalignant T cells are required to avoid the induction of secondary T-cell immunodeficiency. In this review, CD99 tumor associated antigen, which is highly expressed on malignant T cells and lowly expressed on nonmalignant T cells, is proposed to be a potential target for antibody therapy of T-ALL. Since certain clones of anti-CD99 mAbs induce apoptosis only in malignant T cells, these anti-CD99 mAbs might be a promising antibody drug for the treatment of T-ALL with high efficiency and low adverse effects. Moreover, over the past 25 years, many clones of anti-CD99 mAbs have been studied for their direct effects on T-ALL. These outcomes are gathered here. Review Mon, 19 Feb 2024 00:00:00 GMT KamonpornKotemul, WatcharaKasinrerk, NuchjiraTakheaw, Mon, 19 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002207 https://www.explorationpub.com/Journals/etat/Article/1002208 Head and neck cancer (HNC) is a challenging disease that lacks effective treatment, particularly in the cases that spread locoregionally and metastasize distantly, dramatically reducing patient survival rates. Expanding the understanding of the mechanisms of the metastatic cascade is critical for creating more effective therapeutics that improve outcomes for HNC patients. A true grasp of cancer metastasis requires the consideration of all cell types that contribute to the inflammatory HNC microenvironment as drivers of this process. More emphasis now is being placed on exploring the roles of the different immune cells in cancer control, tumorigenesis and metastasis. Myeloid cells are the most numerous immune cell types in the body, and they are actively recruited and reprogrammed by tumor cells to behave in a variety of ways. These cells are remarkably diverse in phenotype and function, and the part they play in tumor spread greatly differs based on the cell type. This review will focus on summarizing the roles of macrophages, neutrophils, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs) in driving HNC metastasis by examining the current knowledge base and offering potential new routes through which to target and treat this deadly process. Mini Review Mon, 19 Feb 2024 00:00:00 GMT Dakota Dike DimegwuOkwuone, DeriMorgan, Gregory N.Gan, Mon, 19 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002208 https://www.explorationpub.com/Journals/etat/Article/1002209 Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers with high mortality rate. Among its various etiological factors, one of the major risk factors for HCC is a chronic infection of hepatitis B virus (HBV). HBV X protein (HBx) has been identified to play an important role in the HBV-induced HCC pathogenesis since it may interfere with several key regulators of many cellular processes. HBx localization within the cells may be beneficial to HBx multiple functions at different phases of HBV infection and associated hepatocarcinogenesis. HBx as a regulatory protein modulates cellular transcription, molecular signal transduction, cell cycle, apoptosis, autophagy, protein degradation pathways, and host genetic stability via interaction with various factors, including its association with various non-coding RNAs. A better understanding on the regulatory mechanism of HBx on various characteristics of HCC would provide an overall picture of HBV-associated HCC. This article addresses recent data on HBx role in the HBV-associated hepatocarcinogenesis. Review Tue, 20 Feb 2024 00:00:00 GMT AgustiningsihAgustiningsih, Muhammad RezkiRasyak, Turyadi, SriJayanti, CaeciliaSukowati, Tue, 20 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002209 https://www.explorationpub.com/Journals/etat/Article/1002210 Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed. Review Fri, 23 Feb 2024 00:00:00 GMT TomasKoltai, LarryFliegel, Fri, 23 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002210 https://www.explorationpub.com/Journals/etat/Article/1002211 Long noncoding RNAs (lncRNAs) derived from noncoding regions in the human genome were once regarded as junks with no biological significance, but recent studies have shown that these molecules are highly functional, prompting an explosion of studies on their biology. However, these recent efforts have only begun to recognize the biological significance of a small fraction (< 1%) of the lncRNAs. The basic concept of these lncRNA functions remains controversial. This controversy arises primarily from conventional biased observations based on limited datasets. Fortunately, emerging big data provides a promising path to circumvent conventional bias to understand an unbiased big picture of lncRNA biology and advance the fundamental principles of lncRNA biology. This review focuses on big data studies that break through the critical concepts of the lncRNA functional system and its endogenous regulatory roles in all cancers. lncRNAs have unique functional systems distinct from proteins, such as transcriptional initiation and regulation, and they abundantly interact with mitochondria and consume less energy. lncRNAs, rather than proteins as traditionally thought, function as the most critical endogenous regulators of all cancers. lncRNAs regulate the cancer regulatory regime by governing the endogenous regulatory network of all cancers. This is accomplished by dominating the regulatory network module and serving as a key hub and top inducer. These critical conceptual breakthroughs lay a blueprint for a comprehensive functional picture of the human genome. They also lay a blueprint for combating human diseases that are regulated by lncRNAs. Review Wed, 28 Feb 2024 00:00:00 GMT AnyouWang, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002211 https://www.explorationpub.com/Journals/etat/Article/1002213 Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin’s lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response. Review Wed, 28 Feb 2024 00:00:00 GMT HirokiGoto, YoshiokiShiraishi, SeijiOkada, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002213 https://www.explorationpub.com/Journals/etat/Article/1002214 Immunotherapy treatments for cancer are known to cause adverse thyroid events which present a diagnostic challenge to clinicians and radiologists. This case report highlights the importance of a high clinical index of suspicion and careful assessment of the thyroid on serial imaging studies to make the diagnosis. The case involves a 65-year-old male with malignant melanoma who was started on immunotherapy as part of a clinical trial. He developed thyroid dysfunction followed by an attack of acute neck pain. Ultrasound of his thyroid was performed which showed significant atrophy. A review of previous imaging was undertaken which confirmed the patient had suffered from thyroiditis and subsequent atrophy. Following this, the diagnosis of immunotherapy-induced thyroid dysfunction was made. Thyroxine supplementation and steroid dose were then adjusted causing his thyroid function and symptoms to improve. Immunotherapy agents for cancers are becoming more and more common. As the case report shows, physicians and radiologists will need to be vigilant to diagnose and treat any adverse events. Case Report Wed, 28 Feb 2024 00:00:00 GMT GeorgePears, AbhishekMahajan, AnnaOlsson-Brown, JosephSacco, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002214 https://www.explorationpub.com/Journals/etat/Article/1002215 Triple negative breast cancer (TNBC) represents an aggressive disease associated with a high risk of recurrence after curative treatment and a poor prognosis in the metastatic setting. Chemotherapy was for years the only treatment available in the early and metastatic setting, due to the lack of actionable targets. Clinical practice has changed following the results obtained with the addition of immunotherapy to standard chemotherapy, the development of novel drugs [i.e. antibody-drug conjugates (ADCs)], and the use of targeted treatments for patients carrying germline pathogenic breast cancer susceptibility genes (BRCA) 1 or BRCA 2 variants. The treatment of early-stage disease has had a shift in clinical practice since July 2021, after the Food and Drug Administration (FDA) approval of pembrolizumab in association with chemotherapy as neoadjuvant treatment for TNBC and as a single agent in the subsequent adjuvant setting. This intensive treatment based on the combination of a poly-chemotherapy and an immune checkpoint inhibitor (ICI) led to the improvement of short- and long-term outcomes, but it has highlighted some new unmet clinical needs in the treatment of early-stage TNBC: the selection of the most effective adjuvant therapy and the integration of pembrolizumab with other therapeutic strategies [capecitabine, poly(ADP-ribose) polymerase (PARP) inhibitors] based on the achievement of pathologic complete response (pCR); the identification of predictive biomarkers to select patients who could most benefit from the addition of ICI, to minimize toxicities and to maximize outcomes; the possibility of de-escalating chemotherapy in favor of immune-combo or novel agents, such as ADCs; the role of immunotherapy in estrogen receptor (ER)-low patients. The advent of immunotherapy not only addresses current challenges in TNBC treatment but also holds the promise of a radical transformation in its therapeutic paradigm, enhancing significantly clinical outcomes and offering new perspectives for patients grappling with this aggressive form of breast cancer. Review Wed, 28 Feb 2024 00:00:00 GMT PierluigiDe Santis, MartinaPerrone, ChiaraGuarini, Anna NataliziaSantoro, CarmeloLaface, DanielaCarrozzo, Gaia RacheleOliva, PalmaFedele, Wed, 28 Feb 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002215 https://www.explorationpub.com/Journals/etat/Article/1002216 Adaptor proteins play essential roles in various intracellular signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that possesses pleckstrin homology (PH) and Src homology 2 (SH2) domains, as well as a YXXQ signal transducer and activator of transcription 3 (STAT3)-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (BRK). STAP-2/BRK expression is deregulated in breast cancers and enhances STAT3-dependent cell proliferation. In prostate cancer cells, STAP-2 interacts with and stabilizes epidermal growth factor receptor (EGFR) after stimulation, resulting in the upregulation of EGFR signaling, which contributes to cancer-cell proliferation and tumor progression. Therefore, inhibition of the interaction between STAP-2 and BRK/EGFR may be a possible therapeutic strategy for these cancers. For this purpose, peptides that interfere with STAP-2/BRK/EGFR binding may have great potential. Indeed, the identified peptide inhibitor successfully suppressed the STAP-2/EGFR protein interaction, EGFR stabilization, and cancer-cell growth. Furthermore, the peptide inhibitor suppressed tumor formation in human prostate- and lung-cancer cell lines in a murine xenograft model. This review focuses on the inhibitory peptide as a promising candidate for the treatment of prostate and lung cancers. Mini Review Fri, 08 Mar 2024 00:00:00 GMT TaigaMaemoto, YutoSasaki, FumiyaOkuyama, YuichiKitai, KenjiOritani, TadashiMatsuda, Fri, 08 Mar 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002216 https://www.explorationpub.com/Journals/etat/Article/1002217 International Guidelines as well as Cancer Associations recommend a multidisciplinary approach to lung cancer care. A multidisciplinary team (MDT) can significantly improve treatment decision-making and patient coordination by putting different physicians and other health professionals “in the same room”, who collectively decide upon the best possible treatment. However, this is not a panacea for cancer treatment. The impact of multidisciplinary care (MDC) on patient outcomes is not univocal, while the effective functioning of the MDT depends on many factors. This review presents the available MDT literature with an emphasis on the key factors that characterize high-quality patient care in lung cancer. The study was conducted with a bibliographic search using different electronic databases (PubMed Central, Scopus, Google Scholar, and Google) referring to multidisciplinary cancer care settings. Many key elements appear consolidated, while others emerge as prevalent and actual, especially those related to visible barriers which work across geographic, organizational, and disciplinary boundaries. MDTs must be sustained by strategic management, structured within the entity, and cannot be managed as a separate care process. Furthermore, they need to coordinate with other teams (within and outside the organization) and join with the broad range of services delivered by multiple providers at various points of the cancer journey or within the system, with the vision of integrated care. Review Thu, 21 Mar 2024 00:00:00 GMT AlessandroMorabito, EdoardoMercadante, PaoloMuto, AnnaManzo, GiulianoPalumbo, VincenzoSforza, AgneseMontanino, ClaudiaSandomenico, RaffaeleCostanzo, GiovannaEsposito, GiuseppeTotaro, Rossella DeCecio, CarminePicone, AnnamariaPorto, NicolaNormanno, ArturoCapasso, MonicaPinto, MauraTracey, GiuseppeCaropreso, GiacomoPascarella, Thu, 21 Mar 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002217 https://www.explorationpub.com/Journals/etat/Article/1002218 Aim: Triple negative breast cancer (TNBC) is usually treated with high doses of paclitaxel, whose effectiveness may be modulated by the action of environmental contaminants such as hexachlorobenzene. High doses of paclitaxel cause adverse effects such as low cellular selectivity and the generation of resistance to treatment due to an increase in the expression of multidrug resistance proteins (MRPs). These effects can be reduced using a metronomic administration scheme with low doses. This study aimed to investigate whether hexachlorobenzene modulates the response of cells to conventional chemotherapy with paclitaxel or metronomic chemotherapy with paclitaxel plus carbachol, as well as to study the participation of the MRP ATP-binding cassette transporter G2 (ABCG2) in human TNBC MDA-MB231 cells. Methods: Cells were treated with hexachlorobenzene alone or in combination with conventional or metronomic chemotherapies. The effects of treatments on cell viability were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the nuclear factor kappa B pathway participation was evaluated using a selective inhibitor. ABCG2 expression and its modulation were determined by western blot. Results: Results confirmed that paclitaxel reduces MDA-MB231 cell viability in a concentration-dependent manner. Results also showed that both conventional and metronomic chemotherapies reduced cell viability with similar efficacy. Although hexachlorobenzene did not modify cell viability per se, it did reverse the effect induced by the conventional chemotherapy, without affecting the efficacy of the metronomic chemotherapy. Additionally, a differential modulation of ABCG2 expression was determined, mediated by the nuclear factor kappa B pathway, which was directly related to the modulation of cell sensitivity to another cycle of paclitaxel treatment. Conclusions: The findings indicate that, in human TNBC MDA-MB231 cells, in the presence of hexachlorobenzene, the metronomic combination of paclitaxel plus carbachol is more effective in affecting the tumor biology than the conventional therapeutic administration scheme of paclitaxel. Original Article Fri, 22 Mar 2024 00:00:00 GMT YamilaSanchez, Mariana AbigailVasquez Callejas, Noelia VictoriaMiret, GabinoRolandelli, CatalinaCostas, Andrea SilvanaRandi, AlejandroEspañol, Fri, 22 Mar 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002218 https://www.explorationpub.com/Journals/etat/Article/1002219 Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance. Review Tue, 23 Apr 2024 00:00:00 GMT James MichaelVerner, Harry FrederickArbuthnott, RaghavskandhanRamachandran, ManiniBharadwaj, NatashaChaudhury, EricJou, Tue, 23 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002219 https://www.explorationpub.com/Journals/etat/Article/1002221 Hematologists, geneticists, and clinicians came to a multidisciplinary agreement on the classification of lymphoid neoplasms that combines clinical features, histological characteristics, immunophenotype, and molecular pathology analyses. The current classification includes the World Health Organization (WHO) Classification of tumours of haematopoietic and lymphoid tissues revised 4th edition, the International Consensus Classification (ICC) of mature lymphoid neoplasms (report from the Clinical Advisory Committee 2022), and the 5th edition of the proposed WHO Classification of haematolymphoid tumours (lymphoid neoplasms, WHO-HAEM5). This article revises the recent advances in the classification of mature lymphoid neoplasms. Artificial intelligence (AI) has advanced rapidly recently, and its role in medicine is becoming more important as AI integrates computer science and datasets to make predictions or classifications based on complex input data. Summarizing previous research, it is described how several machine learning and neural networks can predict the prognosis of the patients, and classified mature B-cell neoplasms. In addition, new analysis predicted lymphoma subtypes using cell-of-origin markers that hematopathologists use in the clinical routine, including CD3, CD5, CD19, CD79A, MS4A1 (CD20), MME (CD10), BCL6, IRF4 (MUM-1), BCL2, SOX11, MNDA, and FCRL4 (IRTA1). In conclusion, although most categories are similar in both classifications, there are also conceptual differences and differences in the diagnostic criteria for some diseases. It is expected that AI will be incorporated into the lymphoma classification as another bioinformatics tool. Perspective Wed, 24 Apr 2024 00:00:00 GMT JoaquimCarreras, RifatHamoudi, NaoyaNakamura, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002221 https://www.explorationpub.com/Journals/etat/Article/1002222 Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors. Review Wed, 24 Apr 2024 00:00:00 GMT Mohammad SadiqJeeyavudeen, NavinMathiyalagan, CorneliusFernandez James, Joseph M.Pappachan, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002222 https://www.explorationpub.com/Journals/etat/Article/1002223 Fluoropyrimidines, crucial in cancer treatment, often cause toxicity concerns even at standard doses. Toxic accumulation of fluoropyrimidine metabolites, culminating in adverse effects, can stem from impaired dihydropyrimidine dehydrogenase (DPYD) enzymatic function. Emerging evidence underscores the role of single nucleotide polymorphisms (SNPs) in DPYD gene, capable of inducing DPYD activity deficiency. Consequently, DPYD genotyping’s importance is on the rise in clinical practice before initiating fluoropyrimidine treatment. Although polymerase chain reaction (PCR) followed by Sanger sequencing (SS; PCR-SS) is a prevalent method for DPYD genotyping, it may encounter limitations. In this context, there is reported a case in which a routine PCR-SS approach for genotyping DPYD SNP rs55886062 failed in a proband of African descent. The Clinical Pharmacogenetics Implementation Consortium (CPIC) categorizes the guanine (G) allele of this SNP as non-functional. The enforcement of whole genome sequencing (WGS) approach led to the identification of two adenine (A) insertions near the PCR primers annealing regions in the proband, responsible for a sequence frameshift and a genotyping error for rs55886062. These SNPs (rs145228578, 1-97981199-T-TA and rs141050810, 1-97981622-G-GA) were extremely rare in non-Finnish Europeans (0.05%) but prevalent in African populations (16%). Although limited evidence was available for these SNPs, they were catalogued as benign variants in public databases. Notably, these two SNPs exhibited a high linkage disequilibrium [LD; squared correlation coefficient (R2) = 0.98]. These findings highlighted the importance to consider the prevalence of genetic variants within diverse ethnic populations when designing primers and probes for SNP genotyping in pharmacogenetic testing. This preventive measure is essential to avoid sequence frameshifts or primer misalignments arising from SNP occurrences in the genome, which can compromise PCR-SS and lead to genotyping failures. Furthermore, this case highlights the significance of exploring alternative genotyping approaches, like WGS, when confronted with challenges associated with conventional techniques. Case Report Wed, 24 Apr 2024 00:00:00 GMT AnnalauraMontella, SuevaCantalupo, GiuseppeD’Alterio, VincenzoDamiano, AchilleIolascon, MarioCapasso, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002223 https://www.explorationpub.com/Journals/etat/Article/1002224 Aerobic glycolysis also known as the Warburg effect, remains a hallmark of various cancers, including ovarian cancer. Cancer cells undergo metabolic changes to sustain their tumorigenic properties and adapt to environmental conditions, such as hypoxia and nutrient starvation. Altered metabolic pathways not only facilitate ovarian cancer cells’ survival and proliferation but also endow them to metastasize, develop resistance to chemotherapy, maintain cancer stem cell phenotype, and escape anti-tumor immune responses. Glucose transporters (GLUTs), which play a pivotal role as the rate-limiting step in glycolysis, are frequently overexpressed in a variety of tumors, including ovarian cancer. Multiple oncoproteins can regulate GLUT proteins, promoting tumor proliferation, migration, and metastasis, either dependent or independent of glycolysis. This review examines the alteration of GLUT proteins, particularly GLUT1, in ovarian cancer and its impact on cancer initiation, progression, and resistance to treatment. Additionally, it highlights the role of these proteins as biomarkers for diagnosis and prognosis in ovarian cancer, and delves into novel therapeutic strategies currently under development that target GLUT isoforms. Review Wed, 24 Apr 2024 00:00:00 GMT FatimaBen Ali, ZinebQmichou, MohamedOukabli, NadiaDakka, YoussefBakri, MohammedEddouks, RabiiAmeziane El Hassani, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002224 https://www.explorationpub.com/Journals/etat/Article/1002225 In the 21st century, advances in basic research have provided new insights in the field of pediatric oncology. Pediatric patients tend to experience higher levels of distressing symptoms, which together form a symptom cluster. In clinical practice, these symptom clusters are reported daily by children and adolescents with cancer. Translational research has emerged as the translation of new knowledge from basic science into clinical practice. Understanding how neuroimmunoendocrine pathways regulate cancer development and the aspects underlying the specific therapies, such as chemotherapy and immunotherapy, is an important frontier for future research in pediatric oncology. The goal of translational research is to show how different variables in tumor and patient characteristics explain the differential effects of interventions, as translational research provides new insights into the management of cancer symptoms in children and adolescents with cancer. Together, this approach could lead to improvements in pediatric oncology care worldwide. Perspective Wed, 24 Apr 2024 00:00:00 GMT Luciana ChainVeronez, Luís CarlosLopes-Júnior, Wed, 24 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002225 https://www.explorationpub.com/Journals/etat/Article/1002226 Colorectal cancer (CRC) is a heterogeneous disease. Conventional two-dimensional (2D) culture employing cell lines was developed to study the molecular properties of CRC in vitro. Although these cell lines which are isolated from the tumor niche in which cancer develop, the translation to human model such as studying drug response is often hindered by the inability of cell lines to recapture original tumor features and the lack of heterogeneous clinical tumors represented by this 2D model, differed from in vivo condition. These limitations which may be overcome by utilizing three-dimensional (3D) culture consisting of spheroids and organoids. Over the past decade, great advancements have been made in optimizing culture method to establish spheroids and organoids of solid tumors including of CRC for multiple purposes including drug screening and establishing personalized medicine. These structures have been proven to be versatile and robust models to study CRC progression and deciphering its heterogeneity. This review will describe on advances in 3D culture technology and the application as well as the challenges of CRC-derived spheroids and organoids as a mode to screen for anticancer drugs. Review Thu, 25 Apr 2024 00:00:00 GMT Sahira SyamimiAhmad Zawawi, Elyn AmielaSalleh, MarahainiMusa, Thu, 25 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002226 https://www.explorationpub.com/Journals/etat/Article/1002227 Cancer continues to be a global health concern, necessitating innovative solutions for treatment. Tri-specific killer engagers (TriKEs) have emerged as a promising class of immunotherapeutic agents, offering a multifaceted approach to cancer treatment. TriKEs simultaneously engage and activate natural killer (NK) cells while specifically targeting cancer cells, representing an outstanding advancement in immunotherapy. This review explores the generation and mechanisms of TriKEs, highlighting their advantages over other immunotherapies and discussing their potential impact on clinical trials and cancer treatment. TriKEs are composed of three distinct domains, primarily antibody-derived building blocks, linked together by short amino acid sequences. They incorporate critical elements, anti-cluster of differentiation 16 (CD16) and interleukin-15 (IL-15), which activate and enhance NK cell function, together with specific antibody to target each cancer. TriKEs exhibit remarkable potential in preclinical and early clinical studies across various cancer types, making them a versatile tool in cancer immunotherapy. Comparative analyses with other immunotherapies, such as chimeric antigen receptor-T (CAR-T) cell therapy, immune checkpoint inhibitors (ICIs), cytokine therapies, and monoclonal antibodies (mAbs), reveal the unique advantages of TriKEs. They offer a safer pathway for immunotherapy by targeting cancer cells without hyperactivating T cells, reducing off-target effects and complications. The future of TriKEs involves addressing challenges related to dosing, tumor-associated antigen (TAA) expression, and NK cell suppression. Researchers are exploring innovative dosing strategies, enhancing specificity through tumor-specific antigens (TSAs), and combining TriKEs with other therapies for increased efficacy. Review Fri, 26 Apr 2024 00:00:00 GMT PeeranutWinidmanokul, AussaraPanya, SeijiOkada, Fri, 26 Apr 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002227 https://www.explorationpub.com/Journals/etat/Article/1002228 Recently, the development of targeted therapy approaches such as those based on tyrosine kinase inhibitor (TKI) greatly improved the clinical outcomes of patients affected by oncogene addicted advanced non-small cell lung cancer (NSCLC). Similarly, the improvement of radiation therapy techniques has permitted to deliver high radiation doses to a limited number of metastatic target lesions (oligopersistent or oligoprogressive), with limited high-dose normal tissue exposure that leads to low severe toxicity rates. The aim of this narrative review was to provide an overview of the currently established definition of oligometastatic and oligoprogressive disease, to define first line and subsequent lines targeted therapies and the role of consolidative non-invasive local ablative treatments (LATs) in these settings. The potential benefit of local treatment (LT) such as radiotherapy (RT) or surgery might be represented by an overall reduction of switching to subsequent systemic treatments lowering the risk of further systemic dissemination. Further randomized clinical trials will clarify the role of LT and their correct timing in relation to systemic targeted therapies. Review Fri, 17 May 2024 00:00:00 GMT FrancescaDi Pressa, FabianaPerrone, AnnaBenini, FrankLohr, MarcelloTiseo, AlessioBruni, Fri, 17 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002228 https://www.explorationpub.com/Journals/etat/Article/1002229 Thymic epithelial tumors (TETs) are rare malignant neoplasms arising in the thymus gland. Nevertheless, TETs, including thymomas (TMs), thymic carcinomas (TCs), and thymic neuroendocrine neoplasms (TNENs), are the most common mediastinal malignancies overall. A multidisciplinary approach is required for the appropriate diagnostic and therapeutic management of TETs. To date, the main therapeutic strategies are largely depended on the stage of the tumor and they include surgery with or without neoadjuvant or adjuvant therapy, represented by platinum-based chemotherapy, radiotherapy or chemoradiotherapy. Immune checkpoint inhibitors (ICIs) are ongoing under evaluation in the advanced or metastatic diseases despite the challenges related to the very low tumor mutation burden (TMB) and the high incidence of immune-related adverse events in TETs. In this regard, predictive impact of tissue biomarkers expression such as programmed cell death ligand-1 (PD-L1), and other emerging biomarkers, as well as their optimal and shared interpretation are currently under evaluation in order to predict response rates to ICIs in TETs. Perspective Tue, 21 May 2024 00:00:00 GMT StefanoLucà, MarinaAccardo, SeveroCampione, RenatoFranco, Tue, 21 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002229 https://www.explorationpub.com/Journals/etat/Article/1002230 In recent times, there have been notable advancements in comprehending the potential anti-cancer effects of chrysin (CH), a naturally occurring flavonoid compound found abundantly in various plant sources like honey, propolis, and certain fruits and vegetables. This active compound has garnered significant attention due to its promising therapeutic qualities and minimal toxicity. CH’s ability to combat cancer arises from its multifaceted mechanisms of action, including the initiation of apoptosis and the inhibition of proliferation, angiogenesis, metastasis, and cell cycle progression. CH also displays potent antioxidant and anti-inflammatory properties, effectively counteracting the harmful molecules that contribute to DNA damage and the development of cancer. Furthermore, CH has exhibited the potential to sensitize cancer cells to traditional chemotherapy and radiotherapy, amplifying the effectiveness of these treatments while reducing their negative impact on healthy cells. Hence, in this current review, the composition, chemistry, mechanisms of action, safety concerns of CH, along with the feasibility of its nanoformulations. To conclude, the recent investigations into CH’s anti-cancer effects present a compelling glimpse into the potential of this natural compound as a complementary therapeutic element in the array of anti-cancer approaches, providing a safer and more comprehensive method of combating this devastating ailment. Review Thu, 23 May 2024 00:00:00 GMT AbhilashaSood, ArpitMehrotra, UjjawalSharma, DiwakarAggarwal, TejveerSingh, MoyadShahwan, Ammar AbdulrahmanJairoun, IshaRani, SeemaRamniwas, Hardeep SinghTuli, VikasYadav, ManojKumar, Thu, 23 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002230 https://www.explorationpub.com/Journals/etat/Article/1002231 Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients. Perspective Thu, 23 May 2024 00:00:00 GMT NicolaNormanno, VincenzaCaridi, MatteoFassan, AntonioAvallone, FortunatoCiardiello, CarminePinto, Thu, 23 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002231 https://www.explorationpub.com/Journals/etat/Article/1002232 Aim: There is limited data on prognostic value of baseline plasma cell free DNA (cfDNA) in advanced squamous non-small cell lung cancer (sq-NSCLC). This prospective observational study aimed to assess change in plasma cfDNA levels in locally-advanced/metastatic sq-NSCLC with chemotherapy and its correlation with symptom-scores and radiological-responses. Methods: Chemotherapy-naive patients with stages-IIIB/IIIC/IV sq-NSCLC (n = 59), smokers with chronic obstructive pulmonary disease [COPD, COPD-controls (CC); n = 27] and healthy-controls (n = 25) were enrolled. Respiratory symptom burden (RSB) and total symptom burden (TSB) were calculated from mean visual-analog-scores (VAS) of dyspnoea, cough, chest pain, hemoptysis RSB, anorexia and fatigue (all six for TSB). cfDNA was isolated from peripheral blood. All patients received platinum-doublet chemotherapy. RSB/TSB/cfDNA assessment and contrast-enhanced computed tomography (CECT)-thorax scans were done at baseline and post-chemotherapy. Results: At baseline, 13/59 (22%) sq-NSCLC, 3/27 (11%) CC and none (0%) healthy-controls had detectable cfDNA. All three CC were heavy smokers with no evidence of malignancy and undetectable cfDNA levels on repeat testing. In sq-NSCLC group, majority were males (95%), current-smokers (88%), heavy-smokers (70%), had metastatic disease (59%) with median age of 65 years. Eastern Co-operative Oncology Group (ECOG) performance status (PS) was 0–1 (56%) and 2 (42%). Median RSB- and TSB-scores were 9 [interquartile range (IQR) = 5–14] and 16 (IQR = 9–23), respectively. Of the 59 patients, 54 received ≥ 1 cycle while 27 underwent post-C4 evaluation with detectable cfDNA levels in 18/27 (66.7%). No baseline characteristic correlated with cfDNA detectability. Median overall survival (OS) and progression-free survival (PFS) were 262 days and 167 days, respectively. ECOG PS ≥ 2, RSB-score > 9 and TSB-score > 16 were all associated with worse OS and PFS as was cfDNA detectability [median OS = 97 days vs. 298 days and median PFS = 97 days vs. 197 days; P = 0.025; hazard ratio (HR) = 2.17]. Conclusions: Baseline cfDNA detectability is independently associated with poor OS and PFS in patients with advanced sq-NSCLC on chemotherapy. Original Article Tue, 28 May 2024 00:00:00 GMT NithiyanandanRavi, ParulGupta, AmanjitBal, Kuruswamy ThuraiPrasad, MandeepGarg, RakeshKapoor, NavneetSingh, Tue, 28 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002232 https://www.explorationpub.com/Journals/etat/Article/1002233 Aim: Metal nanoclusters are emerging nanomaterials applicable for drug delivery. Here, the toxicity and oxidative stress induction of divalent cationic cadmium (Cd2+) was compared with a Cd in the form of nanocluster. Then, it was used for targeted drug delivery into breast cancer cell lines. Methods: Using a green chemistry route, a Cd nanocluster (Cd-NC) was synthesized based on bovine serum albumin. After characterization, its genotoxicity and oxidative stress induction were studied in both in vitro and in vivo. After that, it was conjugated with hyaluronic acid (HA). The efficiency of hyaloronized-Cd-CN (HA-Cd-NC) for loading and releasing crocin (Cro), an anticancer phytochemical, was studied. Finally, it was applied for cell death induction in a panel of breast cancer cell lines. Results: The comet assay results indicated that, unlike Cd2+ and potassium permanganate (KMnO4), no genotoxicity and oxidative stress was induced by Cd-NC in vitro. Then, the pharmacokinetics of this Cd-NC was studied in vivo. The data showed that Cd-NC has accumulated in the liver and excreted from the feces of mice. Unlike Cd2+, no toxicity and oxidative stress were induced by this Cd-NC in animal tissues. Then, the Cd-NC was targeted toward breast cancer cells by adding HA, a ligand for the CD44 cell surface receptor. After that, Cro was loaded on HA-Cd-NC and it was used for the treatment of a panel of human breast cancer cell lines with varying degrees of CD44. The half-maximal drug inhibitory concentration (IC50) of Cro was significantly decreased when it was loaded on HA-Cd-NC, especially in MDA-MB-468 with a higher degree of CD44 at the surface. These results indicate the higher toxicity of Cro toward breast cancers when carried out by HA-Cd-NC. Conclusions: The Cd-NC was completely safe and is a promising candidate for delivering anticancer drugs/phytochemicals into the targeted breast tumors. Original Article Tue, 28 May 2024 00:00:00 GMT MoslemJafarisani, S. AliHashemi, NassimFaridi, Mir F.Mousavi, S. ZahraBathaie, Tue, 28 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002233 https://www.explorationpub.com/Journals/etat/Article/1002234 Antiandrogens have been used for the treatment of prostate cancer as a single agent or in combination with hormone deprivation therapy. New generation antiandrogens act like androgen receptor inhibitors (ARIs). Their binding complex blocks the pathways of cellular proliferation and differentiation of the prostate. Enzalutamide, apalutamide and darolutamide are the new ARIs that demonstrated acceptable tolerability and toxicity, both active in hormone-sensitive and castration-resistant prostate cancer (CRPC). There is no evidence of superiority of one drug over the other, therefore the therapeutic choice depends on the safety profile in relation to the individual patient, their comorbidities and clinical condition. ARIs have also shown promising results in association with new drugs that are active on patients with metastatic CRPC carrying the mutated breast cancer gene (BRCA). Before undergoing new antiandrogenic therapies, patients should be evaluated for cardiological and metabolic risk and possible drug interactions. Perspective Tue, 28 May 2024 00:00:00 GMT FabioCampodonico, LucaFoppiani, VittoriaCampodonico, CarloIntroini, Tue, 28 May 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002234 https://www.explorationpub.com/Journals/etat/Article/1002235 Aim: To investigate the molecular effects of a novel combination [sertraline and plumbagin (comb) with ormeloxifene (Orm)] for anticancer activity in triple negative breast cancer cell line “MDA-MB-231”. Methods: The cytotoxic effect of the drugs was analyzed by the MTT assay and nuclear morphological changes by acridine orange/ethidium bromide (AO/EB) staining. Induction of apoptosis by annexin V-FITC staining, active caspase-3 detection and cell cycle analysis were studied in vitro on “MDA-MB-231” cells. The qRT-PCR was done to explore the upregulation and down regulation of targeted genes for angiogenesis, metastasis, tumor suppression and protein folding on the triple negative breast cancer cells. The preliminary anti-angiogenic effect of the drugs was assessed by chorioallantoic membrane (CAM) assay. Results: Orm showed inhibitory effects in “MDA-MB-231” cells in a dose and time dependent manner whereas; the drugs in combination gave better cytotoxic effects in the screening MTT assay. Orm + comb was more effective than Orm alone in eliciting apoptosis as well as inhibited the single cell to grow into a colony. CAM assay using Orm and Orm + comb suggested the anti-angiogenic potential which was further confirmed by the downregulation of VEGF in “MDA-MB-231” cells by qRT-PCR studies. The combination was found to effectively upregulate the expression of P53 and P21 and downregulate the gene expression of zinc finger E-box binding homeobox 1 (ZEB1) and heat shock protein 70 (HSP70) in “MDA-MB-231” cancer cells. Conclusions: Collectively this study reveals the efficacy of Orm + comb as more significant than the clinically used tamoxifen (Tam). The study elucidates the promising novelty of the combination as a potential chemotherapeutic intervention for mitigating the aggressiveness of triple negative breast cancer and it addresses the intrinsic resistance caused by single drug treatments. Original Article Tue, 11 Jun 2024 00:00:00 GMT ShehnaSharaf, SreelekshmiS, SaikantRegidi, AbiSanthosh Aprem, RajmohanGopimohan, LakshmiS, Tue, 11 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002235 https://www.explorationpub.com/Journals/etat/Article/1002236 Background: This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. Methods: After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. Results: With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65–1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82–1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54–0.77). Conclusions: A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate. Meta-Analysis Mon, 17 Jun 2024 00:00:00 GMT YiwenZhou, JingjingLi, JieerYing, Mon, 17 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002236 https://www.explorationpub.com/Journals/etat/Article/1002237 Passaged cell lines represent currently an integral component in various studies of malignant neoplasms. These cell lines are utilized for drug screening both in monolayer cultures or as part of three-dimensional (3D) tumor models. They can also be used to model the tumor microenvironment in vitro and in vivo through xenotransplantation into immunocompromised animals. However, immortalized cell lines have some limitations of their own. The homogeneity of cell line populations and the extensive passaging in monolayer systems make these models distant from the original disease. Recently, there has been a growing interest among scientists in the use of primary cell lines, as these are passaged directly from human tumor tissues. In this case, cells retain the morphological and functional characteristics of the tissue from which they were derived, an advantage often not observed in passaged cultures. This review highlights the advantages and limitations of passaged and primary cell cultures, their similarities and differences, as well as existing test systems that are based on primary and passaged cell cultures for drug screening purposes. Review Mon, 17 Jun 2024 00:00:00 GMT Vladislava V.Pipiya, Zarema E.Gilazieva, Shaza S.Issa, Albert A.Rizvanov, Valeriya V.Solovyeva, Mon, 17 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002237 https://www.explorationpub.com/Journals/etat/Article/1002238 Aim: The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms. Methods: The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model. Results: The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and β-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3β at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction. Conclusions: The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer. Original Article Tue, 18 Jun 2024 00:00:00 GMT MinghuaLi, YanhongWang, XiaoyangLin, HaiqiangYang, XiaolinZhang, YunBai, XiankunLi, LuluZhang, FengCheng, ChuanhaiCao, QingyuZhou, Tue, 18 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002238 https://www.explorationpub.com/Journals/etat/Article/1002239 Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. Due to the lack of effective screening and early detection strategies, many patients with OC are diagnosed with advanced disease, where treatment is rarely curative. Moreover, OC is characterized by high intratumor heterogeneity, which represents a major barrier to the development of effective treatments. Conventional tumor biopsy and blood-based biomarkers, such as cancer antigen 125 (CA125), have different limitations. Liquid biopsy has recently emerged as an attractive and promising area of investigation in oncology, due to its minimally invasive, safe, comprehensive, and real-time dynamic nature. Preliminary evidence suggests a potential role of liquid biopsy to refine OC management, by improving screening, early diagnosis, assessment of response to treatment, detection, and profiling of drug resistance. The current knowledge and the potential clinical value of liquid biopsy in OC is discussed in this review to provide an overview of the clinical settings in which its use might support and improve diagnosis and treatment. Review Wed, 19 Jun 2024 00:00:00 GMT ElenaTrevisi, CristianaSessa, IlariaColombo, Wed, 19 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002239 https://www.explorationpub.com/Journals/etat/Article/1002240 Bladder cancer (BC) is the tenth most common malignancy globally. Urothelial carcinoma (UC) is a major type of BC, and advanced UC (aUC) is associated with poor clinical outcomes and limited survival rates. Current options for aUC treatment mainly include chemotherapy and immunotherapy. These options have moderate efficacy and modest impact on overall survival and thus highlight the need for novel therapeutic approaches. aUC patients harbor a high tumor mutation burden and abundant molecular alterations, which are the basis for targeted therapies. Erdafitinib is currently the only Food and Drug Administration (FDA)-approved targeted therapy for aUC. Many potential targeted therapeutics aiming at other molecular alterations are under investigation. This review summarizes the current understanding of molecular alterations associated with aUC targeted therapy. It also comprehensively discusses the related interventions for treatment in clinical research and the potential of using novel targeted drugs in combination therapy. Review Fri, 21 Jun 2024 00:00:00 GMT ShihaoShang, LeiZhang, KepuLiu, MaoxinLv, JieZhang, DongenJu, DiWei, ZelongSun, PinxiaoWang, JianlinYuan, ZhengZhu, Fri, 21 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002240 https://www.explorationpub.com/Journals/etat/Article/1002241 Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation. Review Tue, 25 Jun 2024 00:00:00 GMT VanessaPatel, SandraCasimiro, CatarinaAbreu, TiagoBarroso, Rita Teixeirade Sousa, SofiaTorres, Leonor AbreuRibeiro, GonçaloNogueira-Costa, Helena LunaPais, ConceiçãoPinto, LeilaCosta, LuísCosta, Tue, 25 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002241 https://www.explorationpub.com/Journals/etat/Article/1002242 Primary effusion lymphoma (PEL) is a large B-cell neoplasm usually presenting as a serious effusion in body cavities without detectable tumor masses. It is an AIDS-related non-Hodgkin’s lymphoma (HL) with human herpes virus 8 (HHV8)/Kaposi sarcoma-associated herpes virus (KSHV) infection. A combination antiretroviral therapy (cART) prolongs the lifespan of AIDS and AIDS-related malignant lymphoma patients, but PEL continues to have a dismal prognosis. PEL showed disappointing outcomes with standard chemotherapy such as CHOP or CHOP-like regimens. A PEL status highlights the urgent need for new therapeutic approaches and treatment strategies and improve clinical outcomes. This review discusses the current knowledge and some recent clinical trials for PEL in the platform of immunotherapy as well as promising future immunotherapeutic approaches for PEL. Review Wed, 26 Jun 2024 00:00:00 GMT JutatipPanaampon, SeijiOkada, Wed, 26 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002242 https://www.explorationpub.com/Journals/etat/Article/1002244 The management of lung cancer (LC) requires the analysis of a diverse spectrum of molecular targets, including kinase activating mutations in EGFR, ERBB2 (HER2), BRAF and MET oncogenes, KRAS G12C substitutions, and ALK, ROS1, RET and NTRK1-3 gene fusions. Administration of immune checkpoint inhibitors (ICIs) is based on the immunohistochemical (IHC) analysis of PD-L1 expression and determination of tumor mutation burden (TMB). Clinical characteristics of the patients, particularly age, gender and smoking history, significantly influence the probability of finding the above targets: for example, LC in young patients is characterized by high frequency of kinase gene rearrangements, while heavy smokers often have KRAS G12C mutations and/or high TMB. Proper selection of first-line therapy influences overall treatment outcomes, therefore, the majority of these tests need to be completed within no more than 10 working days. Activating events in MAPK signaling pathway are mutually exclusive, hence, fast single-gene testing remains an option for some laboratories. RNA next-generation sequencing (NGS) is capable of detecting the entire repertoire of druggable gene alterations, therefore it is gradually becoming a dominating technology in LC molecular diagnosis. Review Thu, 27 Jun 2024 00:00:00 GMT Evgeny N.Imyanitov, Elena V.Preobrazhenskaya, Sergey V.Orlov, Thu, 27 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002244 https://www.explorationpub.com/Journals/etat/Article/1002243 Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents. Currently, the Food and Drug Administration has granted approval to 12 compounds, with 2 later undergoing withdrawal. Moreover, several other compounds are currently under clinical development at different stages. Despite substantial antitumoral activity observed among different tumor types, adverse events and the development of resistance represent significant challenges in their use. Over the last years, an increasing number of clinical trials have been testing these drugs in different combinations with other anticancer agents, such as traditional chemotherapy, immune checkpoint inhibitors, monoclonal antibodies, and small targeted agents, reporting promising results based on possible synergistic effects and a potential for improved treatment outcomes among different tumor types. Here we will review combinations of ADCs with other antitumor agents aiming at describing the current state of the art and future directions. Review Thu, 27 Jun 2024 00:00:00 GMT GiuliaPretelli, KleidaMati, LuciaMotta, AnastasiosStathis, Thu, 27 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002243 https://www.explorationpub.com/Journals/etat/Article/1002245 Aim: Supratentorial ependymoma (STE) is a rare tumor with distinct genetic alterations, whose imaging features have been scarcely studied. This study aims to review the computed tomography (CT) and magnetic resonance imaging (MRI) features of a cohort of histopathologically proven STE to identify the distinguishing features of STE, and look for specific signs of zinc finger translocation associated (ZFTA) fused STEs. Methods: Ethical clearance was obtained from the institutional ethics committee. The magnetic resonance (MR) images, CT images when available, clinical details, and pathological reports of 25 patients from a single institute with histopathologically proven STE were retrospectively reviewed. Imaging features, demographic details, pathological and molecular features, and type of surgical resection were described and tabulated. Relevant associations with imaging features were computed and tabulated. Results: The study showed that STEs are common in the pediatric population with no sex predilection. The periventricular location was the most common. A significant association between periventricular location and the presence of a cystic component (P value = 0.023) and the presence of the periwinkle sign/stellate sign (P value = 0.045) was found. Common features of ZFTA fused STEs included periventricular or intraventricular location, cystic component, necrosis, and the periwinkle sign. A significant association was found between ZFTA fusion and cystic component (P value = 0.048). Conclusions: This study attempts to identify the imaging features of STEs and their associations with molecular pathology and surgical outcome, and the distinguishing features of ZFTA fused STEs. Original Article Thu, 27 Jun 2024 00:00:00 GMT ArpitaSahu, AditiVenkatesh, AmanSnehil, AbhishekMahajan, AmitJanu, AyushiSahay, EpariSridhar, Thu, 27 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002245 https://www.explorationpub.com/Journals/etat/Article/1002246 Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient’s condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors. Case Report Fri, 28 Jun 2024 00:00:00 GMT Aram A.Musaelyan, Ekaterina M.Anokhina, Alina I.Turdubaeva, Natalia V.Mitiushkina, Anastasia N.Ershova, Anna D.Shestakova, Aigul R.Venina, Evgeny N.Imyanitov, Sergey V.Orlov, Fri, 28 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002246 https://www.explorationpub.com/Journals/etat/Article/1002247 Not applicable. Meeting Abstracts Fri, 28 Jun 2024 00:00:00 GMT ChouaibSalem, Fri, 28 Jun 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002247 https://www.explorationpub.com/Journals/etat/Article/1002248 Not applicable. Correction Mon, 08 Jul 2024 00:00:00 GMT AbhishekMahajan, GurukrishnaB, ShwetaWadhwa, UjjwalAgarwal, UjjwalBaid, SanjayTalbar, Amit KumarJanu, VijayPatil, VanitaNoronha, NaveenMummudi, AnilTibdewal, JPAgarwal, SubhashYadav, Rajiv KumarKaushal, AmeyaPuranik, NilenduPurandare, KumarPrabhash, Mon, 08 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002248 https://www.explorationpub.com/Journals/etat/Article/1002249 Cancer is the primary cause of death worldwide, and conventional treatments are painful, complicated, and have negative effects on healthy cells. However, cancer immunotherapy has emerged as a promising alternative. Principle of cancer immunotherapy is the re-activation of T-cell to combat the tumor that presents the peptide antigen on major histocompatibility complex (MHC). Those peptide antigens are identified with the set of omics technology, proteomics, genomics, and bioinformatics, which referred to immunopeptidomics. Indeed, immunopeptidomics can identify the neoantigens that are very useful for cancer immunotherapies. This review explored the use of immunopeptidomics for various immunotherapies, i.e., peptide-based vaccines, immune checkpoint inhibitors, oncolytic viruses, and chimeric antigen receptor T-cell. We also discussed how the diversity of neoantigens allows for the discovery of novel antigenic peptides while post-translationally modified peptides diversify the overall peptides binding to MHC or so-called MHC ligandome. The development of immunopeptidomics is keeping up-to-date and very active, particularly for clinical application. Immunopeptidomics is expected to be fast, accurate and reliable for the application for cancer immunotherapies. Review Wed, 17 Jul 2024 00:00:00 GMT SutatipPongcharoen, NongphangaKaewsringam, PoorichayaSomaparn, SittirukRoytrakul, YaowapaManeerat, KomsakPintha, SupachaiTopanurak, Wed, 17 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002249 https://www.explorationpub.com/Journals/etat/Article/1002250 Over the last decade, immune checkpoint inhibitors (ICIs) have dramatically improved the systemic treatment of multiple solid tumour types. However, they can also induce inflammation in an extensive range of normal tissues types. The entity of ICI-induced cholangitis is rare and has not been widely described. We present three cases of ICI-induced cholangitis which illustrate the difficulties associated with its diagnosis and management. We also present associated radiological findings that include intrahepatic duct abnormalities consistent with sclerosing cholangitis-progressive worsening of intrahepatic duct dilatation and pericholecystic haziness suggesting inflammation characteristic of this rare, but severe, toxicity. Case Report Fri, 19 Jul 2024 00:00:00 GMT SimonGray, NuriaSantamaria, AnnaOlsson-Brown, Fri, 19 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002250 https://www.explorationpub.com/Journals/etat/Article/1002251 Despite innovative advances in molecular targeted therapy, treatment strategies using immune checkpoint inhibitors (ICIs) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) have not progressed significantly. Accumulating evidence suggests that ICI chemotherapy is inadequate in this population. Biomarkers of ICI therapy, such as programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), are not biomarkers in patients with EGFR mutations, and the specificity of the tumor microenvironment has been suggested as the reason for this. Combination therapy with PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors is a concern because of its severe toxicity and limited efficacy. However, early-stage NSCLC may differ from advanced-stage NSCLC. In this review, we comprehensively review the current evidence and summarize the potential of ICI therapy in patients with EGFR mutations after acquiring resistance to treatment with EGFR-tyrosine kinase inhibitors (TKIs) with no T790M mutation or whose disease has progressed on osimertinib. Review Fri, 19 Jul 2024 00:00:00 GMT KenAkao, YukoOya, TakayaSato, AkiIkeda, TomoyaHoriguchi, YasuhiroGoto, NaozumiHashimoto, MasashiKondo, KazuyoshiImaizumi, Fri, 19 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002251 https://www.explorationpub.com/Journals/etat/Article/1002252 Recently, new data have been added to the interaction between non-coding RNAs (ncRNAs) and epigenetic machinery. Epigenetics includes enzymes involved in DNA methylation, histone modifications, and RNA modifications, and mechanisms underlying chromatin structure, repressive states, and active states operating in transcription. The main focus is on long ncRNAs (lncRNAs) acting as scaffolds to assemble protein complexes. This review does not cover RNA’s role in sponging microRNAs, or decoy functions. Several lncRNAs were shown to regulate chromatin activation and repression by interacting with Polycomb repressive complexes and mixed-lineage leukemia (MLL) activating complexes. Various groups reported on enhancer of zeste homolog 2 (EZH2) interactions with regulatory RNAs. Knowledge of the function of these complexes opens the perspective to develop new therapeutics for cancer treatment. Lastly, the interplay between lncRNAs and epitranscriptomic modifications in cancers paves the way for new targets in cancer therapy. The approach to inhibit lncRNAs interaction with protein complexes and perspective to regulate epitrascriptomics-regulated RNAs may bring new compounds as therapeuticals in various types of cancer. Review Mon, 22 Jul 2024 00:00:00 GMT PalmiroPoltronieri, Mon, 22 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002252 https://www.explorationpub.com/Journals/etat/Article/1002253 Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5–15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL’s mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL’s molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients. Review Tue, 23 Jul 2024 00:00:00 GMT AmattaMirandari, HelenParker, MargaretAshton-Key, BenjaminStevens, RenataWalewska, KostasStamatopoulos, DeanBryant, David G.Oscier, JaneGibson, Jonathan C.Strefford, Tue, 23 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002253 https://www.explorationpub.com/Journals/etat/Article/1002256 Non-small cell lung cancer (NSCLC) that is operable still carries a high risk of recurrence, approaching 50% of all operable cases despite adding adjuvant chemotherapy. However, the utilization of immunotherapy and targeted therapy moving beyond the metastatic NSCLC setting and into early-stage perioperative management has generated tremendous enthusiasm and has been practice-changing. Adjuvant atezolizumab in NSCLC first demonstrated a clinical benefit with an immune checkpoint inhibitor. Then, with studies studying a significant benefit in major pathologic response in surgical patients treated preoperatively with immunotherapy compared to only chemotherapy, neoadjuvant nivolumab and chemotherapy were evaluated and showed significant event-free survival benefit leading to subsequent studies evaluating perioperative immunotherapy and chemotherapy. Meanwhile, with regards to targeted therapies, adjuvant osimertinib in EGFR-mutated NSCLC and adjuvant alectinib in ALK-rearranged NSCLC have both received regulatory approvals following demonstrated clinical benefit in clinical trials. With rapidly evolving changes in the field, new combinations such as multiple immunotherapy agents and antibody-drug conjugates in development, perioperative NSCLC management has quickly become complicated with different pathways to perioperative treatment. Furthermore, circulating tumor DNA and studies looking at better tools to prognosticate immunotherapy response will help with decision-making regarding which patients should receive immunotherapy and if so, either only pre-operatively or both pre- and post-operatively. In this review, we look at the evolution of systemic therapy in the perioperative setting from adjuvant chemotherapy to adjuvant immunotherapy to perioperative immunotherapy and look at perioperative targeted therapy while looking ahead to future considerations. Review Fri, 26 Jul 2024 00:00:00 GMT RobertHsu, Zhaohui LiaoArter, DarinPoei, David J.Benjamin, Fri, 26 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002256 https://www.explorationpub.com/Journals/etat/Article/1002257 Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer therapy. Over the last decade, both their primary focus in trials and clinical application have exponentially risen, with repeated demonstrations of their efficacy in improving survival in various cancer types. The adverse effects of these drugs on various organ systems were recognised in early phase studies. Given their relatively new emergence on the market, there has been increasing interest into short- and long-term effects and management of ICIs in real-world settings. ICI-related hepatobiliary toxicities are often challenging to diagnose and difficult to distinguish from other causes of deranged liver biochemical tests. The aim of this review is to provide an up-to-date and detailed exploration of the hepatobiliary complications of ICIs, including pathogenesis and approaches to diagnosis and management. Review Fri, 26 Jul 2024 00:00:00 GMT DonnaZhuang, DavidZhang, StephenRiordan, Fri, 26 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002257 https://www.explorationpub.com/Journals/etat/Article/1002259 Accurate identification of prostate cancer Gleason grade group remains an important component of the initial management of clinically localized disease. However, Gleason score upgrading (GSU) from biopsy to radical prostatectomy can occur in up to a third of patients treated with surgery. Concern for disease undergrading remains a source of diagnostic uncertainty, contributing to both over-treatment of low-risk disease as well as under-treatment of higher-risk prostate cancer. This review examines the published literature concerning risk factors for GSU from time of biopsy to prostatectomy final pathology. Risk factors identified for Gleason upgrading include patient demographic and clinical factors including age, body mass index, race, prostate volume, and biomarker based assays, including prostate-specific antigen (PSA) density, and testosterone values. In addition, prostate magnetic resonance imaging (MRI) findings have also been associated with GSU. Biopsy-specific characteristics associated with GSU include lower number of biopsy cores and lack of targeted methodology, and possibly increasing percent biopsy core positivity. Recognition of risk factors for disease undergrading may prompt confirmatory testing including repeat sampling or imaging. Continued refinements in imaging guided biopsy techniques may also reduce sampling error contributing to undergrading. Review Wed, 31 Jul 2024 00:00:00 GMT ShayanSmani, VinaikSundaresan, Soum D.Lokeshwar, Ankur U.Choksi, JeffreyCarbonella, JosephBrito, JosephRenzulli, PrestonSprenkle, Michael S.Leapman, Wed, 31 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002259 https://www.explorationpub.com/Journals/etat/Article/1002254 Outcomes for women with breast cancer have improved dramatically in recent decades. However, many patients present with intrinsic drug resistance and others are initially sensitive to anti-cancer drugs but acquire resistance during the course of their treatment, leading to recurrence and/or metastasis. Drug therapy-induced senescence (TIS) is a form of drug resistance characterised by the induction of cell cycle arrest and the emergence of a senescence-associated secretory phenotype (SASP) that can develop in response to chemo- and targeted- therapies. A wide range of anticancer interventions can lead to cell cycle arrest and SASP induction, by inducing genotoxic stress, hyperactivation of signalling pathways or oxidative stress. TIS can be anti-tumorigenic in the short-term, but pro-tumorigenic in the long-term by creating a pro-inflammatory and immunosuppressive microenvironment. Moreover, the SASP can promote angiogenesis and epithelial-mesenchymal transition in neighbouring cells. In this review, we will describe the characteristics of TIS in breast cancer and detail the changes in phenotype that accompany its induction. We also discuss strategies for targeting senescent cancer cells in order to prevent or delay tumour recurrence. Review Fri, 26 Jul 2024 00:00:00 GMT Suraj NarayananChembukavu, Andrew JLindsay, Fri, 26 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002254 https://www.explorationpub.com/Journals/etat/Article/1002255 The prognosis of metastatic esophageal cancer (EC) remains poor with an average life expectancy of around 9–12 months with standard systemic chemotherapy. The concept of oligometastatic disease (OMD) in EC cancer is controversial with no universally accepted definition. From the original cohort of metastatic oesophago-gastric (OG) cancer patients, 4 cases were identified that developed unusually favourable outcome with long-term survival and probable cure. In retrospect, all patients had OMD at presentation with striking similarities in terms of their clinical presentation, staging, treatment response and outcomes. All patients presented with locally advanced EC and 1–2 areas of metastatic disease (bone, lung, non-regional lymph node (LN) involvement). All were treated with combined therapeutic strategy using initial systemic chemotherapy followed by local radiotherapy to primary tumor and adjacent areas of visible/residual metastatic disease (metastasis-directed therapy). All patients experienced long-term survival (range = 7–13 years) with no evidence of recurrence and probable cure. The present case series adds to the growing pool of evidence indicating OM EC cancer represents a distinct and prognostically favorable subgroup. Case Report Fri, 26 Jul 2024 00:00:00 GMT MohanHingorani, HannahStubley, Fri, 26 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002255 https://www.explorationpub.com/Journals/etat/Article/1002258 The landscape of treatment for first-line therapy in advanced urothelial cancer (aUC) and metastatic urothelial cancer (mUC) has rapidly changed in the last year alone. Maintenance avelumab remains a viable treatment option for many patients across the globe for those who have responded or have achieved stable disease after platinum-based chemotherapy. However, the recent FDA approvals based on EV-302 for enfortumab vedotin (EV) and pembrolizumab, as well as CheckMate-904 with gemcitabine and cisplatin with nivolumab (GC+N) followed by maintenance nivolumab have left clinicians with the complicated decision of determining which regimen is most appropriate for their individual patients with untreated aUC. This commentary highlights the key trials that have set the standard-of-care for front-line aUC treatment and suggestions for choosing different regimens for the appropriate patient. Commentary Mon, 29 Jul 2024 00:00:00 GMT MiniraAslanova, Eun-MiYu, Jeanny B.Aragon-Ching, Mon, 29 Jul 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002258 https://www.explorationpub.com/Journals/etat/Article/1002268 For a long time, the family of receptor tyrosine kinases, including epidermal growth factor receptor and insulin-like growth factor 1 receptor, was regarded as the main players stimulating cell proliferative signaling. Today, it is increasingly clear that many G protein-coupled receptors (GPCRs) are also involved in controlling the hallmarks of cancer by activating diverse intracellular signaling networks. GPCRs can therefore be considered as promising drug targets for fighting against diverse types of human malignancies. Although plant polyphenols, flavonoids, are well known for their diverse anticancer effects inhibiting the growth, proliferation, migration, and invasion of malignant cells, involvement of GPCRs in these activities has still remained largely unelucidated. Therefore, in this review article, the current knowledge about the role of GPCRs in anticancer action of structurally varied flavonoids is compiled, highlighting the ability of these natural polyphenols to modulate the expression levels of GPCRs but also suppress the action of endogenous ligands and downstream tumor-promoting events. These data show that targeting the respective GPCRs by specific flavonoids may open new perspectives in the therapeutic intervention in human malignancies. Review Fri, 30 Aug 2024 00:00:00 GMT KatrinSak, Fri, 30 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002268 https://www.explorationpub.com/Journals/etat/Article/1002260 Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 (BRCA1 and BRCA2) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and BRCA genes mutations. In recent years, the benefit of combination therapy consisted of a PARP inhibitor (PARPi) plus an androgen receptor signalling inhibitor (ARSi), was evaluated as first-line treatment of mCRPC, regardless of the mutational state of genes, participating in the homologous recombination repair (HRR). This review explores the role of PARPi in PCa and analyses the data of latest clinical trials exploring the PARPi—ARSi combinations, and how these results could change our clinical practice. Review Fri, 02 Aug 2024 00:00:00 GMT MartinaPanebianco, VittoreCereda, Mario RosarioD’Andrea, Fri, 02 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002260 https://www.explorationpub.com/Journals/etat/Article/1002261 One of the directions in treatment of chemoresistant breast cancer (BC) may include new methods of activating the immune response against tumor cells. Clinically used checkpoint inhibition using antibodies to PD-1 and PD-L1 works in some patients, but the lack of biomarkers means number of respondents is low. The possibility of combining this method with chemotherapy is limited by an increased risk of toxic liver damage, development of immune-related pneumonitis, and thyroid dysfunction. This article includes introduction into the clinic of new methods of immunotherapy for BC, among which epigenetic activation of retroelements, double-stranded transcripts of which stimulate the interferon response against the tumor, is promising. For this purpose, inhibitors of DNA methyltransferase*, histone deacetylase* and histone methyltransferase* are used (* subtitles in the main text). Their antitumor effect is also mediated by removal of repressive epigenetic marks from tumor suppressor genes. However, numerous studies have proven the role of retroelements in the carcinogenesis of various malignant neoplasms, including BC. Moreover, endogenous retroviruses HERV-K and LINE1 retrotransposons are planned to be used as diagnostic biomarkers for BC. Therefore, a rational approach to using viral mimicry in antitumor therapy of BC may be the simultaneous suppression of specific retrotransposons (drivers for carcinogenesis) using reverse transcriptase inhibitors and silencing of specific transposons involved in carcinogenesis using complementary microRNAs. To determine possible pathways of influence in this direction, 35 specific transposon-derived microRNAs* changes in BC were identified, which can become guides for targeted therapy of BC. Review Tue, 06 Aug 2024 00:00:00 GMT Rustam NailevichMustafin, Tue, 06 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002261 https://www.explorationpub.com/Journals/etat/Article/1002262 The bone marrow microenvironment (BMM) has highly specialized anatomical characteristics that provide a sanctuary place for hematopoietic stem cells (HSCs) that allow appropriate proliferation, maintenance, and self-renewal capacity. Several cell types contribute to the constitution and function of the bone marrow niche. Interestingly, uncovering the secrets of BMM and its interaction with HSCs in health paved the road for research aiming at better understanding the concept of leukemic stem cells (LSCs) and their altered niche. In fact, they share many signals that are responsible for interactions between LSCs and the bone marrow niche, due to several biological similarities between LSCs and HSCs. On the other hand, LSCs differ from HSCs in their abnormal activation of important signaling pathways that regulate survival, proliferation, drug resistance, invasion, and spread. Targeting these altered niches can help in better treatment choices for hematological malignancies and bone marrow disorders in general and acute myeloid leukemia (AML) in particular. Moreover, targeting those niches may help in decreasing the emergence of drug resistance and lower the relapse rate. In this article, the authors reviewed the most recent literature on bone marrow niches and their relations with either normal HSCs and AML cells/LSC, by focusing on pathogenetic and therapeutic implications. Review Thu, 15 Aug 2024 00:00:00 GMT ShaimaaKhattab, ManalEl Sorady, AshrafEl-Ghandour, GiuseppeVisani, Pier PaoloPiccaluga, Thu, 15 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002262 https://www.explorationpub.com/Journals/etat/Article/1002263 Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC is primarily attributed to its fibrotic, hypoxic, and immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food and Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors with heat and induces coagulative necrosis, releasing tumor antigens that may trigger a systemic immune response—the abscopal effect. We aim to elucidate the roles of EUS-RFA-mediated thermal and mechanical stress in enhancing anti-tumor immunity in PDAC. A comprehensive literature review focused on radiofrequency immunomodulation and immunotherapy in pancreatic tumors to understand the pathophysiological mechanisms of RFA and its effect on the TME, which could prevent recurrence and resistance. We reviewed clinical, preclinical, and in vitro studies on RFA mechanisms in pancreatic adenocarcinoma, discussing the unique immunomodulatory effects of EUS-RFA. Recent findings suggest that combining RFA with immune adjuvants enhances responses in pancreatic adenocarcinoma. EUS-RFA offers a dual benefit against PDAC by directly reducing tumor viability and indirectly enhancing anti-tumor immunity. Observations of neutrophil-mediated immunomodulation and programmed cell death ligand 1 (PD-L1) modulation support integrating EUS-RFA with targeted immunotherapies for managing pancreatic adenocarcinoma. Integrating EUS-RFA in PDAC treatment promises direct cytoreduction and synergistic effects with molecular targeted therapies. Prospective clinical trials are crucial to assess the efficacy of this combined approach in improving outcomes and survival rates in advanced PDAC cases. Review Fri, 16 Aug 2024 00:00:00 GMT VishaliMoond, BhumiManiyar, Prateek SureshHarne, Jennifer M.Bailey-Lundberg, Nirav C.Thosani, Fri, 16 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002263 https://www.explorationpub.com/Journals/etat/Article/1002264 Cancer remains a concern after years of research in this field. Conventional therapies such as chemotherapy, radiation, and surgery are available for cancer treatment, but they are characterized by various side effects. There are several immunological challenges that make it difficult for the immune system and conventional therapies to treat cancer. Some of these challenges include heterogeneity, resistance to medicines, and cancer relapse. Even advanced treatments like immune checkpoint inhibitors (ICIs), which revolutionized cancer treatment, have associated toxicity and resistance further necessitate the exploration of alternative therapies. Anticancer peptides (ACPs) offer promising potential as cancer-fighting agents and address challenges such as treatment resistance, tumor heterogeneity, and metastasis. Although these peptides exist as components of the defense system in various plants, animals, fungi, etc., but can also be created synthetically and used as a new treatment measure. These peptides possess properties that make them appealing for cancer therapy, such as apoptosis induction, inhibition of angiogenesis, and cell membrane breakdown with low toxicity. Their capacity to specifically target cancer cells selectively holds promise for enhancing treatment environments as well as improving patients’ quality of life. This review provides detailed insights into the different prospects of ACPs, including their characterization, use as immunomodulatory agents in cancer treatment, and their mechanistic details after addressing various immunological challenges in existing cancer treatment strategies. In conclusion, ACPs have promising potential as novel cancer therapeutics due to their target specificity and fewer side effects than conventional therapies. Review Thu, 22 Aug 2024 00:00:00 GMT ApurvaSood, V.V.Jothiswaran, AmritaSingh, AnuradhaSharma, Thu, 22 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002264 https://www.explorationpub.com/Journals/etat/Article/1002265 Aim: Human epidermal growth factor receptor-2 (HER2) is a well-established prognostic and predictive biomarker. It is an FDA-approved therapeutic target for HER2 positive breast, gastroesophageal, and more recently, lung and colon cancers. It is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers. The emergence of new indications warrants further characterization of HER2 expression in diverse cancer populations. This study investigated HER2 expression in solid tumour samples and the feasibility of obtaining these results. Methods: Prospective consent was obtained at a Canadian tertiary academic cancer center from adult oncology patients who were referred for molecular genetic testing of malignant tissue samples. Standard HER2-targeted malignancies were considered breast and gastroesophageal, and were excluded from this study. Between July 2020 and November 2023, 499 samples of solid tumors underwent immunohistochemistry (IHC) HER2 staining. A median turnaround time (TAT) of 14 days would be considered feasible for clinical decision making. Results: The mean age (± SD) of participants was 67 ± 12.5 years, with 270 (54%) male and 229 (46%) female. HER2 protein expression was measured in 42 unique cancer types. IHC levels of 0, 1+, 2+, and 3+ were reported and were 43%, 12%, 35%, and 10% of all analyzable samples respectively (tissue inadequate in 3% of samples). The median TAT for HER2 expression results from time of request to result in release was 18 (interquartile range, 11 to 30) days. Conclusions: HER2 protein expression varies widely between different cancer types. TAT for HER2 IHC results was a median of 18 days, which is close to our feasibility cut-off. Original Article Fri, 23 Aug 2024 00:00:00 GMT SauravVerma, AmandaChapman, Lee-AnnePickard, DaniellePorplycia, HaleyMcConkey, PatriciaJarosz, JamesSinfield, CarolynLauzon-Young, Matthew JCecchini, ChristopherHowlett, NatalieGrindrod, BekimSadikovic, Stephen AWelch, DanielBreadner, Fri, 23 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002265 https://www.explorationpub.com/Journals/etat/Article/1002267 Bladder cancer is a leading cancer type in men. The complexity of treatment in late-stage bladder cancer after systemic spread through the lymphatic system highlights the importance of modulating disease-free progression as early as possible in cancer staging. With current therapies relying on previous standards, such as platinum-based chemotherapeutics and immunomodulation with Bacillus Calmette-Guerin, researchers, and clinicians are looking for targeted therapies to stop bladder cancer at its source early in progression. A new era of molecular therapies that target specific features upregulated in bladder cancer cell lines is surfacing, which may be able to provide clinicians and patients with better control of disease progression. Here, we discuss multiple emerging therapies including immune checkpoint inhibitors of the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, antibody-drug conjugates, modulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) cell proliferation pathway, chimeric antigen receptor T-cell therapy, and fibroblast growth factor receptor targeting. Together, these modern treatments provide potentially promising results for bladder cancer patients with the possibility of increasing remission and survival rates. Review Fri, 30 Aug 2024 00:00:00 GMT Scott D.Bell, Anthony E.Quinn, Tom D.Spitzer, Brady B.Voss, Mark R.Wakefield, YujiangFang, Fri, 30 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002267 https://www.explorationpub.com/Journals/etat/Article/1002266 Prostate cancer (PC) depicts a major health challenge all over the globe due to its complexities in the treatment and diverse clinical trajectories. Even in the advances in the modern treatment strategies, the spectrum of resistance to the therapies continues to be a significant challenge. This review comprehensively examines the underlying mechanisms of the therapy resistance occurred in PC, focusing on both the tumor microenvironment and the signaling pathways implicated in the resistance. Tumor microenvironment comprises of stromal and epithelial cells, which influences tumor growth, response to therapy and progression. Mechanisms such as microenvironmental epithelial-mesenchymal transition (EMT), anoikis suppression and stimulation of angiogenesis results in therapy resistance. Moreover, dysregulation of signaling pathways including androgen receptor (AR), mammalian target of rapamycin/phosphoinositide 3 kinase/AKT (mTOR/PI3K/AKT), DNA damage repair and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways drive therapy resistance by promoting tumor survival and proliferation. Understanding these molecular pathways is important for developing targeted therapeutic interventions which overcomes resistance. In conclusion, a complete grasp of mechanisms and pathways underlying medication resistance in PC is important for the development of individualized treatment plans and enhancements of clinical outcomes. By studying and understanding the complex mechanisms of signaling pathways and microenvironmental factors contributing to therapy resistance, this study focuses and aims to guide the development of innovative therapeutic approaches to effectively overcome the PC progression and improve the survival rate of patients. Review Thu, 29 Aug 2024 00:00:00 GMT NehaThakur, PallaviSingh, AditiBagri, SaumyaSrivastava, VinayDwivedi, AshaSingh, Sunil KumarJaiswal, SunnyDholpuria, Thu, 29 Aug 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002266 https://www.explorationpub.com/Journals/etat/Article/1002270 Background: To summarize the results of available studies for investigating the role of neutrophil to lymphocyte ratio (NLR) in testicular cancer (tCa). Methods: The search was conducted on PubMed, Scopus, and Web of Science up to November 21, 2021. Finally, a total of 31 studies were included in this review. Results: NLR was higher in tCa patients compared to healthy controls and benign testis pathologies, and decreased significantly after orchiectomy. An elevated NLR predicts poor prognosis, advanced stage, presence of nodal or distant metastases, contralateral tumor development, lower time-to-cancer specific death, worse OS, and poorer response to chemotherapy. However, NLR could not differentiate between seminomas and non-seminomatous tCa. Discussion: NLR has a significant diagnostic and prognostic value in tCa. Systematic Review Fri, 20 Sep 2024 00:00:00 GMT ShirinSarejloo, SagharBabadi, ShokoufehKhanzadeh, AmirhosseinSalimi, AlecClark, DinyarKhazaeli, MonirehKhanzadeh, ArshinGhaedi, BrandonLucke-Wold, Fri, 20 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002270 https://www.explorationpub.com/Journals/etat/Article/1002269 Aim: Prostate biopsy can be prone to complications and thus should be avoided when unnecessary. Although the combination of magnetic resonance imaging (MRI), the prostate health index (PHI), and PHI density (PHID) has been shown to improve detection of clinically significant prostate cancer (csPCa), there is limited information available assessing its clinical utility. We sought to determine whether using PHID could enhance the detection of PCa on MRI ultrasound fusion-targeted biopsy (MRF-TB) compared to other biomarker cutoffs. Methods: Between June 2015 and December 2020, 302 men obtained PHI testing before MRF-TB at a single institution. We used descriptive statistics, multivariable logistic regression, and receiver operating characteristic curves to determine the predictive accuracy of PHID and PHI to detect ≥ Gleason grade group (GGG) 2 PCa and identify cutoff values. Results: Any cancer grade was identified in 75.5% of patients and ≥ GGG2 PCa was identified in 45% of patients. The median PHID was 1.05 [interquartile range (IQR) 0.59–1.64]. A PHID cutoff of 0.91 had a higher discriminatory ability to predict ≥ GGG2 PCa compared to PHI > 27, PHI > 36, and prostate specific-antigen (PSA) density > 0.15 (AUC: 0.707 vs. 0.549 vs. 0.620 vs. 0.601), particularly in men with Prostate Imaging Reporting and Data System (PI-RADS) 1–2 lesions on MRI (AUC: 0.817 vs. 0.563 vs. 0.621 vs. 0.678). At this cutoff, 35.0% of all the original biopsies could be safely avoided (PHID < 0.91 and no ≥ GGG2 PCa) and csPCa would be missed in 9.67% of patients who would have been biopsied. In patients with PI-RADS 1–2 lesions using a PHID cutoff of 0.91, 56.8% of biopsies could be safely avoided while missing 0 csPCa. Conclusions: These findings suggest that a PHID cutoff of 0.91 improves the selection of patients with elevated prostate-specific antigen who are referred for prostate biopsy, and potentially in patients with PI-RADS 1–2 lesions. Original Article Sat, 14 Sep 2024 00:00:00 GMT Benjamin H.Press, Soum D.Lokeshwar, LindseyWebb, GhazalKhajir, ShayanSmani, OlamideOlawoyin, MursalGardezi, Syed N.Rahman, Michael S.Leapman, Preston C.Sprenkle, Sat, 14 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002269 https://www.explorationpub.com/Journals/etat/Article/1002271 Immune checkpoint inhibitors (ICI)-based combinations have become the standard first-line treatment for advanced clear cell renal cell carcinoma (ccRCC). Despite significant improvements in survival and the achievement of sustained long-term responses, a subset of patients remains refractory to ICI, and most will eventually develop resistance. Thus, identifying predictive biomarkers for ICI efficacy and resistance is essential for optimizing therapeutic strategies. Up to now, tissue-based biomarkers have not been successful as predictive biomarkers in RCC. Circulating blood-based biomarkers offer a promising alternative. These biomarkers, including circulating immune cells, soluble factors, tumor-derived markers, and those based on metabolomics, are less invasive, offer reproducibility over time, and provide a comprehensive assessment of tumor biology and patient immune status, as well as allow dynamic monitoring during treatment. This review aims to evaluate the current evidence on the different candidate circulating biomarkers being investigated for their potential to predict ICI efficacy in RCC patients. Review Fri, 20 Sep 2024 00:00:00 GMT LoubnaOmri, MarieNaigeon, RonanFlippot, JavierGavira-Díaz, JesusPoveda-Ferriols, DanNguyen, ChaimaeAbdi, AlvaroArroyo-Salgado, NathalieChaput, Guillermo deVelasco, LaurenceAlbigès, LucíaCarril-Ajuria, Fri, 20 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002271 https://www.explorationpub.com/Journals/etat/Article/1002272 Oral squamous cell carcinoma (OSCC) is a highly malignant and invasive tumor with significant mortality and morbidity. Current treatment modalities such as surgery, radiotherapy, and chemotherapy encounter significant limitations, such as poor targeting, systemic toxicity, and drug resistance. There is an urgent need for novel therapeutic strategies that offer targeted delivery, enhanced efficacy, and reduced side effects. The advent of lipid-based nanoparticles (LNPs) offers a promising tool for OSCC therapy, potentially overcoming the limitations of current therapeutic approaches. LNPs are composed of biodegradable and biocompatible lipids, which minimize the risk of toxicity and adverse effects. LNPs can encapsulate hydrophobic drugs, improving their solubility and stability in the biological environment, thereby enhancing their bioavailability. LNPs demonstrate significantly higher ability to encapsulate lipophilic drugs than other nanoparticle types. LNPs offer excellent storage stability, minimal drug leakage, and controlled drug release, making them highly effective nanoplatforms for the delivery of chemotherapeutic agents. Additionally, LNPs can be modified by complexing them with specific target ligands on their surface. This surface modification allows the active targeting of LNPs to the tumors in addition to the passive targeting mechanism. Furthermore, the PEGylation of LNPs improves their hydrophilicity and enhances their biological half-life by reducing clearance by the reticuloendothelial system. This review aims to discuss current treatment approaches and their limitations, as well as recent advancements in LNPs for better management of OSCC. Review Mon, 30 Sep 2024 00:00:00 GMT Anis AhmadChaudhary, MohammadFareed, Salah-Ud-DinKhan, Lina M.Alneghery, MohammedAslam, ArockiaAlex, Md.Rizwanullah, Mon, 30 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002272 https://www.explorationpub.com/Journals/etat/Article/1002273 The treatment of early-stage non-small cell lung cancer (NSCLC) is becoming increasingly complex. Standard of care management for the past decade has been adjuvant chemotherapy following curative intent resection regardless of nodal status or tumour profile. With the increased incorporation of immunotherapy in NSCLC, especially in the locally advanced, unresectable, or metastatic settings, multiple studies have sought to assess its utility in early-stage disease. While there are suboptimal responses to neoadjuvant chemotherapy alone, there is a strong rationale for the use of neoadjuvant immunotherapy in tumour downstaging, based upon the concept of enhanced T cell priming at the time of a high tumour antigen burden, and demonstrated clinically in other solid tumours, such as melanoma. In the NSCLC cancer setting, currently over 20 combinations of chemoimmunotherapy in the neoadjuvant and perioperative setting have been studied with results variable. Multiple large phase III studies have demonstrated that neoadjuvant chemoimmunotherapy combinations result in significant advances in pathological response, disease free and overall survival which has led to practice change across the world. Currently, combination immunotherapy regimens with novel agents targeting alternate immunomodulatory pathways are now being investigated. Given this, the landscape of treatment in resectable early-stage NSCLC has become increasingly complex. This review outlines the literature of neoadjuvant and perioperative immunotherapy and discusses its potential benefits and complexities and ongoing considerations into future research. Review Mon, 30 Sep 2024 00:00:00 GMT ThomasHansen, JonathonHill, GaryTincknell, DerrickSiu, DanielBrungs, PhilipClingan, LorraineChantrill, UditNindra, Mon, 30 Sep 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002273 https://www.explorationpub.com/Journals/etat/Article/1002274 Upper tract urothelial cancer (UTUC) are rare subsets of urothelial cancer, which typically present with more aggressive course. Molecular markers stratifying urothelial tumors as luminal subtype and non-luminal subtype tumors have been proposed to select patients who may have greater or lesser benefit from neoadjuvant systemic therapy in bladder cancer, though not yet evaluated in UTUC. Here, a single-institution study retrospectively obtained clinical and genomic information in patients with UTUC and evaluated four patient tumors using the Decipher Bladder® assay and Foundation Medicine® test. All four patients had non-luminal molecular subtype including basal (N = 4) and mixed basal/claudin-low (N = 2) subtypes. The best clinical response achieved was stable disease in a patient who had basal/claudin-low subtype with residual ypT3 after neoadjuvant chemotherapy. For the remaining three patients, all were treated with platinum-based chemotherapy for eventual metastatic disease but all three showed progressive disease with limited overall survival, highlighting their aggressive course. The non-luminal subtype and lack of FGFR alteration may partly explain the poor overall outcomes while the real-world benefit of next generation sequencing for clinical use in UTUC patients require further clarification in a larger cohort study. Case Report Fri, 18 Oct 2024 00:00:00 GMT Min WooHwang, JasmineKauffeld, SarahBelay, Joep J.de Jong, ElaiDavicioni, WenpingLi, Jeanny B.Aragon-Ching, Fri, 18 Oct 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002274 https://www.explorationpub.com/Journals/etat/Article/1002275 Aim: The present study aims to evaluate the efficacy of rechallenge with immune checkpoint inhibitors (ICIs) compared to chemotherapy and the predictive role of clinical parameters in non-small cell lung cancer (NSCLC) patients who were rechallenged. Methods: The study included 113 metastatic NSCLC patients who had initially responded to ICIs and platinum-based chemotherapy, either in combination in the first line or sequentially in the first and second line, but later experienced disease progression. Of those patients, 52 later received ICI rechallenge and 61 were exposed to chemotherapy. Results: In the rechallenge cohort, the median age was 67 years, 38 patients were men (73.1%), 26 (50.0%) had squamous cell carcinoma. Patients who underwent ICI rechallenge had longer overall survival (OS) compared to those who received chemotherapy (12.9 months vs. 9.6 months, P = 0.008). Multivariate analysis for progression-free survival (PFS) and OS revealed that poor Eastern Cooperative Oncology Group Performance Status (ECOG PS; PFS: P = 0.013 and OS: P = 0.037), absence of objective response during initial ICI therapy (PFS: P = 0.014 and OS: P = 0.028), and baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3.8 (PFS: P = 0.001 and OS: P = 0.003) were negative predictive factors of ICI rechallenge. The three parameters were included in a risk model named as the NEO score, which stratified patients who received ICI rechallenge into two predictive groups. Patients with ECOG PS 0-1, objective response during initial ICI treatment, and NLR < 3.8 (favorable group) had longer PFS (8.6 months vs. 3.0 months, P < 0.001) and OS (16.6 months vs. 5.5 months, P < 0.001) compared to those with absence of all three markers (poor group). There was no association between the NEO score and survival outcomes in patients who did not undergo rechallenge. Conclusions: ICI rechallenge showed a survival benefit, particularly in NSCLC patients with NLR < 3.8, good ECOG PS, and objective response. Original Article Fri, 18 Oct 2024 00:00:00 GMT Aram A.Musaelyan, Svetlana V.Odintsova, Karina A.Musaelyan, Magaripa A.Urtenova, Ekaterina P.Solovyova, Lyubov I.Menshikova, Sergey V.Orlov, Fri, 18 Oct 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002275 https://www.explorationpub.com/Journals/etat/Article/1002276 Fibroblast-activated protein (FAP) expression in glial cells is attributed to FAP-positive foci on tumor vessels and neoplastic cells. Preclinical and pilot studies have shown FAP expression in high-grade gliomas. We aimed at comparing PET imaging with FAP-inhibitor (FAPI-PET) with current standard, i.e., fluoro-ethyl tyrosine (FET) PET in post-treatment setting to differentiate recurrence and post-treatment changes. 6 patients with WHO Grade III and IV glioma who received standard treatment underwent Ga-68-FAPI-04 PET/CT (FAPI-PET/CT). Tracer uptake greater than background was considered positive. FET PET was performed and interpreted as per institutional standards, which formed the basis of treatment decision. There was concordance between FAPI expression and FET uptake in 5 patients suggestive of disease recurrence. There was no FAPI expression seen in 1 patient, in whom FET PET was suggestive of post-treatment changes. FAPI PET uptake correlated with amino acid expression to differentiate post treatment changes from recurrence in high-grade glial tumors; further validation with prospective study and histopathological confirmation is needed. Short Communication Fri, 01 Nov 2024 00:00:00 GMT Indraja D.Dev, Ameya D.Puranik, VenkateshRangarajan, SukritiPatra, NilenduPurandare, ArpitaSahu, AmitkumarChoudhary, KajariBhattacharya, TejpalGupta, AbhishekChatterjee, ArchyaDasgupta, AliasgarMoiyadi, PrakashShetty, VikasSingh, EpariSridhar, AyushiSahay, AektaShah, SuchismitaGhosh, SayakChoudhury, SnehaShah, ArchiAgrawal, Fri, 01 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002276 https://www.explorationpub.com/Journals/etat/Article/1002277 Lung cancer is the leading cause of cancer mortality globally, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Despite advancements in first-line treatments such as immunotherapy and targeted therapies, resistance to these treatments is common, creating a significant unmet need for effective second-line therapies. This review evaluates current and emerging second-line therapeutic options for advanced or metastatic NSCLC, focusing on their efficacy and potential to improve patient outcomes. Anti-angiogenic drugs like ramucirumab combined with chemotherapy, particularly docetaxel, have shown moderate success. Antibody-drug conjugates (ADCs) targeting specific tumor antigens offer a promising avenue for targeted therapy, while chimeric antigen receptor (CAR)-T cell therapy and T-cell receptor therapy leverage the patient’s immune system to combat cancer more effectively. mRNA vaccines, although in early stages, show potential for inducing robust immune responses against cancer-specific antigens. Building on this foundation, recent advancements in molecular testing and the exploration of the tumor microenvironment are opening new therapeutic avenues, further enhancing the potential for personalized second-line treatments in NSCLC. While ADCs and bispecific antibodies are gaining traction, more precise biomarkers are needed to optimize treatment response. Regular monitoring through techniques like liquid biopsies allows real-time tracking of mutations such as EGFR T790M, enabling timely therapeutic adjustments. Additionally, the role of neutrophils and macrophages in the tumor microenvironment is increasingly being recognized as a potential therapeutic avenue, with Smad3 emerging as a key target. Further research into drug sequencing, toxicity management, and biomarker development remains crucial to improving NSCLC treatment outcomes. Review Fri, 01 Nov 2024 00:00:00 GMT KinsleyWang, AlexisLeyba, RobertHsu, Fri, 01 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002277 https://www.explorationpub.com/Journals/etat/Article/1002278 Not applicable. Editorial Wed, 20 Nov 2024 00:00:00 GMT StefanoMarletta, AntonioRizzo, GrazianaSpoto, LucaFalzone, Wed, 20 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002278 https://www.explorationpub.com/Journals/etat/Article/1002279 Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%. Platinum-based chemotherapy has been the backbone of the first-line treatment of aUC for over 40 years. Only in the last decade, the treatment of aUC has evolved and been enriched with new classes of drugs that demonstrated pivotal improvements in terms of oncological responses and, ultimately, survival. Thus, the approach to aUC is becoming more and more tailored to the single patient, particularly owing to targeted therapies, such as fibroblast growth factor receptor (FGFR) inhibitors, antibody-drug conjugates (ADCs) targeting TROP2 and Nectin-4, anti-Her-2 therapies and others. However, due to the rapidly evolving scenario, the optimal sequence of systemic treatment is unknown and several important research questions remain unanswered, including the identification of reliable biomarkers to guide treatment decisions. Through ongoing research and clinical trials, we can continue to refine personalized treatment strategies and ultimately enhance patient care in this challenging disease setting. In this review, we provide a comprehensive overview of the current and emerging landscape of targeted therapies for aUC. We delved into the opportunities and challenges presented by personalized treatment approaches and explored potential future directions in this rapidly evolving field. Review Thu, 21 Nov 2024 00:00:00 GMT IreneTesti, Giulia ClaireGiudice, GiuseppeSalfi, MartinoPedrani, SaraMerler, FabioTurco, LuigiTortola, UrsulaVogl, Thu, 21 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002279 https://www.explorationpub.com/Journals/etat/Article/1002280 There has been a rapid expansion of immunotherapy options for non-small cell lung cancer (NSCLC) over the past two decades, particularly with the advent of immune checkpoint inhibitors. Despite the emerging role of immunotherapy in adjuvant and neoadjuvant settings though, relatively few patients will respond to immunotherapy which can be problematic due to expense and toxicity; thus, the development of biomarkers capable of predicting immunotherapeutic response is imperative. Due to the promise of a noninvasive, personalized approach capable of providing comprehensive, real-time monitoring of tumor heterogeneity and evolution, there has been wide interest in the concept of using circulating tumor DNA (ctDNA) to predict treatment response. Although the use of ctDNA to detect actionable mutations such as EGFR is now integral in the standard of care for patients with NSCLC, several large studies have also shown its potential as a biomarker of immunotherapeutic response. Ongoing ctDNA interventional clinical trials, such as the BR.36 trial, will help to clarify the potential role of ctDNA for therapeutic guidance. Despite the promise of this technology, there are many limitations and considerations that clinicians need to be aware of prior to widespread implementation in clinical practice, such as the effect of underlying comorbidities, ctDNA fraction, stage of underlying malignancy, and concordance between aberrations detected in ctDNA and tumor tissue. Perspective Tue, 26 Nov 2024 00:00:00 GMT Brandon JosephHebert, JamesBradley, Tue, 26 Nov 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002280 https://www.explorationpub.com/Journals/etat/Article/1002281 The emergence of immunotherapy has ushered in a new era in the management of non-small cell lung cancer (NSCLC). Various immune check point inhibitors have demonstrated significant benefit in the management of locally advanced NSCLC that are treated with either surgery or concurrent chemoradiation. We provide a comprehensive and up-to-date review of data from key studies, discuss the challenging clinical issue regarding the timing and duration of immunotherapy in patients undergoing surgery, and highlight the unmet needs and future directions of immunotherapy in NSCLC. Review Fri, 06 Dec 2024 00:00:00 GMT Justin J.Kuhlman, ShenduoLi, RamiManochakian, YanyanLou, YujieZhao, Fri, 06 Dec 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002281 https://www.explorationpub.com/Journals/etat/Article/1002282 Despite the fact that life expectancies are increasing and the burden of infectious diseases is decreasing, global cancer incidence rates are on the rise. Cancer outcome metrics are dismal for low- and middle-income countries (LMICs), including sub-Saharan Africa, where adequate resources and infrastructure for cancer care and control are lacking. Nigeria, the most populous country in Africa, exemplifies the miserable situation. However, the investigation of medicinal plants for better and safer anti-cancer drugs has now increased tremendously. While scientific evidence is emerging of the potential of some constituents of medicinal plants used in traditional medicine in Nigeria to have anti-cancer effects, there is now a critical need for platforms that integrate ethnomedicinal information on such plants with emerging scientific data on them, to support and accelerate the discovery and development of more efficacious and safer anti-cancer drugs and recipes. Thus, this review highlights the scientific evidence to date for the anti-cancer potential of plants commonly used in traditional medicine to treat cancers in Nigeria. Scientific databases such as PubMed, Science Direct, Scopus, Google Scholar, and Web of Science, as well as related sources, were searched to retrieve relevant information on anti-cancer medicinal plants. Ethnobotanical/ethnomedicinal details of the identified plants were then linked with the available scientific data on their anti-cancer potential, including the cytotoxicity to cancer and normal cells of the extracts and constituent compounds responsible for the activity. This annotated chronicle of Nigerian medicinal plants with potential anticancer activity is a great resource for all stakeholders in the prevention and management of cancers. Review Mon, 09 Dec 2024 00:00:00 GMT Mansurah A.Abdulazeez, Hiba A.Jasim, Temidayo D.Popoola, Saheed O.Benson, JiradejManosroi, Abdullahi B.Sallau, Musa A.Tabari, Amos A.Fatokun, Mon, 09 Dec 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002282 https://www.explorationpub.com/Journals/etat/Article/1002283 Aim: Immune checkpoint inhibitors improved the survival of advanced non-small cell lung cancer. However, only 20% of patients respond to these treatments and the search for predictive biomarkers of response is still topical. The objective of this work is to analyze the anti-PD-1 monotherapy benefit based on genetic alterations diagnosed by next generation sequencing (NGS), in advanced non-small cell lung cancer. Methods: Patients with advanced non-small cell lung cancer treated with immunotherapy were retrospectively included in this monocentric study. Clinical data, immunohistochemical expression of PD-L1 and molecular data, with a 22-genes NGS panel, were collected. Results: 107 patients were included. The median age was 65 years [59; 73], 70 were men (65%), 96 had adenocarcinoma (90%), 33 were receiving a first line (31%). 54 patients had KRAS mutation (50%) and 56 had TP53 mutation (52%). The remaining mutations were present in fewer than 10 patients. There was no statistically significant differences in median of progression-free or overall survival based on KRAS-only, TP53-only or KRAS-TP53 mutations co-mutated compared to double wild-type patients (P = 0.46 and P = 0.72 respectively). Conclusions: The search for a predictive composite biomarker remains a major issue in the coming years. Original Article Wed, 18 Dec 2024 00:00:00 GMT HortenseDe Saint Basile, RezaElaidi, ZinebMaaradji, HélèneBlons, RymBenDhiab, LaureGibault, ElizabethFabre, Wed, 18 Dec 2024 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002283 https://www.explorationpub.com/Journals/etat/Article/1002284 Aim: Breast cancer (BC), a disease in which abnormal breast cells grow out of control and form tumors, is a prevalent life-threatening disease worldwide. Oxidative stress has been implicated in the development and progression of various cancers, including BC. Assessing lipid peroxidation and overall antioxidant status in BC offers valuable information on disease progression, patient prognosis, and the effectiveness of therapeutic options. Methods: A total of 150 women were categorized into three groups: normal, benign mass, and BC. Participants were selected and evaluated at the cancer clinic; fasting blood samples were collected, and total antioxidant capacity (TAC), oxidized low-density lipoprotein (Ox-LDL), cancer antigen (CA) 15-3, and carcinoembryonic antigen (CEA) were measured. Subsequently, statistical analysis was performed to compare the levels of these parameters in different groups and examine the analytical performance of TAC and Ox-LDL in BC. Results: In patients with malignancy, the serum level of TAC was significantly decreased compared with the benign group (8.3 U/mL and 16.04 U/mL, respectively) (P < 0.001). Healthy controls exhibited higher levels of TAC (43.4 U/mL). The levels of Ox-LDL in BC were significantly increased in both malignant and benign groups (3,831 pg/mL and 1,234 pg/mL, respectively) compared with normal controls (682 pg/mL) (P < 0.001). CEA and CA15-3 were drastically increased in the BC groups compared with the control group. A significant area under the curve was observed in the receiver operating characteristic (ROC) curve analysis for TAC (0.975, P < 0.001) and Ox-LDL (0.986, P < 0.001). Conclusions: This study revealed that patients with BC had lower TAC and higher Ox-LDL serum levels, indicating elevated oxidative stress. These levels may serve as promising monitoring parameters in BC. Original Article Fri, 03 Jan 2025 00:00:00 GMT Abdullatif TahaBabakr, Mohamed MahmoudNour Eldein, Fri, 03 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002284 https://www.explorationpub.com/Journals/etat/Article/1002286 The discovery of oncogenes and tumor suppressor genes led to a better understanding of tumorigenesis, and prompted the development of molecularly targeted therapy. Over the past 30 years, many new drugs, which are primarily aimed at activated oncogenic proteins in signal transduction pathways involved in cell proliferation and survival, have been introduced in the clinic. Despite its rational design, the overall efficacy of targeted therapy has been modest. Recently, the noncoding RNAs (ncRNAs) have emerged as key regulators of important cellular processes in addition to the known regulatory proteins. It now appears that dual epigenetic regulatory systems exist in higher eukaryotic cells: a ncRNA network that governs essential cell functions, like cell fate decision and maintenance of homeostasis, and a protein-based system that presides over core physiological processes, like cell division and genomic maintenance. Modifications of the ncRNA network due to altered ncRNAs can cause the cell to shift towards to neoplastic phenotype; this is cancer initiation. Mutations in the well-known cancer driver genes provide the incipient cancer cell with a selective growth advantage and fuel its consequent clonal expansion. Because of the crucial role of the altered ncRNAs in tumorigenesis, targeting them may be a reasonable therapeutic strategy. Perspective Thu, 16 Jan 2025 00:00:00 GMT AmilShah, Thu, 16 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002286 https://www.explorationpub.com/Journals/etat/Article/1002287 Aim: The interaction of concomitant benzodiazepine (BZD) exposure during immune checkpoint blockade has not been comprehensively investigated to date. This research aimed to determine the influence of BZD intake on the survival outcomes of patients with metastatic non-small-cell lung cancer (NSCLC) receiving pembrolizumab-based therapies. Methods: We included consecutive patients with advanced NSCLC who were given frontline pembrolizumab, whether as exclusive therapy or combined with platinum-based chemotherapy. The classification of BZD relied on the molecular composition, distinguishing between N-substituted and N-unsubstituted compounds. Results: During the time frame from April 2018 to May 2023, we enrolled 258 patients, 156 (60.5%) and 102 (39.5%) of whom received pembrolizumab alone or the combination regimen, respectively. We identified 108 (41.8%) exposed patients (BZD cohort) in comparison to all others (no-BZD cohort). After applying propensity-score matching, 108 cases were relevant for each cohort. After a median follow-up of 16.3 [95% confidence interval (CI) 13.1–19.7] months, univariate analysis revealed no significant differences in terms of progression-free survival (PFS) or overall survival (OS) between BZD cohorts. However, patients exposed to N-substituted compounds had significantly longer PFS and OS than those who did not take BZD. Conversely, patients exposed to N-unsubstituted compounds experienced significantly shortened OS. Multivariate testing showed that taking unspecified BZD had no impact on PFS or OS, while N-substituted BZD exposure correlated independently with longer PFS [hazard ratio (HR) 0.52 (95% CI 0.34–0.79); P = 0.002] and OS [HR 0.58 (95% CI 0.38–0.88); P < 0.001]. In contrast, N-unsubstituted BZD intake had worsening effects on OS [HR 1.92 (95% CI 1.20–3.06); P = 0.006]. Conclusions: BZD exposure may impact the efficacy of immune checkpoint inhibitors in patients with advanced NSCLC. The specific composition may influence the choice among different compounds. Original Article Mon, 20 Jan 2025 00:00:00 GMT FabrizioNelli, Enzo MariaRuggeri, AntonellaVirtuoso, DianaGiannarelli, ArmandoRaso, FedericaNatoni, GloriaPessina, DanieleRemotti, Mario GiovanniChilelli, CarloSignorelli, AgneseFabbri, Mon, 20 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002287 https://www.explorationpub.com/Journals/etat/Article/1002288 Bladder cancer is currently the most common malignant tumor of the urinary system. The traditional treatment methods for bladder cancer are mainly surgery, chemotherapy, radiotherapy, and targeted therapy; however, these treatment methods do not improve the clinical prognosis of patients with advanced or metastatic bladder cancer. Consequently, there is an urgent need to develop new treatment methods to improve the survival rate and quality-of-life of patients with bladder cancer. Over recent years, the rapid development of tumor immunotherapy has become a significant alternative to traditional treatment, and provides new hope to patients. This review aims to introduce neoantigens and their possible role in the treatment of bladder cancer, and to explore the current limitations of neoantigens for the treatment of bladder cancer. Review Sun, 26 Jan 2025 00:00:00 GMT RuiyangLv, ZhenzhuLiu, MaoxinLv, YuzeSong, JunlinWang, HuizhiMu, YuZhang, XuejianWang, Sun, 26 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002288 https://www.explorationpub.com/Journals/etat/Article/1002289 Background: Telomere length is a potential prognostic biomarker in breast cancer, but its clinical utility remains uncertain due to inconsistent findings across the literature. This systematic review and meta-analysis aims to evaluate the association between telomere length and breast cancer survival outcomes, including overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS). Methods: A systematic search of ten sources, including databases and publishers (JSTOR, Nature, ProQuest, PubMed, Sage Journals, ScienceDirect, Science, Scopus, Springer, and Wiley) was conducted to identify studies published up to December 31, 2023. Studies reporting associations between telomere length and survival outcomes in breast cancer patients were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) were extracted or calculated. Quality assessment was performed using the Newcastle-Ottawa Scale, and publication bias was evaluated using funnel plots, Egger’s, and Begg’s tests. Results: Nine studies involving 3,145 breast cancer patients were included. Shorter telomere length was significantly associated with increased recurrence risk (DFS/RFS) (pooled HR: 1.97; 95% CI: 1.04–3.74, P = 0.039), indicating a nearly twofold increase in risk. Trends toward worse OS (pooled HR: 1.60; 95% CI: 0.90–2.86, P = 0.110) and DSS (pooled HR: 1.09; 95% CI: 0.80–1.49, P = 0.565) were observed, but did not reach statistical significance. Additionally, shorter telomere length was significantly associated with premenopausal status (pooled OR: 1.34; 95% CI: 1.06–1.70, P = 0.01). Discussion: Shorter telomere length is associated with an increased risk of recurrence in breast cancer, highlighting its potential as a prognostic biomarker. However, further research is needed to standardize telomere length measurement methodologies and validate these findings across diverse populations and breast cancer subtypes. Meta-Analysis Fri, 14 Feb 2025 00:00:00 GMT Dhyas Munandar AryaSasmita, Kavi GilangPermana, TeguhAryandono, Didik SetyoHeriyanto, Sumadi LukmanAnwar, Fri, 14 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002289 https://www.explorationpub.com/Journals/etat/Article/1002290 Background: Preclinical animal studies have demonstrated that radiation treatment (RT) can induce effects beyond the anatomical site of irradiation. Non-targeted effects of RT (NTER) have been sporadically reported in clinical settings. However, with the advent of high-dose stereotactic radiation techniques (SRT) and immunotherapy (IT), renewed attention has been given to NTER. This systematic review aims to summarize current knowledge about NTER across various malignancies, with a focus on cases involving SRT. Methods: A systematic database search was performed, and records were screened following PRISMA guidelines. Only full-text original articles written in English and reporting clinical studies involving NTER after SRT were included. The results are categorized by cancer type, with separate general and critical analyses. Results: Sixty-three studies were reviewed, including 32 case reports/case series, 18 retrospective studies, and 13 prospective studies, predominantly published after 2018. NTER was most frequently observed in melanoma and lung cancer and commonly reported as the abscopal effect (AE), albeit with varying criteria. In most cases, IT with suboptimal response was ongoing at the time of SRT, and the median time to NTER onset was 3 months. Overall, NTER was documented in 297 patients: 34 from single cases and 263 from a pool of 1,212 evaluable patients (22%) across other studies. Prospective trials reported an NTER rate of 36%, rising to 56% in lung cancer. Discussion: In prospective clinical studies, the phenomenon of NTER following SRT has been observed in a significant proportion of patients. Nevertheless, the literature is limited, with small patient cohorts. Interest in NTER has grown, particularly in the context of IT. Standardization of definitions and reporting, along with the conduct of more clinical trials, is essential to better understand how NTER can be induced by SRT. Systematic Review Fri, 14 Feb 2025 00:00:00 GMT AngelaBarillaro, MaraCaroprese, ChiaraFeoli, EmanueleChioccola, Christina AmandaGoodyear, CaterinaOliviero, StefaniaClemente, AntonioFarella, ManuelConson, RobertoPacelli, Fri, 14 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002290 https://www.explorationpub.com/Journals/etat/Article/1002291 Multikinase inhibitors (MKIs) and highly selective tyrosine kinase inhibitors (HS-TKIs) positively impact the progression-free survival (PFS) of locally advanced and metastatic thyroid cancer cases. Moreover, disease-specific survival (DSS) and overall survival (OS) improvements were observed in some instances, suggesting a general benefit in disease control. In advanced and metastatic thyroid cancers, other conventional treatments are often ineffective when surgery cannot be performed due to the extension of the disease and/or the invasion of vital neck structures (such as the larynx, trachea, esophagus, recurrent laryngeal nerve, and carotid artery). In these cases, systemic treatments with MKIs and HS-TKIs have recently been evaluated for their potential to block tumor growth and reduce tumor size to make surgery possible or improve the control of metastatic disease. The study aimed to evaluate the performance of these systemic drugs in the neoadjuvant treatment of thyroid cancer patients, focusing on their efficacy according to the different histology. Review Fri, 14 Feb 2025 00:00:00 GMT LauraValerio, AntonioMatrone, Fri, 14 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002291 https://www.explorationpub.com/Journals/etat/Article/1002292 Laryngeal cancer, a subtype of head and neck cancer, poses significant challenges due to its profound impact on essential functions such as speech and swallowing and poor survival rates in advanced stages. Traditional treatments—surgery, radiotherapy, and chemotherapy—are often associated with high morbidity and substantial recurrence rates, emphasizing the urgent need for novel therapeutic approaches. Immune checkpoint inhibitors (ICIs) have revolutionized oncology by countering tumor-induced immune evasion, restoring immune surveillance, and activating T-cell responses against cancer. This review examines the role of ICIs in laryngeal cancer management, with a focus on pembrolizumab and nivolumab (anti-PD-1 agents), which are clinically established, as well as investigational therapies such as dostarlimab (anti-PD-1), atezolizumab (anti-PD-L1), and ipilimumab (anti-CTLA-4). Pembrolizumab, in combination with platinum-based chemotherapy and 5-fluorouracil, is approved as a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), based on evidence from the Keynote-048 trial. This pivotal trial demonstrated significant overall survival (OS) benefits over the cetuximab-based standard regimen. Similarly, nivolumab showed improved OS in the CheckMate-141 trial, supporting its approval as a second-line therapy for patients with platinum-refractory disease. ICIs have shown durable survival benefits and a more manageable toxicity profile compared to traditional chemotherapy. Immune-related adverse events are generally mild and controllable; however, in some cases, they can become severe and even life-threatening. Furthermore, ICIs are being investigated in combination with radiotherapy, as well as in neoadjuvant and adjuvant settings, where preliminary findings suggest these approaches may enhance efficacy, preserve organ function, and overcome resistance to conventional treatments. The integration of ICIs into multimodal treatment strategies holds promise for transforming the therapeutic landscape of advanced laryngeal cancer. This review synthesizes current evidence, highlights ongoing research, and explores strategies to enhance survival and quality of life for patients facing this challenging malignancy. Review Tue, 18 Feb 2025 00:00:00 GMT MichailAthanasopoulos, PinelopiSamara, GeorgiosAgrogiannis, IoannisAthanasopoulos, NikolaosKavantzas, EfthymiosKyrodimos, Nicholas S.Mastronikolis, Tue, 18 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002292 https://www.explorationpub.com/Journals/etat/Article/1002293 Background: Breast cancer is a leading cause of mortality in women. Hormone therapy plays a crucial role in treatment of hormone receptor-positive metastatic breast cancer. Elacestrant is a selective estrogen receptor degrader (SERD) that has shown promise in early-phase clinical trials. This post-hoc analysis systematically evaluates elacestrant’s effectiveness in hormone receptor-positive metastatic breast cancer patients, providing insights into its efficacy, safety, and potential advantages over existing treatments. Methods: We adhered to the PRISMA Statement 2020 guidelines and systematically searched the databases PubMed/MEDLINE, ClinicalTrials.gov, Web of Science, and Embase. We conducted the post-hoc analysis using R software (V 4.3.3), applying the inverse variance method and the DerSimonian-Laird estimator to pool effect estimates with a random-effects model. We assessed heterogeneity using the Cochran’s Q test and the I2 statistic. Results: Our post-hoc analysis encompassed 3 clinical trials and a total of 835 participants. The mean age of all 835 participants across the three trials was 59.5 years (95% CI: 58.7–60.3). The pooled progression-free survival (PFS)—was estimated at 4.38 (95% CI: –7.58–16.35, P = 0.47), and the pooled objective response rate (ORR) was 7% (95% CI: 2–18%, P = 0.04), with significant heterogeneity observed among the studies. Discussion: Elacestrant shows promise for improving outcomes in hormone receptor-positive metastatic breast cancer, but further research is needed to confirm its effectiveness. Future studies should include larger sample sizes, comprehensive phase II and III trials, and investigation of elacestrant in combination with other drugs or in preoperative settings. Meta-Analysis Fri, 21 Feb 2025 00:00:00 GMT AzzaSarfraz, MuznaSarfraz, FaheemJavad, MusfiraKhalid, BushraShah, AmnaGul, Mohammad ArfatGaniyani, AreebaIsmail, KhadijaCheema, Fri, 21 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002293 https://www.explorationpub.com/Journals/etat/Article/1002294 Glioblastoma, an aggressive and lethal brain tumor, presents enormous clinical challenges, including molecular heterogeneity, high recurrence rates, resistance to conventional therapies, and limited therapeutic penetration across the blood-brain barrier. The glioblastoma microenvironment, characterized by a dynamic interplay of cellular and non-cellular components, is a key driver of tumor growth and therapeutic resistance. Neuroinflammatory cytokines, particularly interleukins and tumor necrosis factor-alpha, play pivotal roles in this microenvironment, contributing to tumor progression and immune evasion. This review highlights oncolytic virotherapy as a promising therapeutic avenue, focusing on its potential to modulate neuroinflammatory responses, induce localized immune reactions, and deliver immunomodulatory factors directly to the tumor site. While encouraging outcomes have been observed, challenges such as overcoming the blood-brain barrier, managing host antiviral immunity, and mitigating potential risks to normal neuronal cells remain critical barriers to clinical translation. By analyzing the intricate interactions of oncolytic viruses with the glioblastoma microenvironment and synthesizing findings from preclinical and clinical trials, this review provides actionable insights into developing personalized and effective therapeutic strategies for this aggressive tumor based on oncolytic virotherapy alone or when using it combined with conventional therapies, immunotherapy, natural killer-cell therapy, chimeric antigen receptor-T cell therapy, and dendritic cell therapy. Review Tue, 25 Feb 2025 00:00:00 GMT NarimeneBeder, Seyedeh NasimMirbahari, MouradBelkhelfa, HamidMahdizadeh, MehdiTotonchi, Tue, 25 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002294 https://www.explorationpub.com/Journals/etat/Article/1002285 Cancer is the greatest cause of mortality worldwide. Various drug classes treat various cancers. Nanoformulations made from natural sources are being studied for treating several diseases, including cancer. Surgery, chemotherapy, immunotherapy, and radiation have mostly failed to treat cancer. These drugs may damage quickly dividing healthy tissues, structural anomalies, bodily toxicity, long-term side effects, tumor cell drug resistance, and psychiatric disturbances. Researchers are developing nanoscale medicines using natural medications like Malva sylvestris and Curcumin to lower concentrations and improve target specificity. Nanoparticles’ small size and unique properties make them beneficial. They encapsulate medicinal ingredients, improving solubility, medication release, cellular absorption, and delivery. Nanoparticles may better identify and bind to cancer cells when functionalized with ligands. Natural chemicals and nanotechnology may improve medication availability, distribution, and targeting to cancer cells, making cancer treatments more effective and safe. Nanomedicine, which employs nanoparticles to treat cancer and malignant cells, has grown rapidly because nanodrugs are more effective and have fewer side effects than current commercial cancer drugs. Nanotechnology-based natural chemicals and pharmaceutical delivery methods for cancer therapy are covered in this review article. The paper discusses nanoparticle pros and cons and natural chemicals’ cancer-fighting appeal. Review Fri, 03 Jan 2025 00:00:00 GMT RoshanYadav, Himmat SinghChawra, GauravDubey, Md SabirAlam, VikramKumar, PragyaSharma, Navneet KumarUpadhayay, TejpalYadav, Fri, 03 Jan 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002285 https://www.explorationpub.com/Journals/etat/Article/1002295 Aim: Colorectal cancer is the most prevalent gastrointestinal malignancy with limited therapeutic options in the metastatic setting. The WNT/β-catenin/adenomatous polyposis coli (APC) pathway is commonly deregulated in the disease and presents a rational target for therapeutic exploitation. Methods: The publicly available genomic data from the colorectal cancer cohort of the Cancer Genome Atlas (TCGA) were used to define groups of colorectal cancers with alterations in APC or other key genes of the WNT/β-catenin/APC pathway and to identify genomic characteristics of interest in each group. In vitro sensitivity data for drugs targeting the pathway were compiled from the Genomics of Drug Sensitivity in Cancer (GDSC) project. Results: Three-fourths of colorectal cancers possessed APC alterations and about one in four of these cases possessed also concomitant alterations in other genes of the WNT/β-catenin/APC pathway, including RNF43, CTNNB1, and TCF7L2. Colorectal cancers with alterations in one or more of the three genes of the WNT/β-catenin pathway, RNF43, CTNNB1, and TCF7L2, in the absence of APC alterations, were frequently microsatellite instability (MSI) high and had high tumor mutation burden (TMB). Cancers with these same alterations in the three genes with or without APC alterations presented a high frequency of mutations in receptor tyrosine kinases, PI3K/AKT pathway genes, and DNA damage response genes. Cell lines without mutations in WNT/β-catenin/APC pathway components displayed numerically greater sensitivity to inhibitors of the pathway in vitro. Conclusions: Groups of colorectal cancers differing in WNT/β-catenin/APC pathway alterations present diverse genomic landscapes that could have therapeutic implications for the rational development of inhibitors of the pathway. Original Article Wed, 26 Feb 2025 00:00:00 GMT Ioannis A.Voutsadakis, Wed, 26 Feb 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002295 https://www.explorationpub.com/Journals/etat/Article/1002296 Cervical cancer remains a significant global health challenge, ranking as the fourth most common cancer among women. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiological factor, leading to immune evasion mechanisms that promote tumor development and progression. Immunotherapy has emerged as a transformative approach in the management of cervical cancer, aiming to restore and enhance the body’s immune response against tumor cells. Checkpoint inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1) have shown promising results in patients with advanced or recurrent cervical cancer. Pembrolizumab, a PD-1 inhibitor, has been approved for PD-L1-positive cervical cancer, demonstrating durable responses. However, low response rates necessitate exploration of combination strategies. Trials are underway combining checkpoint inhibitors with chemotherapy, radiation, or other immunotherapeutic agents to enhance efficacy. Therapeutic vaccines targeting HPV antigens, such as E6 and E7 oncoproteins, are also a focus of active research. These vaccines aim to elicit robust cytotoxic T-cell responses, offering a potential strategy for early intervention and disease control. Adoptive T-cell therapies, including engineered T-cell receptor (TCR) and chimeric antigen receptor (CAR)-T cells, represent cutting-edge advancements, though challenges with tumor heterogeneity and off-target effects persist. However, challenges such as limited response rates and immune evasion mechanisms remain. The tumor microenvironment (TME) in cervical cancer, characterized by immunosuppressive cells and cytokines, poses a significant barrier to effective immunotherapy. Emerging approaches targeting the TME, such as cytokine modulation, hold promise in overcoming resistance mechanisms. Key gaps include a lack of biomarkers for patient selection, insufficient understanding of TME dynamics, and suboptimal strategies for overcoming antigen heterogeneity and immune resistance. This review addresses these issues by providing a comprehensive analysis of the current landscape of cervical cancer immunotherapy, identifying critical barriers, and highlighting emerging approaches, such as combination therapies, novel immune targets, and strategies to modulate the TME, to guide future research and clinical practice. Review Mon, 03 Mar 2025 00:00:00 GMT TreshitaDey, SushmaAgrawal, Mon, 03 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002296 https://www.explorationpub.com/Journals/etat/Article/1002297 Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity. Review Fri, 14 Mar 2025 00:00:00 GMT LuisCabezón-Gutiérrez, MagdaPalka-Kotlowska, SaraCustodio-Cabello, BeatrizChacón-Ovejero, VilmaPacheco-Barcia, Fri, 14 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002297 https://www.explorationpub.com/Journals/etat/Article/1002298 Although immune checkpoint inhibitors (ICIs) are widely used in clinical oncology, less than half of treated cancer patients derive benefit from this therapy. Both tumor- and host-related variables are implicated in response to ICIs. The predictive value of PD-L1 expression is confined only to several cancer types, so this molecule is not an agnostic biomarker. Highly elevated tumor mutation burden (TMB) caused either by excessive carcinogenic exposure or by a deficiency in DNA repair is a reliable indicator for ICI efficacy, as exemplified by tumors with high-level microsatellite instability (MSI-H). Other potentially relevant tumor-related characteristics include gene expression signatures, pattern of tumor infiltration by immune cells, and, perhaps, some immune-response modifying somatic mutations. Host-related factors have not yet been comprehensively considered in relevant clinical trials. Microbiome composition, markers of systemic inflammation [e.g., neutrophil-to-lymphocyte ratio (NLR)], and human leucocyte antigen (HLA) diversity may influence the efficacy of ICIs. Studies on ICI biomarkers are likely to reveal modifiable tumor or host characteristics, which can be utilized to direct the antitumor immune defense. Examples of the latter approach include tumor priming to immune therapy by cytotoxic drugs and elevation of ICI efficacy by microbiome modification. Review Mon, 17 Mar 2025 00:00:00 GMT Evgeny N.Imyanitov, Elena V.Preobrazhenskaya, Natalia V.Mitiushkina, Mon, 17 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002298 https://www.explorationpub.com/Journals/etat/Article/1002300 Background: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow, constituting approximately 13% of all hematologic malignancies. Isatuximab is a monoclonal antibody targeting the CD38 protein on myeloma cells, causing cell death through various immune-mediated mechanisms. Clinical trials have shown that adding isatuximab to standard regimens for MM significantly enhances efficacy but introduces some notable toxicities. The purpose of this study is to determine the risk of pneumonia, upper respiratory tract infections (URTIs), and venous thromboembolism (VTE) in patients with MM treated with isatuximab. Methods: We conducted a comprehensive literature search using Medline, Embase, and Cochrane databases from inception through July 22nd, 2024. Phase III randomized controlled trials (RCTs) utilizing isatuximab in newly diagnosed MM (NDMM) and relapsed and refractory MM (RRMM) reporting pneumonia, URTIs, and VTE as adverse events were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1,044 patients from three phase III RCTs (ICARIA-MM, IKEMA, IMROZ) were included for pneumonia and URTI analysis, while 1,403 patients from three trials (IKEMA, IMROZ, GMMG-HD7) were included for VTE evaluation. The incidence of any-grade pneumonia was higher in the isatuximab group (30.1% vs. 23.2%; RR, 1.31; 95% CI 1.06–1.61; P = 0.01), as was high-grade pneumonia (20.8% vs. 15.3%; RR, 1.38; 95% CI 1.06–1.81; P = 0.02). No statistically significant differences were observed between the isatuximab and control groups for any-grade URTIs, high-grade URTIs, or VTE. Discussion: This meta-analysis highlights a significant increase in the incidence of pneumonia with the addition of isatuximab to standard myeloma regimens, underscoring the need for routine antibiotic prophylaxis, thromboprophylaxis, vigilant monitoring and early intervention to mitigate these risks. Meta-Analysis Thu, 20 Mar 2025 00:00:00 GMT Daniel ThomasJones, HazemAboaid, RamadityaSrinivasmurthy, KevinNguyen, Rishi KumarNanda, JasonTa, Benjamin Tzer-MingChuang, Yin MonMyat, AishwaryaHanspal, Kyaw ZinThein, Thura WinHtut, Thu, 20 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002300 https://www.explorationpub.com/Journals/etat/Article/1002301 Bladder cancer (BCa) is among the most frequently diagnosed urinary tract cancers, characterized by a high recurrence rate and significant clinical heterogeneity. Effective diagnosis and treatment of BCa demand continuous advancements in medical technologies, particularly given the limitations of classical methods such as cystoscopy and urine cytology. A comprehensive search of PubMed and Web of Science was conducted using relevant keywords to structure this narrative review. Additionally, specialist journals were reviewed. Only articles in English were included, with selection based on titles, abstracts, and availability of full texts. In recent years, biomarkers have emerged as crucial tools complementing traditional techniques, providing more precise, sensitive, and non-invasive methods for early detection, prognosis, and monitoring treatment response in BCa. Molecular, genetic, and protein biomarkers enable a deeper understanding of BCa biology, creating opportunities for personalized therapy tailored to individual patient needs. However, despite their potential, certain challenges remain, including standardization, validation, and integration into routine clinical practice. This review highlights recent advancements in BCa biomarkers and their transformative potential in oncological care. It underscores the importance of incorporating these innovations to refine diagnostic and therapeutic approaches, ultimately improving patient outcomes. Modern diagnostic and prognostic tools for BCa can enhance treatment outcomes by enabling early disease detection and reducing recurrence risks. This progress promises to improve patients’ quality of life by minimizing disease burden and fostering effective, tailored care strategies. Review Tue, 25 Mar 2025 00:00:00 GMT DominikGodlewski, DorotaBartusik-Aebisher, SaraCzech, JakubSzpara, DavidAebisher, Tue, 25 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002301 https://www.explorationpub.com/Journals/etat/Article/1002302 Small cell lung cancer (SCLC) is an aggressive tumor characterized by early metastasis and resistance to treatment, making it a prime target for therapeutic investigation. The current standard of care for frontline treatment involves a combination of chemotherapeutic agents and immune checkpoint inhibitors (ICIs), though durability of response remains limited. The genetic heterogeneity of SCLC also complicates the development of new therapeutic options. Adoptive cell therapies show promise by targeting specific mutations in order to increase efficacy and minimize toxicity. There has been significant investigation in three therapeutic classes for application towards SCLC: antibody drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR)-T cell therapies. This review summarizes the recent advances and challenges in the development of adoptive cell therapies. Genetic targets such as delta-like ligand 3 (DLL3), trophoblast cell surface antigen 2 (Trop2), B7-H3 (CD276), gangliosides disialoganglioside GD2 (GD2) and ganglioside GM2 (GM2) have been found to be expressed in SCLC, which makes them prime targets for therapy development. While investigated therapies such as rovalpituzumab tesirine (Rova-T) have failed, several insights from these trials have led to the development of compelling new agents such as sacituzumab govitecan (SG), ifinatamab deruxtecan (I-DXd), tarlatamab, and DLL3-targeted CAR-T cells. Advancing development of molecular testing and improving targeted approaches remain integral to pushing forward the progress of adoptive cell therapies in SCLC. Review Wed, 26 Mar 2025 00:00:00 GMT Eljie IsaakBragasin, JustinCheng, LaurenFord, DarinPoei, SanaAli, RobertHsu, Wed, 26 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002302 https://www.explorationpub.com/Journals/etat/Article/1002308 Immunotherapy has gathered significant attention and is now a widely used cancer treatment that uses the body’s immune system to fight cancer. Despite initial successes, its broader clinical application is hindered by limitations such as heterogeneity in patient response and challenges associated with the tumor immune microenvironment. Recent advancements in nanotechnology have offered innovative solutions to these barriers, providing significant enhancements to cancer immunotherapy. Nanotechnology-based approaches exhibit multifaceted mechanisms, including effective anti-tumor immune responses during tumorigenesis and overcoming immune suppression mechanisms to improve immune defense capacity. Nanomedicines, including nanoparticle-based vaccines, liposomes, immune modulators, and gene delivery systems, have demonstrated the ability to activate immune responses, modulate tumor microenvironments, and target specific immune cells. Success metrics in preclinical and early clinical studies, such as improved survival rates, enhanced tumor regression, and elevated immune activation indices, highlight the promise of these technologies. Despite these achievements, several challenges remain, including scaling up manufacturing, addressing off-target effects, and navigating regulatory complexities. The review emphasizes the need for interdisciplinary approaches to address these barriers, ensuring broader clinical adoption. It also provides insights into interdisciplinary approaches, advancements, and the transformative potential of nano-immunotherapy and promising results in checkpoint inhibitor delivery, nanoparticle-mediated photothermal therapy, immunomodulation as well as inhibition by nanoparticles and cancer vaccines. Review Fri, 11 Apr 2025 00:00:00 GMT SuphiyaParveen, Dhanshree VikrantKonde, Safal KumarPaikray, Nigam SekharTripathy, LizaSahoo, Himansu BhusanSamal, FahimaDilnawaz, Fri, 11 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002308 https://www.explorationpub.com/Journals/etat/Article/1002303 Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, poses a significant therapeutic challenge due to its highly invasive nature and resistance to conventional therapies, including surgery, chemotherapy, and radiotherapy. Despite advances in standard treatments, patient survival remains limited, requiring the exploration of innovative strategies. Photodynamic therapy (PDT) has emerged as a promising approach, leveraging light-sensitive photosensitizers (PSs), molecular oxygen, and specific light wavelengths to generate reactive oxygen species (ROS) that selectively induce tumor cell death. Originally developed for skin cancer, PDT has evolved to target more complex malignancies, including GBM. The refinement of second- and third-generation PS, coupled with advancements in nanotechnology, has significantly improved PDT’s selectivity, bioavailability, and therapeutic efficacy. Moreover, the combination of PDT with chemotherapy, targeted therapy, and immunotherapy, among other therapeutic modalities, has shown potential in enhancing therapeutic outcomes. This review provides a comprehensive analysis of the preclinical and clinical applications of PDT in GBM, detailing its mechanisms of action, the evolution of PS, and novel combinatory strategies that optimize treatment efficacy. However, several challenges remain, including overcoming GBM-associated hypoxia, enhancing PS delivery across the blood-brain barrier, and mitigating tumor resistance mechanisms. The integration of PDT with molecular and genetic insight, alongside cutting-edge nanotechnology-based delivery systems, may revolutionize GBM treatment, offering new prospects for improved patient survival and quality of life. Review Fri, 28 Mar 2025 00:00:00 GMT Bruno A.Cesca, KaliPellicer San Martin, Matías D.Caverzan, Paula M.Oliveda, Luis E.Ibarra, Fri, 28 Mar 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002303 https://www.explorationpub.com/Journals/etat/Article/1002304 Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME’s complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically “cold” tumors, which lack immune cell infiltration, into “hot” tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME’s complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC. Review Tue, 01 Apr 2025 00:00:00 GMT AnnaDi Spirito, SaharBalkhi, VeronicaVivona, LorenzoMortara, Tue, 01 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002304 https://www.explorationpub.com/Journals/etat/Article/1002306 The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS/MAPK, PI3K/Akt/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS/MAPK pathway, GNAQ/GNA11 mutations occur which account for more than 80% of UM cases. The PI3K/Akt/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. GNAQ/GNA11 mutations activate YAP via the Trio-RhoGTPase/RhoA/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by p53 mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including NSB1, MDM2 and CCND1 amplification, and BAP1 mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies. Review Wed, 02 Apr 2025 00:00:00 GMT MajidBanimohammad, ParsaKhalafi, DanialGholamin, ZahraBangaleh, NahidAkhtar, Abhishikt DavidSolomon, Pranav KumarPrabhakar, SamiraSanami, AjitPrakash, HamidrezaPazoki-Toroudi, Wed, 02 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002306 https://www.explorationpub.com/Journals/etat/Article/1002305 The combination of lenvatinib and pembrolizumab (Len + Pembro) demonstrated significant efficacy in the phase 3 CLEAR study for metastatic renal cell carcinoma (RCC). However, poor-risk patients represented only a small proportion of the trial population. This multicenter retrospective cohort study assessed the real-world efficacy and safety of Len + Pembro in patients with clear-cell metastatic RCC and intermediate or poor International Metastatic RCC Database Consortium risk. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Sixty patients were analyzed, with a median age of 56 years. Poor risk was identified in 53% of patients, and 90% had metastases to ≥ 2 organs. ORR was 48.33%, disease control rate was 86.7%, and median PFS was 19.0 months. Grade ≥ 3 adverse events occurred in 25% of patients, with 33.3% requiring lenvatinib dose reductions. Lenvatinib plus pembrolizumab demonstrated robust efficacy and a manageable safety profile in a real-world population with advanced disease and poor-risk features, consistent with outcomes reported in clinical trials. Short Communication Wed, 02 Apr 2025 00:00:00 GMT IlyaTsimafeyeu, AlexanderSultanbaev, DariaDubovichenko, MakhabbatMurzalina, AlexanderVolkov, RashidaOrlova, IgorUtyashev, GeorgyMalina, MarkGluzman, Wed, 02 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002305 https://www.explorationpub.com/Journals/etat/Article/1002307 The combination of enfortumab vedotin and pembrolizumab (EVP) has been recently approved for patients with locally advanced and metastatic urothelial carcinoma. This combination showed a higher objective response rate and superior progression-free survival and overall survival over traditional platinum-based chemotherapy in the frontline setting in the pivotal EV-302 trial. Despite the success, a subset of patients has primary refractory disease, and another subset will develop secondary resistance over time. Resistance to enfortumab vedotin may include the downregulation of nectin-4 expression to minimize antibody binding, upregulation of efflux pumps against the toxin, or direct resistance by the tubulin against the toxin. Resistance to pembrolizumab includes several methods to downregulate the immune system. Additionally, the type of histology of the urothelial carcinoma likely plays an important role in resisting EVP. This review summarizes these possible mechanisms of primary and secondary resistance, potential biomarkers predictive of response and resistance, and methods to overcome the resistance to EVP. Review Tue, 08 Apr 2025 00:00:00 GMT AlbertJang, Jason R.Brown, Tue, 08 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002307 https://www.explorationpub.com/Journals/etat/Article/1002309 The ultrastructural morphology of eosinophil cytolysis and extracellular trap cell death (ETosis) has predominantly been examined in non-neoplastic eosinophil-associated diseases, with a limited investigation in neoplasms. This current electron microscopy study examined the ultrastructural characteristics of eosinophil cytolysis and ETosis across four distinct gastric cancer cases: three cases (cases 1–3) exhibited non-ETotic cytolysis, while one case (case 4) presented eosinophils at various stages of ETosis. In cases 1–3, eosinophil non-ETotic cytolysis was characterized by localized plasma membrane disruption, the presence of free extracellular granules (FEGs), and the maintenance of a round or oval nuclear lobe profile. In case 4, eosinophils were observed in progressive stages of ETosis, arbitrarily subdivided into early, intermediate, and advanced. Although early ETosis and non-ETotic cytolysis exhibited overlapping ultrastructural features, chromatin decondensation and nuclear envelope enlargement were more pronounced in early ETosis. Nuclear envelope disruption, loss of the round or oval nuclear lobe profile (intermediate stage), extracellular DNA trap deposition, and the appearance of Charcot-Leyden crystals (advanced stage) were all distinctive features of ETosis. The findings of this case report confirm previous observations of eosinophil cytolysis with or without ETosis in non-neoplastic diseases and extend them to advanced gastric carcinoma. Since Charcot-Leyden crystals were only seen in case 4, their correlation with ETosis was further supported. In gastric cancer, the release of FEGs during non-ETotic cytolysis and the release of both FEGs and DNA traps during ETotic cytolysis may contribute to the formation of an antitumor microenvironment. Case Report Tue, 22 Apr 2025 00:00:00 GMT RosarioCaruso, ValerioCaruso, LucianaRigoli, Tue, 22 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002309 https://www.explorationpub.com/Journals/etat/Article/1002311 This review explores the intricate relationship between viral infections and Bacillus Calmette-Guerin (BCG) efficacy, emphasizing immune modulation mechanisms that may influence treatment outcomes. Since its introduction in 1976, intravesical BCG has been a cornerstone in managing non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumors (TURBT). Despite its success, variability in response rates suggests that host immune status, influenced by persistent infections, immunosenescence, and antigenic overload, may play a crucial role in therapeutic effectiveness. Chronic viral infections can modulate T cell responses, leading to immune exhaustion and impaired antitumor immunity. This review discusses the interplay between viral antigenic load, immune dysfunction, and tumor microenvironment remodeling, highlighting their potential impact on immunotherapies. By integrating insights from virome analysis, immune profiling, and tumor characterization, this review proposes personalized strategies to enhance immunotherapy efficacy. A deeper understanding of viral-induced immune dysregulation may improve prognostic assessment, optimize treatment protocols, and reduce healthcare costs associated with bladder cancer. Future research should focus on targeted interventions to mitigate the immunosuppressive effects of chronic infections, ultimately improving patient outcomes in NMIBC management. Review Thu, 24 Apr 2025 00:00:00 GMT Lívia BitencourtPascoal, MehrsaJalalizadeh, GabrielaBarbosa, Andrea Nazare Monteiro Rangelda Silva, Maria Alice FreitasQueiroz, EkaterinaLaukhtina, Shahrokh F.Shariat, AlessandraGambero, Leonardo O.Reis, Thu, 24 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002311 https://www.explorationpub.com/Journals/etat/Article/1002310 Exportin-1 (XPO1) is a nuclear export protein that, when overexpressed, can facilitate cancer cell proliferation and survival and is frequently overexpressed or mutated in cancer patients. As such, selective inhibitors of XPO1 (XPO1i) function have been developed to inhibit cancer cell proliferation and induce apoptosis. This review outlines the evidence for the immunomodulatory properties of XPO1 inhibition and discusses the potential for combining and sequencing XPO1i with immunotherapy to improve the treatment of patients with cancer. Selinexor is a first-in-class XPO1i that is FDA-approved for the treatment of patients with relapsed and refractory (RR) multiple myeloma and RR diffuse large B cell lymphoma. In addition to the cancer cell intrinsic pro-apoptotic activity, increasing evidence suggests that XPO1 inhibition has immunomodulatory properties. In this review, we describe how XPO1i can lead to a skewing of macrophage polarisation, inhibition of neutrophil extracellular traps, modulation of immune checkpoint expression, blockade of myeloid-derived suppressor cells (MDSCs) and sensitisation of cancer cells to T cell and NK (natural killer) cell immunosurveillance. As such, there is an opportunity for selinexor to enhance immunotherapy efficacy and thus a need for clinical trials assessing selinexor in combination with immunotherapies such as immune checkpoint inhibitors, direct targeting monoclonal antibodies, chimeric antigen receptor (CAR)-T cells and cereblon E3 ligase modulators (CELMoDs). Review Thu, 24 Apr 2025 00:00:00 GMT Jack G.Fisher, Laura G.Bartlett, TrinayanKashyap, Christopher J.Walker, Salim I.Khakoo, Matthew D.Blunt, Thu, 24 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002310 https://www.explorationpub.com/Journals/etat/Article/1002313 Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments. Review Sun, 27 Apr 2025 00:00:00 GMT Moawiah MNaffaa, Ola AAl-Ewaidat, SopikoGogia, ValikoBegiashvili, Sun, 27 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002313 https://www.explorationpub.com/Journals/etat/Article/1002312 Emerging cancer immunotherapy methods, notably cytokine-based ones that modify immune systems’ inflammatory reactions to tumor cells, may help slow gastric cancer progression. Cytokines, tiny signaling proteins that communicate between immune cells, may help or hinder cancer growth. Pro-inflammatory cytokines encourage tumor development, whereas antitumor ones help the host reject cancer cells. This study considers cytokine-targeted methods for gastric cancer pro-inflammatory and antitumor immune responses. Researchers want to renew immune cells like cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells by delivering cytokines like interleukin-2 (IL-2), interferons (IFNs), and tumor necrosis factor-alpha (TNF-α) to activate inflammatory pathways and combat tumors. Since cytokines have significant pleiotropic effects, their therapeutic use is difficult and may cause excessive systemic inflammation or immunological suppression. This review covers current advancements in synthetic cytokines, cytokine-conjugates, and local administration of these aimed to enhance the therapeutic index: increase the potential to kill cancer cells while minimizing off-target damage. The study examines the relationship between cytokines and tumor microenvironment (TME), revealing the role of immunosuppressive cytokines like IL-10 and transforming growth factor-beta (TGF-β) in promoting an immune-evasive phenotype. These results suggest that inhibitory pathway targeting, and cytokine-based therapy may overcome resistance mechanisms. Cytokine-based immunotherapies combined with immune checkpoint inhibitors are predicted to change gastric cancer therapy and rebuild tumor-immune microenvironment dynamics, restoring antitumor immunity. Comprehensive data from current clinical studies will assist in establishing the position of these treatments in gastric cancer. Review Sun, 27 Apr 2025 00:00:00 GMT Mathan Muthu ChinakannuMarimuthu, Bhavani SowndharyaBalamurugan, Vickram AgaramSundaram, SaravananAnbalagan, HiteshChopra, Sun, 27 Apr 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002312 https://www.explorationpub.com/Journals/etat/Article/1002316 Background: Different tumor markers are utilized in the assessment of breast cancer. The function of these markers in assessing, tracking, and following up on breast cancer has drawn the interest of numerous researchers. Nonetheless, contradictory findings from research continue to raise questions regarding their effectiveness. Consequently, this research was carried out to evaluate the efficacy of carbohydrate antigen-125 (CA-125) in the treatment of breast cancer. Methods: A thorough investigation was performed in the PubMed, Scopus, and Web of Science databases utilizing relevant keywords: CA-125, breast cancer, screening and diagnosis, and Mesh to locate articles published before August 2023 without any time limitations. The analysis included observational studies in English pertinent to the study’s objective, while review articles, case reports, editor letters, comments, and other reports were not considered. Articles were sought, examined, included, and evaluated according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The EndNote X9 program has been utilized for item management. The review included articles that investigated the predictive function of CA-125 in the screening, diagnosis, and anticipation for the early and proper detection of breast cancer. Results: In the initial search, 1,475 articles were obtained. After screening and eligibility assessment, 33 studies were reviewed. Based on the findings of the studies, CA-125 can play a role in the diagnosis of breast cancer, its type and stage, early detection of recurrence and metastasis, treatment efficiency, prognosis, and survival rate. Discussion: The role of CA-125 as a biomarker for early detection, staging, and monitoring of recurrence and metastasis in breast cancer is still uncertain and needs additional research. Systematic Review Thu, 15 May 2025 00:00:00 GMT ZohreMomenimovahed, AfroozMazidimoradi, LeilaAllahqoli, ZohreKhalajinia, HamidSalehiniya, IbrahimAlkatout, Thu, 15 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002316 https://www.explorationpub.com/Journals/etat/Article/1002315 With the escalating application of immune checkpoint inhibitors (ICIs) in solid tumors, these therapies have demonstrated clinical benefits but remain hampered by relatively low response rates. Reliable biomarkers to predict ICIs responsiveness are essential for selecting appropriate patients and optimizing therapeutic outcomes. Given the pivotal role of tumor-draining lymph nodes (TDLNs) in orchestrating systemic antitumor immunity, their intrinsic features—such as dynamic organization in T cell subsets and functional status of antigen-presenting cells, hold considerable potential as predictive biomarkers for ICIs. Moreover, the complexity of ICIs-induced responses in TDLNs necessitates integrating multiple biomarkers for accurate prediction. Through continuous refinement of predictive strategies, TDLNs are poised to play an indispensable role in enhancing ICIs efficacy and guiding personalized immunotherapy. Here, we provide a review to discuss the possibility of using the intrinsic features of TDLNs as a predictive marker for ICI therapy. Review Tue, 13 May 2025 00:00:00 GMT ZihanChen, JiangnanYu, ZhikunGuo, ShuxianChen, YinaLi, QianZhou, LeiWang, Tue, 13 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002315 https://www.explorationpub.com/Journals/etat/Article/1002314 Despite major improvements in cancer treatment, detection, and health promotion, the mortality rates of late-stage cancer remain high. This is a critical issue because a large proportion of cancer mortality is experienced by patients who have late-stage disease at diagnosis. As survival is substantially higher for almost all cancers when diagnosed at an early stage, effective early cancer detection strategies could drastically reduce overall cancer mortality. Advances in various technologies have culminated in the development of liquid biopsies. The tumour biomarkers applied for non- or minimally-invasive cancer detection include tumour cells and their components in bodily fluids, especially peripheral blood for circulating tumour biomarkers. The most well-studied circulating tumour biomarkers in recent years for the early detection of cancer are circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), with research into other classes rapidly expanding. CTCs and ctDNA have been detected at an early stage in several types of cancer with high specificity, aiding risk stratification and, in some cases, identifying clinically actionable molecular features. Therefore, these circulating biomarkers offer several advantages over the traditional cancer detection methods. Although their limitations are considerable, the evolving evidence suggests they have tremendous potential as tools for early cancer detection. In this review, we evaluate the development and applications of circulating biomarkers for early cancer detection, with a focus on CTCs and ctDNA. We also briefly explore the emerging evidence on extracellular vesicles, circulating proteins and synthetic biomarkers, discuss the limitations of current approaches and provide suggestions to achieve further progress in this setting. Review Tue, 13 May 2025 00:00:00 GMT David SinclairThomas Junior, JunjieChai, Yong-JieLu, Tue, 13 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002314 https://www.explorationpub.com/Journals/etat/Article/1002317 The role of circulating tumor DNA (ctDNA) in urothelial cancers is a rapidly evolving area of research. Urothelial cancer is the most common subtype of bladder cancer, and biomarkers that predict response or prognosticate outcomes have been long sought after. Tumor-informed ctDNA assays have been utilized in several other cancers and increasingly used in both muscle invasive bladder cancer (MIBC) and metastatic urothelial cancer (mUC) to inform treatment decision-making. While a universal consensus on ctDNA testing has not been fully defined and discussed herein, understanding its benefits and limitations is important to help guide the practical application in the clinic. Commentary Tue, 20 May 2025 00:00:00 GMT Jeanny B.Aragon-Ching, Tue, 20 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002317 https://www.explorationpub.com/Journals/etat/Article/1002319 Musculoskeletal sarcomas represent heterogeneous and rare malignant bone and soft tissue tumors, affecting children and adults. Patients exhibiting poor clinical outcomes are often described, being associated with non-response to chemotherapy, amputation needs, or metastatic disease. Potential biomarkers contributing to diagnosis, prognosis, and treatment response could improve this scenario. Despite this, little is known about the genomic aspects of musculoskeletal sarcomas. DNA methylation is the most studied epigenetic mechanism, where changes in methylation profiling are characteristic hallmarks of cancer. Cancer-related methylome profiling has been investigated both in tumor biopsies (genomic DNA) and liquid biopsies (cell-free DNA). Epigenetic therapies by using DNA-demethylating drugs are promising strategies for cancer treatment. This review will discuss translational studies describing how DNA methylation landscape of musculoskeletal sarcomas can be a powerful molecular tool to improve diagnostic accuracy, predict prognosis, and treatment response. Additionally, this review will describe the promising role of epigenetics-targeted drugs as well as the ongoing clinical trials for sarcomas, highlighting the challenges and future directions. Review Mon, 26 May 2025 00:00:00 GMT MarianaChantre-Justino, WalterMeohas, Mon, 26 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002319 https://www.explorationpub.com/Journals/etat/Article/1002318 Aim: This research aims to guide future strategies for personalized treatment of primary mediastinal large B-cell lymphoma (PMBCL), particularly to identify high-risk patients who may benefit from incorporating immune checkpoint inhibitors (ICIs) in the first-line setting. Methods: A retrospective, single-center study included 254 newly diagnosed PMBCL patients treated with rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (R-DA-EPOCH), rituximab, modified protocol NHL-BFM-90 (RmNHL-BFM-90), or R-DA-EPOCH combined with nivolumab. Clinical parameters, immunohistochemical markers [programmed death ligand-1 (PD-L1), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), human leucocyte antigen (HLA)-DR, Ki-67, multiple myeloma oncogene 1 (MUM1)], molecular markers (mutations in tumor protein p53 (TP53), CD58, beta-2-microglobulin (B2M), and exportin 1 (XPO1) genes; short tandem repeats at 6p21.3 [major histocompatibility complex (MHC) class I/II], 9p24.1 (PD-L1/PD-L2), 16p13.13 [class II, MHC, transactivator gene (CIITA)]), and cytogenetic profiles [myelocytomatosis oncogene (MYC)/8q24, B-cell lymphoma 2 (BCL2)/18q21, BCL6/3q27, del17p13, and karyotype abnormalities] were analyzed. Results: The addition of nivolumab to R-DA-EPOCH as a first-line regimen significantly improved event-free survival (EFS; P = 0.018). This study identified that adverse prognostic factors for PMBCL include allelic imbalance at specific loci 6p21.3 (MHC class I/II), 9p24.1 (PD-L1/PD-L2), and 16p13.13 (CIITA). Incorporating nivolumab into the R-DA-EPOCH regimen as a first-line therapy has shown potential in reducing adverse prognostic factors. Conclusions: These findings suggest that high-risk patients may benefit significantly from the early incorporation of ICIs into their treatment plans. Original Article Wed, 21 May 2025 00:00:00 GMT Yana K.Mangasarova, Runiza R.Abdurashidova, Natalya V.Risinskaya, Bella V.Biderman, Tatiana V.Abramova, Vadim L.Surin, Irina A.Shupletsova, Tatiana N.Obukhova, Rasul I.Iusupov, Yulia A.Chabaeva, Aminat U.Magomedova, Lena E.Nikulina, Sergei M.Kulikov, Eugene E.Zvonkov, Alla M.Kovrigina, Andrey B.Sudarikov, Wed, 21 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002318 https://www.explorationpub.com/Journals/etat/Article/1002320 Aim: Circular RNA (circRNA) is a class of noncoding, single-stranded RNA generated by backsplicing, a process where the 5’ and 3’ ends of an RNA are covalently joined. Virally encoded circRNAs have been identified in several members of Gammaherpesvirinae, including Kaposi’s sarcoma-associated herpesvirus (KSHV). In KSHV, the viral interferon regulatory factor 4 (vIRF4) region produces two isoforms of circRNA (circ-vIRF4) that are detectable during latency and reactivation. Given the growing literature implicating circRNA in human diseases, a role may exist for circ-vIRF4 in the development of KSHV malignancies. Therefore, the aim of this study is to characterize the function of vIRF4 circRNAs. Methods: A KSHV mutant (Δcirc-vIRF4) was generated in the BAC16 bacmid and transfected into 293T and iSLK cells. Expression of circRNA after mutagenesis was assessed by qualitative and quantitative PCR. Host and viral gene expression in iSLK cells during both viral latency and reactivation were also assessed by RNA-seq. Results: RT-PCR of Δcirc-vIRF4-infected iSLK cells demonstrated no expression of wild-type (WT) isoforms, but PCR cloning showed that alternative backsplice sites were used to express novel vIRF4 circRNAs, where the most prominent isoform was a 1,020 nt isoform. RNA-seq analyses comparing WT- and Δcirc-vIRF4-infected iSLK cells demonstrated significant differential expression of both host and viral genes during both phases of the viral life cycle. Gene ontology analyses returned terms related to cell adhesion, proliferation, and migration for both datasets, as well as kinase signaling and apoptosis for the lytic dataset. Conclusions: These results show that KSHV can switch to an alternative backsplice site for vIRF4 circRNA production in the absence of a canonical splice site and that circ-vIRF4 contributes to the regulation of both host and viral gene expression through an unknown mechanism. Original Article Thu, 29 May 2025 00:00:00 GMT SoleilTorres, VaibhavJain, DanielStribling, Lauren A.Gay, MuhammedNaeem, MelodyBaddoo, Erik K.Flemington, Scott A.Tibbetts, RolfRenne, Thu, 29 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002320 https://www.explorationpub.com/Journals/etat/Article/1002321 Circulating tumor cells (CTCs) are cancer cells that are detached from the primary and metastatic tumor site and invade the bloodstream. Most importantly, CTCs are the key players in the development of metastasis. As one of the main components of liquid biopsy, they may significantly contribute to improvements in early cancer diagnosis, monitoring response to therapy, and predicting recurrence of the disease. Although identifying and analyzing CTCs offers the potential for a real-time liquid biopsy, their detection is associated with a number of challenges, which mainly stem from three sources: complexity of the CTCs, complexity of the media (blood), and performance of the detection assays. Particularly, low concentration of the CTCs and the presence of a vast population of hematopoietic cells in the blood make their detection technically complex. The heterogeneity of the target cells and not enough sensitivity of the measuring platforms are also among major technical challenges in CTC detection. Therefore, this review aims to give an update on various methods developed for CTC isolation, including chip-based assays and biosensors. The work will elucidate various challenges associated with the isolation and detection of CTCs and showcase the studies that aimed to tackle them. A number of available commercial platforms for CTC detection and hurdles associated with their widespread applications in clinical settings will also be discussed. Review Fri, 30 May 2025 00:00:00 GMT ZhuldyzMyrkhiyeva, KuanyshSeitkamal, ZhannatAshikbayeva, AssiyaTaizhanova, DanieleTosi, AliyaBekmurzayeva, Fri, 30 May 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002321 https://www.explorationpub.com/Journals/etat/Article/1002323 Aim: Penile cancer (PeCa) is a rare malignancy strongly associated with poor genital hygiene and is more prevalent in regions with low socioeconomic status. PeCa accounts for approximately 2% to 4% of all male cancers in Brazil, with higher incidence in the North and Northeast regions. Despite its aggressive nature, the molecular mechanisms underlying PeCa remain poorly understood. We performed whole-exome sequencing in a Brazilian cohort of patients with PeCa to identify potentially pathogenic genetic alterations associated with tumor development and progression. Methods: Tumor tissue samples were obtained from patients diagnosed with PeCa. DNA was extracted and subjected to whole-exome sequencing. Human papillomavirus (HPV) genotyping was performed for subtypes 16 and 18. Control samples were collected from individuals without PeCa or other genital diseases. Results: The cohort demonstrated considerable genetic heterogeneity. Multiple gene mutations were identified in tumor samples, many of which are involved in carcinogenesis-related biological pathways. Distinct molecular profiles were observed, suggesting diverse tumorigenic mechanisms. MUC16 (present in 11/12 patients, 91.7%) and PABPC1 (8/12 patients, 66.7%) were the most frequently mutated genes. HPV-16 was detected in a subset of cases; however, no consistent association with more aggressive disease was identified. Conclusions: This study provides new insights into the genomic landscape of PeCa in a Brazilian population. The findings highlight the presence of heterogeneous and potentially pathogenic mutations, reinforcing the need for further molecular characterization and exploration of novel therapeutic targets in PeCa. Original Article Fri, 06 Jun 2025 00:00:00 GMT Renato Mendes RossiDe Lucca, Danielle BarbosaBrotto, Claudia Tarcila GomesSares, Kelly GomesDuarte, Wilson AraujoSilva Junior, Philippe E.Spiess, Shahrokh F.Shariat, Natália DalsenterAvilez, Caio deOliveira, Leonardo O.Reis, Rodolfo Borges dosReis, Fri, 06 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002323 https://www.explorationpub.com/Journals/etat/Article/1002324 Osteosarcoma is the most prevalent primary malignant bone tumor affecting adolescents and young adults. Despite advancements in cancer therapies, its prognosis remains poor due to its aggressive nature and early propensity for metastasis—often present at the time of diagnosis. The etiology of osteosarcoma is multifactorial, involving genetic predispositions, environmental exposures, and familial syndromes. While treatment strategies are largely dictated by tumor stage, neoadjuvant chemotherapy followed by surgical resection remains the cornerstone of management. This review provides a comprehensive overview of osteosarcoma, including its historical context, subclassifications, clinical presentation, diagnostic approaches, and evolving treatment modalities. Recent therapeutic innovations—such as gene therapy, immunotherapy, radiation advances, and tyrosine kinase inhibitors—are discussed in detail, highlighting their mechanisms and clinical potential. By synthesizing current literature and identifying ongoing challenges, this review aims to inform clinicians and researchers of recent progress while highlighting critical gaps to guide future research and improve patient outcomes in osteosarcoma care. Review Mon, 16 Jun 2025 00:00:00 GMT Guraustin S.Brar, Aidan A.Schmidt, Logan R.Willams, Mark R.Wakefield, YujiangFang, Mon, 16 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002324 https://www.explorationpub.com/Journals/etat/Article/1002325 Aim: BRCA1/2-associated breast and ovarian carcinomas are often regarded as a single entity, assuming that BRCA1 and BRCA2 genes are almost equivalent with regard to their clinical significance. However, BRCA1 and BRCA2 genes differ in their function; therefore, a comparison of treatment outcomes in BRCA1 vs. BRCA2 carriers is warranted. Methods: This study focused on consecutive patients treated with neoadjuvant chemotherapy (NACT), given that these subjects are treatment-naive and accessible for immediate assessment of pathological and clinical outcomes. Results: BRCA2-associated high-grade serous ovarian carcinomas (HGSOCs) demonstrated significantly higher rates of pathologic complete response (pCR) as compared to BRCA1-related cancers [8/15 (53%) vs. 7/48 (15%), P = 0.004]. In contrast, HER2-negative breast cancer (BC) patients showed a numerically higher rate of pCR in BRCA1 vs. BRCA2 mutation carriers [38/69 (55%) vs. 13/36 (36%), P = 0.1]. However, the comparison with BRCA-wild-type (WT) tumors revealed that this tendency was mainly attributed to the increased prevalence of hormone receptor (HR)-negative disease in the former group. When BC patients were stratified according to the tumor receptor status, the response rates in triple-negative patients were consistently higher than in HR+/HER2– patients across all analyzed subgroups [BRCA1: 35/59 (59%) vs. 3/10 (30%); BRCA2: 5/10 (50%) vs. 8/26 (31%); WT: 31/76 (41%) vs. 12/74 (16%); Mantel-Haenzsel P < 0.001]. Logistic regression analysis revealed that the odds ratio (OR) for achieving pCR was higher for receptor status (triple-negative vs. HR+: OR = 3.4, 95% CI 1.9–6.0, P < 0.001) than for BRCA status (any mutation vs. WT: OR = 2.1, 95% CI 1.2–3.6, P = 0.008). The addition of carboplatin did not improve pCR rates in BRCA1- or BRCA2-associated BCs, while there was a numerically higher efficacy of carboplatin-containing regimens in patients with WT triple-negative tumors [14/26 (54%) vs. 15/44 (34%), P = 0.13]. Conclusions: Hereditary ovarian carcinomas demonstrate better NACT outcomes in BRCA2 vs. BRCA1 mutation carriers. The opposite trend is observed in BC, which is likely to be attributed to a high frequency of triple-negative disease in BRCA1- but not BRCA2-associated BCs. Triple-negative receptor status rather than BRCA1/2 status is the strongest predictor of response to NACT in BC. Original Article Thu, 19 Jun 2025 00:00:00 GMT AnnaSokolenko, TatianaGorodnova, DianaEnaldieva, AnnaShestakova, AlexandrIvantsov, AnnaNyuganen, IgorBerlev, PetrKrivorotko, AlexeyBelyaev, EvgenyImyanitov, Thu, 19 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002325 https://www.explorationpub.com/Journals/etat/Article/1002330 Aim: This study aimed at the identification of new druggable alterations in non-small cell lung carcinomas (NSCLCs). Methods: RNA next generation sequencing (NGS) analysis for 650 protein kinase genes was performed for 89 NSCLCs obtained from young-onset and/or female non-smokers, who were negative for activating events involving EGFR, ALK, ROS1, RET, MET, NTRK1/2/3, BRAF, HER2, KRAS, or NRAS genes. Results: RNA sequencing identified 32 in-frame rearrangements, including 9 instances of fully preserved and 8 tumors with partially preserved tyrosine kinase domains. These 17 translocations were further analyzed in 1,059 mutation-negative NSCLCs, which resulted in the identification of two additional tumors with ADK::KAT6B rearrangement and one carcinoma carrying RPS6KB1::VMP1 fusion. The recently reported CLIP1::LTK gene fusion was tested in 2,754 NSCLCs, which were negative for all known actionable mutations, however, no new instances of this translocation have been observed. We further analyzed RNA sequencing results of 89 NSCLCs for mutations affecting the kinase domain of the involved gene. There were 53 substitutions with a combined annotation dependent depletion (CADD) score above 25; all these lesions turned out to be unique, as the analysis of 551 additional NSCLCs revealed no recurrent alterations. ROS1, LTK, and FGFR4 high-level overexpression was observed in 1 out of 89 tumors each. Conclusions: This study demonstrates the scarcity of yet unknown kinase-activating alterations in NSCLCs. Original Article Thu, 10 Jul 2025 00:00:00 GMT Elena V.Preobrazhenskaya, Rimma S.Mulkidjan, Fyodor A.Zagrebin, Alexandr A.Romanko, Evgeniya S.Saitova, Polina R.Korzun, Jeyla O.Binnatova, Vladislav I.Tiurin, Ilya V.Bizin, Evgeny N.Imyanitov, Thu, 10 Jul 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002330 https://www.explorationpub.com/Journals/etat/Article/1002326 Pancreatic ductal adenocarcinoma (PDAC) is among the top causes of cancer-induced mortality, frequently diagnosed too late to be treated effectively, due to the poor prognosis and the limited successful therapeutic options. Apart from the conventional treatments, new multimodal therapies have emerged utilizing different scientific fields for the improvement of the survival and quality of patients’ lives. The advancement of nanotechnology leads the way to more personalized medicine and the use of targeted theranostics carriers for deep-seated cancers such as PDAC. New nanotechnology innovations such as specialized photo-sensitizing drug nanocarriers, can effectively improve photodynamic therapy (PDT) of PDAC and enhance phototherapy’s action through surface plasmon resonance phenomenon, as another recently re-emerged non- or minimally invasive possible treatment of such diseases. Despite the scientific advancements, significant hurdles remain and many parameters need to be examined. However, the novel application of nano-biophotonic techniques and the convergence of different science fields offer promise for the treatment of difficult-to-treat diseases, like PDAC. Review Thu, 19 Jun 2025 00:00:00 GMT KyriakosKokkinogoulis, AristomenisKollas, DavidSimeonidis, PavlosPapakostas, KalliopiPlatoni, Efstathios P.Efstathopoulos, MersiniMakropoulou, Thu, 19 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002326 https://www.explorationpub.com/Journals/etat/Article/1002327 Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in the progression of various cancers through its involvement in cell proliferation, survival, and differentiation. More recently, FGFR1 has been implicated in the mechanisms of immune evasion, particularly its role in resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Targeting FGFR1 with monoclonal antibodies and tyrosine kinase inhibitors has emerged as a promising therapeutic strategy to enhance ICI efficacy by altering the tumor microenvironment and countering immune suppression. Preclinical studies demonstrate that combining FGFR1 inhibitors, such as the novel monoclonal antibody OM-RCA-01, with ICIs significantly improves antitumor activity, enhancing T cell responses and cytokine production. This article explores the role of FGFR1 in cancer biology, its contribution to immunotherapy resistance, and the therapeutic potential of targeting FGFR1 to enhance the efficacy of ICIs. Perspective Fri, 20 Jun 2025 00:00:00 GMT IlyaTsimafeyeu, Fri, 20 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002327 https://www.explorationpub.com/Journals/etat/Article/1002328 Biliary tract cancers (BTCs) are aggressive malignancies associated with poor prognosis and limited treatment options. Advances in precision oncology, notably the identification of recurrent molecular alterations such as fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, ERBB2 amplifications, and v-Raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutations, have introduced new therapeutic avenues and modest survival benefits for patients with advanced disease. However, the practical implementation of targeted therapies remains hampered by challenges in tumor tissue acquisition and molecular testing, highlighting the need for alternative genomic profiling strategies. This comprehensive review examines the role of liquid biopsy as a non-invasive strategy for molecular profiling in BTCs, with a focus on the clinical applications of plasma and bile-derived circulating tumor DNA (ctDNA). We synthesized findings from recent clinical studies evaluating mutation detection rates, concordance between liquid biopsy and tissue-based assays, and the comparative performance of plasma versus bile ctDNA. Liquid biopsy demonstrates high rates of mutation detection and good concordance with tissue analyses. Bile-derived ctDNA, owing to its proximity to the tumor, consistently shows higher sensitivity and mutant allele frequencies (MAFs) than plasma ctDNA. Nevertheless, challenges remain, including lower sensitivity for detecting structural alterations (e.g., gene fusions), variability in ctDNA yield depending on disease status, and a lack of assay standardization across platforms. Liquid biopsy, particularly through bile ctDNA analysis, emerges as a promising adjunct to tissue biopsy for molecular profiling in BTCs. It offers opportunities for earlier, less invasive, and more personalized treatment decisions. Future directions should aim at developing tumor-informed liquid biopsy strategies that increase precision, reduce costs, and ultimately improve patient outcomes. Prospective studies are needed to confirm its clinical utility and survival impact. Review Tue, 24 Jun 2025 00:00:00 GMT JamesGutmans, HibaMechahougui, Tue, 24 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002328 https://www.explorationpub.com/Journals/etat/Article/1002329 Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. Emerging evidence highlights the significant role of gut microbiota dysbiosis, characterized by a reduction in beneficial bacteria and an increase in pro-inflammatory and pro-carcinogenic bacteria, in CRC pathogenesis. Both genetic and environmental factors, including diet, antibiotic use, physical activity, aging, and obesity, contribute to this microbial imbalance. Dysbiosis promotes chronic inflammation and immune dysregulation, which facilitates tumor initiation and progression. This review examines the intricate interactions between gut microbiota, immune modulation, and CRC development. It explores current and emerging therapeutic strategies that target the microbiome to enhance treatment efficacy, discusses interventions aimed at restoring healthy microbiota in CRC patients, and outlines future directions for microbiome-based therapies to improve clinical outcomes. Review Fri, 27 Jun 2025 00:00:00 GMT GurkaranjotSingh, ZuhairChaudhry, AnikBoyadzhyan, KayvanSasaninia, VikrantRai, Fri, 27 Jun 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002329 https://www.explorationpub.com/Journals/etat/Article/1002331 Aim: Clinico-pathological features have traditionally guided prognosis and adjuvant therapy for breast cancer (BC) patients. In the past decade, genomic tests such as Oncotype DX entered clinical practice to refine risk stratification and predict chemotherapy benefit for hormone-receptor positive (HR+)/human epidermal growth factor-receptor 2 negative (HER2–) BC patients after surgery. This is a retrospective analysis to investigate the correlation between histopathological parameters and recurrence score (RS), accounting for menopausal status. Methods: Data on HR+/HER2– early BC patients who underwent Oncotype DX were collected using an institutional database. Clinico-pathological characteristics were retrieved. Linear regression was used with RS as a continuous outcome, while logistic regression was performed for pre- and post-menopausal patients, dichotomizing RS at thresholds of 16 and 25, respectively. Results: A total of 180 women were included (35% pre-menopausal, 65% post-menopausal). Median age was 57.5 years. Most patients had pT1, pN0, G2 BC, with median estrogen receptor (ER) expression of 95% and a median Ki67 of 25%. Median RS was 16 [interquartile range (IQR) 12–22] in the overall cohort, 15 in pre-menopausal, and 17 in post-menopausal women. In the entire cohort, RS significantly correlated with G3 (P = 0.01), Ki67% (P < 0.0001), ER% (P = 0.03), and progesterone receptor (PgR)% (P < 0.0001). In pre-menopausal patients, only Ki67% (P = 0.02), ER% (P = 0.01), and PgR% (P < 0.0001) showed significant correlations, while in post-menopausal patients, G3 (P = 0.03), Ki67% (P = 0.001), and PgR% (P < 0.0001) achieved statistical significance. Logistic regression analysis showed that in pre-menopausal patients, PgR% predicted RS > 16 [odds ratio (OR) 0.95, P = 0.001]. In post-menopausal women, Ki67% (OR 1.08, P = 0.031) and PgR% (OR 0.95, P < 0.0001) predicted RS > 25. Conclusions: In this patient cohort, classical clinico-pathological features showed varying correlations with RS, depending on menopausal status. These findings highlight the complexity of risk stratification, suggesting that further research is needed to better understand the factors influencing RS and its clinical utility. Original Article Fri, 18 Jul 2025 00:00:00 GMT FedericaMartorana, SabrinaNucera, GianmarcoMotta, Maria VitaSanò, CarloCarnaghi, MarialuisaPuglisi, ClaudiaGelsomino, GiuseppeCorsaro, ChiaraConti, LuciaMotta, GiulianaPavone, StefanoMarletta, Giada MariaVecchio, GaetanoMagro, GiuseppeCatanuto, GaetanoCastiglione, FrancescoCaruso, AntonioRizzo, MicheleCaruso, PaoloVigneri, Fri, 18 Jul 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002331 https://www.explorationpub.com/Journals/etat/Article/1002332 Aim: Angiogenesis, invasion, and tube formation are critical processes in tumor progression and metastasis. The use of nanoparticles derived from natural products presents a promising approach for targeted cancer therapy. This study evaluates the anti-angiogenic and anti-invasive effects of Moringa oleifera silver nanoparticles (MO-AgNPs) as a therapeutic strategy against these processes. Methods: The anti-angiogenic and anti-invasive activities of MO-AgNPs were investigated using a series of in vitro and ex vivo models. These included the rat aortic ring assay, endothelial tube formation assay, cell invasion assay using endothelial cell lines (Ea.hy926), and a three-dimensional (3D) co-culture spheroid model to simulate tumor microenvironment behavior. Comparisons were made with known inhibitors: quercetin (15.11 μg/mL) and suramin (100 μg/mL). Results: MO-AgNPs at 12 μg/mL significantly inhibited Ea.hy926 cell invasion by 62.10% and significantly suppressed endothelial tube formation, comparable to the effect of quercetin. In the ex vivo aortic ring assay, MO-AgNPs reduced microvessel sprouting by 83.824 ± 0.081%, surpassing the inhibition achieved by suramin. Additionally, in the 3D spheroid model, MO-AgNPs at concentrations of 12 μg/mL and 6 μg/mL, as well as quercetin, significantly reduced spheroid diameter by day 14, indicating suppressed invasive potential and angiogenic support. Conclusions: MO-AgNPs exhibit strong anti-angiogenic and anti-invasive effects across various tumor-relevant models, highlighting their potential as a therapeutic agent against tumor progression and angiogenesis-related diseases. These results support further investigation of MO-AgNPs as a novel nanotherapeutic for cancer treatment. Original Article Mon, 28 Jul 2025 00:00:00 GMT RollaAl-Shalabi, VuanghaoLim, IbrahimAl-Deeb, MelissaKilus, NozlenaAbdul Samad, Mon, 28 Jul 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002332 https://www.explorationpub.com/Journals/etat/Article/1002333 Liquid biopsy (LB) is a complex of procedures aimed at the detection of tumor-derived fragments (nucleic acids, proteins, cells, etc.) persisting in the blood or other body fluids. It can be utilized for early cancer diagnosis, analysis of biomarkers of tumor drug sensitivity and prognosis, monitoring of minimal residual disease (MRD), etc. Circulating tumor DNA (ctDNA) is an accessible and reliable LB analyte as it may contain tumor-specific mutations and is amenable to efficient detection by next-generation sequencing (NGS) or droplet digital PCR (ddPCR). High level of ctDNA is typically associated with increased tumor burden and poor prognosis, whereas treatment-related ctDNA clearance increases the probability of a favorable disease outcome. Major efforts have been invested in enhancing the analytical performance of ctDNA detection. Stimulation of apoptosis of tumor cells by irradiation of cancer lumps has been shown to result in a transient but modest increase in ctDNA concentration. There are several sophisticated modifications of ultra-deep NGS protocols, which discriminate between “true” low-copy mutation-specific signals and sequencing artifacts. Slowing physiological ctDNA decay by interfering with liver macrophages and circulating nucleases has shown promise in animal experiments. Reproducibility of ctDNA-based LB assays remains insufficient for samples with ultra-low content of ctDNA; hence, interlaboratory harmonization of ctDNA testing procedures is of paramount importance. Review Fri, 08 Aug 2025 00:00:00 GMT Ekaterina S.Kuligina, Grigoriy A.Yanus, Evgeny N.Imyanitov, Fri, 08 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002333 https://www.explorationpub.com/Journals/etat/Article/1002335 O6-Methylguanine-DNA methyltransferase (MGMT) acts as a genomic custodian, reversing alkylation damage to preserve DNA integrity. However, when its regulatory balance tips via promoter methylation, polymorphisms, or epigenetic silencing, MGMT can become a liability, fuelling cancer progression, treatment resistance, and poor outcomes across malignancies. This review uncovers the nuanced control of MGMT, revealing how its genetic and epigenetic shifts shape tumor behavior, therapeutic response, and risk stratification. We aim to transform molecular insights into actionable clinical strategies, reimagining MGMT as both a biomarker and therapeutic lever. We curated high-impact studies (up to 2025) from PubMed, Scopus, and Web of Science, focusing on MGMT modulation, synthetic lethality, CRISPR-based restoration, and epigenetic therapies. Emerging multi-omics and translational frameworks were prioritized. MGMT’s activity is choreographed by an intricate interplay of promoter methylation, histone marks, transcriptional regulation, and microRNA influence. These dynamics critically affect sensitivity to alkylating agents like temozolomide. Intriguingly, MGMT also engages with the immune landscape modulating response to immunotherapies. Innovations in multi-omics, single-cell analytics, and AI-based biomarker profiling are unveiling previously hidden regulatory layers. Decoding MGMT’s regulation unlocks new therapeutic frontiers. Cutting-edge strategies from CRISPR to liquid biopsy promise more personalized, resistance-proof cancer care. Review Fri, 29 Aug 2025 00:00:00 GMT ShishirSingh, RajeevNema, MonishaBanerjee, Atar SinghKushwah, Fri, 29 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002335 https://www.explorationpub.com/Journals/etat/Article/1002334 Cancer is the second leading cause of death globally and in the United States, second only to cardiovascular disease. Unlike many cardiovascular conditions, cancer is often less preventable, manageable, and curable—even with ongoing technological advancements in medicine. The adverse effects of cancer treatments on cancer patients remain profound due to shared cellular characteristics between cancerous and normal cells; one of the primary adverse effects is treatment-induced inflammation. These inflammatory responses aim to eliminate cancerous cells but often damage normal tissues. Notably, inflammatory side effects vary considerably across the growing diversity of therapeutic approaches. This study reviewed studies between 2007 and 2024, comparing the inflammatory profiles associated with five major radiation therapies (RTs): Three-Dimensional Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), Image-Guided Radiation Therapy (IGRT), Stereotactic Body Radiation Therapy (SBRT), and Proton Beam Therapy (PBT)—each characterized by distinct mechanistic and therapeutic features. In addition to each radiation modality eliciting distinct inflammatory responses, tissue-specific variability further complicates clinical outcomes. Accordingly, this review also undertakes a cross-tissue comparison of radiation-induced inflammation, with a focus on the gastrointestinal (GI) system, central nervous system (CNS), and skin. However, the variation in treatment modalities and organ-specific inflammatory biomarkers greatly hinders direct comparison across studies. Finally, this review highlights potential inflammatory mitigations, including ambroxol, that may be employed synergistically with RTs, minimizing side effects and enhancing patient outcomes. Taken together, while all modalities offer therapeutic value alongside certain limitations, proton-based therapy demonstrates the greatest potential for minimizing toxicity though its broader adoption remains limited by cost-effectiveness concerns. Review Fri, 29 Aug 2025 00:00:00 GMT YutingSheng, Daniel M.Han, Mark R.Wakefield, YujiangFang, Fri, 29 Aug 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002334 https://www.explorationpub.com/Journals/etat/Article/1002336 Aim: During radiation treatment, reactive oxygen species (ROS) and nitrogen species (RNS) are produced and, by extension, DNA adducts known as 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-nitroguanine (8-NG), respectively. However, one of the most common side effects induced by radiotherapy is skin toxicity, which affects patients’ quality of life. In the present study, we aimed to investigate the potential predictive value of 8-OHdG and 8-NG by exploring the correlations between the alterations in the concentration levels of the two lesions and radiation-induced tissue injury upon exposure to external beam radiotherapy. Methods: For the purpose of this work, we collected blood serum samples from 33 breast cancer patients who received adjuvant radiotherapy. To conduct statistical analysis, we used: (1) linear adjustment to correlate the percent changes of 8-OHdG and 8-NG with the degree of toxicity; and (2) polynomial adaptation and exponential fitting to correlate the percent changes of 8-OHdG and 8-NG with the correlation coefficient r for the development of radiation dermatitis, respectively. Results: According to our findings, there is a statistically significant correlation between the alterations in the 8-OHdG and 8-NG levels and skin grade toxicity across time and varying radiation doses (p < 0.05). Conclusions: Both DNA lesions seem to possess a promising predictive role in radiation dermatitis, while the severity and exact grade of radiation-induced skin toxicity can be determined. Original Article Mon, 22 Sep 2025 00:00:00 GMT Emmanouil K.Verigos, SofiaSagredou, Kosmas E.Verigos, KyriakosOrfanakos, Constantinos E.Alifieris, Maria V.Deligiorgi, PanagiotisDalezis, Mihalis I.Panayiotidis, Petros N.Karamanakos, Dimitrios T.Trafalis, Mon, 22 Sep 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002336 https://www.explorationpub.com/Journals/etat/Article/1002337 Microsatellite-stable metastatic colorectal cancer (MSS mCRC) is currently treated with chemotherapy and targeted agents based on RAS and BRAF mutational status. Although these therapies offer initial benefit, most patients rapidly develop resistance, with fewer than 20% remaining progression-free at two years. This review aims to synthesize emerging evidence on the metabolic mechanisms driving treatment resistance in MSS mCRC, with a particular focus on the immune-metabolic signature (IMMETCOLS) classification. We conducted a comprehensive review of preclinical models, transcriptomic datasets, and clinical trial results addressing metabolic adaptations to chemotherapy and targeted therapies in MSS mCRC. The IMMETCOLS framework defines three metabolic subtypes—IMC1, IMC2, and IMC3—each associated with distinct resistance mechanisms. IMC1 exhibits glycolysis and transforming growth factor-β (TGF-β)-dependent signaling enriched in inflammatory fibroblasts, conferring resistance to chemotherapy. IMC2 relies on oxidative phosphorylation and glutamine metabolism, supporting antioxidant defenses and resistance to both cytotoxic agents and anti-EGFR therapies. IMC3 demonstrates lactate-fueled respiration and pentose phosphate pathway activation, contributing to redox balance, DNA repair, and resistance to targeted therapies such as anti-BRAF or KRAS inhibitors. All subtypes display metabolic plasticity under therapeutic pressure. Emerging clinical data support tailoring targeted therapy combinations based on IMMETCOLS subtype, particularly in BRAF- and HER2-positive populations. Understanding subtype-specific metabolic rewiring in MSS mCRC offers novel opportunities to overcome drug resistance. Targeting the metabolic vulnerabilities defined by the IMMETCOLS signature may improve response durability and inform precision treatment strategies. Review Tue, 23 Sep 2025 00:00:00 GMT MariamRojas, MalenaManzi, SergioMadurga, Fernando EnriqueGarcía Velásquez, Maira AlejandraRomero, SilviaMarín, MartaCascante, JoanMaurel, Tue, 23 Sep 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002337 https://www.explorationpub.com/Journals/etat/Article/1002339 Lung cancer remains the leading cause of cancer mortality worldwide, with progress limited by tumor heterogeneity, drug resistance, and conventional therapy limitations. Nanotechnology-enabled drug delivery offers a transformative approach, enabling the precise engineering of nanocarriers for selective targeting, controlled release, and reduced toxicity. Recent innovations include inhalable systems that achieve localized pulmonary deposition, stimuli-responsive nanocarriers that release drugs in response to tumor microenvironment cues, and nano-immunotherapies that synergize with immune checkpoint blockade. Exosome-based vesicles further offer biomimetic advantages of low immunogenicity and natural tissue tropism. In parallel, theranostic platforms integrate treatment with imaging to enable real-time monitoring of drug delivery and tumor response. This review synthesizes mechanistic advances and translational developments in lung cancer nanomedicine, with emphasis on strategies that overcome biological barriers such as hypoxia, extracellular matrix density, and efflux pump activity. Clinical progress between 2020 and 2025 highlights next-generation antibody—drug conjugates, nanoparticle vaccines, and gene-loaded systems, several of which have reached regulatory approval or advanced trial stages. Together, these advances highlight the potential of nanocarriers to transform lung cancer therapy into more precise, personalized, and less toxic interventions. Review Mon, 13 Oct 2025 00:00:00 GMT HeayyeanLee, KhadijahSajid, JeehooLee, Mon, 13 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002339 https://www.explorationpub.com/Journals/etat/Article/1002340 Aim: The current study uses the depicted approach to synthesize curcumin-piperine loaded Poloxamer F-68 coated magnetic nanoparticles (CUR-PIP-F68-Fe3O4 NPs) to achieve a synergistic anti-cancer impact on an in vitro HCT-116 colon cancer cell. Integrating magnetic nanoparticle technology with phytoconstituents enhances the potential for targeted drug delivery with minimal systemic toxicity and facilitates therapeutic outcomes. Methods: A Box-Behnken design was employed to optimize the CUR-PIP-F68-Fe3O4 NPs prepared by the co-precipitation method. Optimized formulation was evaluated for morphological characteristics, elemental composition, and magnetic properties. An in vitro cytotoxicity assay was conducted to observe the % viability of cells and to further calculate the IC50. Cellular uptake studies were investigated using confocal microscopy. Results: Results showed that the optimised nanoparticles possessed a particle size of 158.7 ± 0.057 nm, zeta potential of –30.3 ± 0.1 mV, and encapsulation efficiency of 98.85 ± 0.066%. Analysis by vibrational sample magnetometer revealed that magnetic saturation was 75.6 emu/g and 50.7 emu/g for bare Fe3O4 nanoparticles and drug-loaded magnetic nanoparticles, respectively. Scanning electron microscopy (SEM) depicted the morphological characteristics; elemental composition of synthesized magnetic nanoparticles was confirmed by energy dispersive X-ray (EDX) analysis by illustrating the presence of C (13.50 ± 0.30%), Fe (78.81 ± 1.23%), and O (7.69 ± 0.29%). The MTT assay and cellular uptake studies unveiled that CUR-PIP-loaded magnetic nanoparticles possess a synergistic cytotoxic effect and the highest drug uptake against the HCT-116 colon cell line. Conclusions: The combination approach of curcumin-piperine magnetic nanoparticles to HCT-116 cells enhanced the anticancer efficacy of the curcumin and further demonstrated the potential of this approach to conduct in vivo studies. Original Article Tue, 21 Oct 2025 00:00:00 GMT RitikaPuri, VimalArora, Tue, 21 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002340 https://www.explorationpub.com/Journals/etat/Article/1002341 The green synthesis of silver nanoparticles (AgNPs) has recently gained prominence as a sustainable and eco-friendly alternative to conventional physical and chemical methods. Utilizing biological entities such as plant extracts, bacteria, fungi, and biomolecules, the method acts by both reducing and stabilizing mechanisms. It does not use any harmful chemical substances, thus proving to be eco-friendly. Green-synthesized AgNPs exhibit enhanced biocompatibility, stability, and targeted delivery of the drug due to the use of naturally derived surface capping agents. These unique characteristics allow selective interference with cancer cells. The mechanism involved is the generation of reactive oxygen species (ROS), the induction of apoptosis, DNA damage, and cell cycle arrest. Green AgNPs also possess broad-spectrum antimicrobial, catalytic, antiparasitic, and anti-inflammatory properties, supporting the fact that they can be utilised in biomedical fields such as drug delivery, bioimaging, biosensing, tissue engineering, and regenerative medicine. Recent advancements have focused on controlling NP size, shape, and surface functionality to maximize efficacy while simultaneously minimizing cytotoxicity. This review provides a comprehensive analysis of the latest green synthesis strategies, their characterizations, and the molecular mechanisms by which they exert anticancer effects. Recent patents highlight the clinical potential of AgNPs in cancer therapy. US Patent 12201650 (2025) describes green synthesis using Caralluma sinaica, while other patents (WO2007001453, US7462753) outline adaptable biomedical formulations. Studies on biogenic AgNPs also show significant tumor inhibition and selective cytotoxicity against cancer cells. Furthermore, the article discusses current biomedical applications and critically evaluates the limitations, such as reproducibility, toxicity concerns, and scalability for clinical translation. Addressing these challenges is essential for the integration of green AgNPs into mainstream cancer therapeutics. The convergence of nanotechnology and biologically derived synthesis opens promising avenues for the development of safe, effective, and environmentally sustainable medical innovations. Review Thu, 23 Oct 2025 00:00:00 GMT PujaKumari, KhushiQuadri, RenuKadian, SaloniMishra, AafrinWaziri, KaustubJumle, Kumar SambhavVerma, Md SabirAlam, Thu, 23 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002341 https://www.explorationpub.com/Journals/etat/Article/1002342 Aim: TNF-related apoptosis-inducing ligand (TRAIL) is a promising targeted anti-cancer agent for several types of cancer, including non-small cell lung cancer (NSCLC). The proteasome inhibitor bortezomib can further potentiate rhTRAIL-induced apoptosis in NSCLC cells. Here, the mechanisms underlying this sensitization were examined in TRAIL-sensitive H460 and TRAIL-resistant A549 and SW1573 NSCLC cells. Methods: NSCLC cell lines were treated with rhTRAIL and bortezomib, and apoptosis was assessed through caspase activation assays, western blotting, and gene silencing of key apoptotic regulators, including Bid, XIAP, and cFLIP. Clonogenic assays were performed to evaluate long-term tumor growth suppression. Results: Bortezomib sensitization mechanisms varied across NSCLC cell lines. Combined rhTRAIL/bortezomib treatment enhanced apoptosis across all cell lines. In TRAIL-sensitive H460 cells, rapid caspase activation was observed, with both extrinsic and intrinsic apoptotic pathways contributing to cell death. Sensitization in H460 cells was predominantly mediated via the caspase-8/Bid amplification loop. In A549 cells, the bortezomib sensitizing effect also relied on the caspase-8/Bid amplification loop. Additionally, the inhibition of Bid and XIAP emphasized the critical role of mitochondrial pathways in apoptosis. In SW1573 cells, limited caspase cleavage was detected, with distinct cleavage patterns suggesting cell-specific apoptotic mechanisms. In this cell line, bortezomib primarily enhanced the extrinsic apoptotic pathway, with XIAP depression further increasing apoptosis. Silencing cFLIP, a caspase-8 inhibitor, significantly improved rhTRAIL sensitivity, emphasizing the critical role of caspase-8 activation in overcoming resistance in SW1573. The clonogenic assay demonstrated that bortezomib combined with rhTRAIL significantly suppressed tumor growth, especially in resistant cell lines. Conclusions: This study underscores bortezomib’s ability to differentially enhance rhTRAIL-induced apoptosis by targeting multiple apoptotic regulators. The variety of effects that bortezomib can exert to enhance rhTRAIL-induced apoptosis makes it a very powerful combination for the treatment of NSCLC and various other types of cancer cells. Original Article Wed, 29 Oct 2025 00:00:00 GMT PawełKochany, Janet H.Stegehuis, Leonie H.A.M.de Wilt, GerritJansen, Stevende Jong, Godefridus J.Peters, Frank A.E.Kruyt, Wed, 29 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002342 https://www.explorationpub.com/Journals/etat/Article/1002344 Aim: Hepatocellular carcinoma (HCC) displays both shared and ethnicity-specific molecular characteristics. Using transcriptomic data from The Cancer Genome Atlas (TCGA), we compared gene expression profiles between Asian and Caucasian HCC patients. Methods: Gene expression profiles were analyzed using the PyDESeq2 implementation of DESeq2, applying size factor normalization and dispersion estimation. Differentially expressed genes (DEGs) were identified with thresholds of false discovery rate (FDR) of < 0.05 and |log2FC| ≥ 1.0. Gene annotation, visualization, and pathway enrichment were conducted using Sanbomics, seaborn, and gene set enrichment analysis (GSEA) via the GSEApy package. Results: A total of 387 and 250 genes were commonly upregulated and downregulated, respectively, in both populations, including the upregulations of GPC3 and PLVAP and the downregulations of FCN3 and OIT3, indicating their potential as universal HCC markers. Conversely, 16 genes were upregulated in Asians but downregulated in Caucasians, and 25 showed the reverse pattern. Asian-specific upregulation of AKR1B10, UBE2C, and S100P suggests links to viral etiology and immune modulation, while MDK, LCN2, and NQO1 were upregulated in Caucasians, implicating proliferative and metabolic roles. Functional enrichment analysis revealed distinct immune and metabolic pathways. Asians showed elevated ubiquitin ligase activity and suppressed inflammatory responses, while Caucasians exhibited enhanced cytokine signaling, complement activation, and xenobiotic metabolism. Conclusions: These findings highlight key molecular differences in HCC across ethnicities and emphasize the value of TCGA data for identifying both shared targets and population-specific therapeutic strategies. Understanding these differences is crucial for advancing precision oncology and developing tailored interventions. Original Article Mon, 03 Nov 2025 00:00:00 GMT Muhammad RezkiRasyak, SriJayanti, CyrollahDisoma, BensPardamean, CaeciliaSukowati, Mon, 03 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002344 https://www.explorationpub.com/Journals/etat/Article/1002343 Not applicable. Retraction Wed, 29 Oct 2025 00:00:00 GMT , Wed, 29 Oct 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002343 https://www.explorationpub.com/Journals/etat/Article/1002345 Gynecological cancer remains one of the leading causes of mortality worldwide. Recent advances in genomic and molecular sequencing have significantly enhanced our understanding of the biological pathways that drive tumor progression and resistance to therapy. Targeted therapies, including monoclonal antibodies (mAbs), have revolutionized cancer treatment by selectively interfering with oncogenic proteins expressed on cancer cells. However, the long-term clinical benefit is often limited due to the emergence of drug resistance, frequently mediated by compensatory signaling pathways or immune escape mechanisms. To overcome these limitations, bispecific antibodies (bsAbs) represent an innovative class of therapeutic agents that have shown promising results across various medical fields. They have been developed to engage two distinct targets simultaneously, such as tumor antigens, immune effectors, or immunomodulatory checkpoints, thereby enhancing anti-tumor activity and reducing the risk of resistance. There are 17 bsAbs approved for clinical use in various countries, with numerous others currently in active development and over 600 bsAbs undergoing clinical trials worldwide. Among these, 11 have received FDA approval for the treatment of hematologic malignancies as well as solid tumors, including uveal melanoma, metastatic non-small cell lung cancer, small cell lung cancer, and biliary tract cancers. Although some studies have explored bsAbs in gynecological cancers, this area remains underdeveloped compared to other oncology fields. Most ongoing studies in this area are still in their early phases (phase I or phase II), and there is a need for optimization in terms of antibody design, efficacy, and safety profiles. Therefore, the purpose of this review is to present a comprehensive summary of the current research on bsAbs in gynecological cancers, with a focus on endometrial, cervical, and ovarian cancers. We will highlight ongoing clinical trials, discuss the mechanisms of action of these agents, and explore their potential benefits in enhancing treatment outcomes. Review Thu, 06 Nov 2025 00:00:00 GMT SaraParola, IlariaColombo, Thu, 06 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002345 https://www.explorationpub.com/Journals/etat/Article/1002346 Cancer is one of the leading global causes of mortality and morbidity, so it needs early diagnosis and therapies. Traditional diagnostic and therapeutic strategies are inadequate due to several limitations, such as poor specificity, systemic toxicity, and delays, while metal-grafted Gr nanostructures have emerged as promising theranostic platforms due to their unique electronic, optical, and structural properties. Metals such as Fe3O4, Au, Ag, TiO2, Pd, Pt, Bi, ZnO, and Cu grafted onto the Gr surface impart electronic modulation, enhance surface area, flexibility, conductivity, reactivity, biomolecular interactions, and biosensing, thereby enabling precise biomarker detection, targeted drug delivery, imaging, and photothermal/photodynamic therapy (PTT/PDT). Eco-friendly synthesis using plant extracts and microbes offers a sustainable and biocompatible alternative to conventional chemical synthesis. However, challenges remain, such as homogenous doping, synthetic complexity, long-term safety, and clinical scalability. Innovations such as scalable, cost-effective, biocompatible nanofibers, nanopapers, microfluidic, and wearable biosensors are being explored by incorporating AI and advanced diagnostic tools for advanced biomedical devices. In vitro, half maximum inhibitory concentrations (IC50) studies show that size- and dose-dependent nanohybrids such as Fe3O4-Gr, γ-Fe2O3-Gr, Au-Gr, and Bi-Gr exhibited safer responses at lower concentrations 10–200 µg/mL across HBE, MCF-7, HeLa B, and LNCaP cell lines. Bi-Gr was tested on human liver cancer (HepG2) cell line, which exhibits higher reactivity despite a safer profile of Bi at ~53–88 µg/mL. Pd-Gr and Pt-Gr significantly reduced viability in prostate and ovarian cancer cells at 10–50 µg/mL, while ZnO-Gr, Ag-Gr, and Cu-Gr showed safer activity at lower concentrations on MCF-7. In vivo studies remain limited; median lethal dose (LD50) values for Fe3O4-Gr and γ-Fe2O3-Gr were determined to be associated with rapid lethal biodistribution observed in the liver, lungs, and spleen. Metal-grafted Gr nanohybrids demonstrate immense potential for multifunctional cancer theranostics, though systematic in vivo toxicity studies still need to be explored by the intravenously administered route to lower the LD50 of nanohybrids for their clinical translation. Review Tue, 11 Nov 2025 00:00:00 GMT Prashant H.Gohil, GopalAvashthi, Tue, 11 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002346 https://www.explorationpub.com/Journals/etat/Article/1002347 Immune checkpoint inhibitors (ICIs) are established treatments for various malignancies, including lung, kidney, and colorectal cancers. However, their broad use has led to an increase in immune-related adverse events (irAEs), with thyroiditis, colitis, and pneumonitis being the most common. Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe irAE characterized by excessive immune activation, leading to systemic inflammation and multi-organ dysfunction. We present three cases of ICI-induced HLH in patients with lung cancer who were treated with ICIs. All patients showed elevated inflammatory markers and responded to high-dose corticosteroids without the addition of etoposide. These cases underscore the importance of early recognition and treatment of HLH in patients receiving ICIs to mitigate morbidity and mortality. Large-scale studies are needed to establish standardized guidelines for diagnosing and managing ICI-induced HLH. Case Report Wed, 12 Nov 2025 00:00:00 GMT Abdul WaliKhan, SimranChandra, HimilMahadevia, JanakiramanSubramanian, BenPonvilawan, DhruvBansal, Wed, 12 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002347 https://www.explorationpub.com/Journals/etat/Article/1002348 The realization that the composition and functionality of gut microbiota have an impact on the outcome of immune checkpoint inhibition (ICI) therapy of cancer has initiated research into the potential of microbiota management as adjunctive therapy. Fecal microbiota transplantation can improve the outcome of ICI, but for optimal donor selection, safety, and large-scale implementation, there remain bottlenecks. Alternative strategies, such as the use of selected bacterial species, require fundamental knowledge of the underlying mechanisms governing the interaction between (intestinal) microbiota and the immune system. Gut microbiota also appears to be able to colonize the tumor microenvironment. Some bacterial species directly or indirectly promote tumor growth. Other defined species have tumoricidal properties. These findings and insights are now being used to further optimize the functionality of the immune system and shape the tumor microenvironment in order to improve the outcome of ICI. Review Tue, 18 Nov 2025 00:00:00 GMT Ger T.Rijkers, YonahLangcauon, Pippevan Leersum, LaraPopović, Frans J.van Overveld, Tue, 18 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002348 https://www.explorationpub.com/Journals/etat/Article/1002349 The convergence of DNA nanotechnology with nanofluidics has catalyzed a transformative shift in precision drug delivery. DNA origami, a self-assembled nanoscale architecture constructed via programmable base pairing, offers atomically precise control over size, shape, and function—making it an ideal scaffold for site-specific therapeutic cargo loading and release. When integrated into nanofluidic systems, these origami nanostructures form intelligent platforms capable of navigating biological barriers, sensing intracellular cues, and delivering payloads in a spatially and temporally controlled manner. This review explores the fabrication principles, design strategies, and intracellular trafficking mechanisms that underpin the efficacy of these smart nanofluidic DNA origami systems. We highlight key stimuli-responsive features such as pH-triggered unfolding, enzyme-cleavable hinges, redox-sensitive disassembly, and light-mediated gate release. Case studies from preclinical models demonstrate their superiority in overcoming drug resistance, enhancing tumor selectivity, and minimizing systemic toxicity compared to conventional nanocarriers. We also evaluate methods for surface modification, channel integration, and stimulus modulation using electron-beam lithography and soft lithography techniques. Additional biosafety and scalability challenges are discussed, alongside regulatory and immunogenicity considerations. The review concludes by outlining future directions involving AI-assisted DNA origami design, microfluidic diagnostics, and digital therapeutics. The synthesis of programmable nanocarriers with smart fluidic control represents a new frontier in targeted therapy, combining modularity, precision, and adaptability. As such, nanofluidic DNA origami systems hold immense promise for next-generation therapeutics in oncology, gene therapy, and personalized medicine, paving the way for dynamic and autonomous intracellular delivery platforms with real-world translational potential. Review Wed, 19 Nov 2025 00:00:00 GMT DilpreetSingh, SatvirSingh, NitinTandon, NeenaBedi, Wed, 19 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002349 https://www.explorationpub.com/Journals/etat/Article/1002350 Therapeutic cancer vaccines harness the adaptive immune system to eradicate malignancies by targeting tumor-specific antigens. This review charts the evolution of cancer vaccine platforms—from shared tumor-associated antigens (TAAs) and dendritic cell (DC) vaccines to next-generation neoantigen-messenger ribonucleic acid (mRNA) vaccines—highlighting advances in vaccine delivery, antigen discovery, computational prediction, and translational efficacy. We explore cutting-edge clinical data, including long-lived T-cell memory and promising outcomes in various cancer types, including pancreatic ductal adenocarcinoma (PDAC), melanoma, head and neck cancers, renal cell carcinoma (RCC), and others. We address critical challenges, including tumor heterogeneity, manufacturing scalability, biomarker development, and regulatory frameworks, and propose an integrated translational ecosystem to accelerate the adoption of personalized cancer vaccines. Review Mon, 24 Nov 2025 00:00:00 GMT Panagiotis J.Vlachostergios, Mon, 24 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002350 https://www.explorationpub.com/Journals/etat/Article/1002351 Colorectal cancer (CRC) is a significant global health problem, ranking as the third most common cancer and the second leading cause of cancer deaths in the world. The highest incidence of CRC is found in developed regions, thus underlining its characterization as a Western disease. Major risk factors for CRC include an unhealthy diet, lack of physical exercise, and cigarette smoking. The gut microbiota refers to the complex community of microorganisms inhabiting the digestive tract and plays a crucial role in the maintenance of host health and modulation of immune responses. Gut dysbiosis can be caused by poor diet and alcohol consumption, increasing CRC risk. Specific bacteria, such as Fusobacterium nucleatum and Escherichia coli, may have a close relationship with CRC development, while the beneficial bacteria are frequently depleted in CRC patients. This paper will discuss the mechanisms of colorectal carcinogenesis, focusing on the effects of bacterial genotoxins, immune evasion, inflammation, and diet. Additionally, it reviews preventative strategies including short-chain fatty acids (SCFAs), prebiotics, probiotics, synbiotic supplements, and the method of fecal microbiota transplantation (FMT), showing their potential to improve overall gut health and reduce the risk for CRC. Understanding these mechanisms and implementing specific preventative strategies could significantly enhance clinical interventions and reduce the global burden of CRC. Mini Review Tue, 25 Nov 2025 00:00:00 GMT Tallha W.Khawaja, LeiZhao, RaiqSiddiq, Mohammad U.Ahmad, Caitlin P.Burns, Jacob M.Parker, Mark R.Wakefield, YujiangFang, Tue, 25 Nov 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002351 https://www.explorationpub.com/Journals/etat/Article/1002352 Radiation exposure to the eye during cancer treatment can lead to ocular radiation injury (ORI), a devastating condition that can have a profound and permanent impact on vision-related quality of life. Rodent models do not have adequate ocular anatomy to accurately simulate human ORI, and modeling in non-human primates is limited by logistical and ethical concerns. To improve future translational research investigating ways to treat or prevent ORI, we developed protocols for a tree shrew model of ORI. Northern tree shrews (Tupaia belangeri) were obtained by our laboratory. Custom housing and handling methods were developed, including custom body suits to maintain the tree shrew’s body temperature during procedures. Radiation delivery was optimized to accurately deliver radiation, and imaging was performed to observe fundus changes from ORI. Optimization of tree shrew handling, housing, anesthesia approaches, radiation delivery, and clinically-relevant ocular imaging permitted successful induction and assessment of ORI in tree shrews. With these protocols, tree shrews can be used as a highly relevant model organism with key anatomic features similar to humans to study ORI. Protocol Tue, 02 Dec 2025 00:00:00 GMT Lauren A.Dalvin, Kjersten J.Anderson, Tommy A.Rinkoski, David R.Miley, HienOng, Angela M.Schechinger, Cassandra A.Fjeld, Catherine R.Leblond, Mackenzie K.Keown, Sierra D.Palmer, Danielle M.Burgenske, Brett L.Carlson, Lauren L.Ott, Brian C.Samuels, Michael F.Romero, Jann N.Sarkaria, Felicia DukeBoynton, Gavin W.Roddy, Tue, 02 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002352 https://www.explorationpub.com/Journals/etat/Article/1002353 Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment. Letter to the Editor Wed, 17 Dec 2025 00:00:00 GMT YilinMa, MengqinGuo, YangLiu, ZhengweiHuang, Wed, 17 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002353 https://www.explorationpub.com/Journals/etat/Article/1002354 Immune checkpoint inhibitor (ICI) therapy has revolutionized metastatic melanoma treatment, yet only a subset of patients respond effectively, and the treatment can induce a variety of immune-related adverse events (irAEs), including colitis. The gut microbiome plays a critical role in determining patient responses to immunotherapy, prompting exploration of gut-modifying strategies such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) to overcome both primary and acquired resistance and improve treatment outcomes. Prebiotics, defined as dietary substrates that selectively support the growth and/or activity of beneficial gut microorganisms, represent a feasible and safe strategy for microbiome reshaping. Plant-derived prebiotics like castalagin, inulin, fructooligosaccharides, galactooligosaccharides, mushroom extract, kale extract, and konjac glucomannan offer unique advantages over synthetic or animal-derived alternatives due to their natural fiber content alongside their ability to enhance gut microbial diversity. Prebiotics are known to achieve health benefits by selectively stimulating beneficial gut bacteria, producing short-chain fatty acids (SCFAs) that modulate the host immune system, suppressing pathogenic microbes, enhancing mucin production, and modulating systemic and gut-associated immune responses. SCFAs generated through prebiotic fermentation influence host innate and adaptive immunity and regulate metabolic activity via inhibition of histone deacetylases (HDACs), influencing mTOR/MAPK signaling and cytokine production. They also act as ligands for G-protein-coupled receptors (GPCRs), altering intracellular calcium and cAMP to modulate immune cell gene expression. However, the specific mechanisms by which individual prebiotics interact with host genetics, beneficial gut bacteria, and their metabolites are not very well understood. This is crucial to optimize their therapeutic potential in cancer immunotherapy. This review synthesizes current evidence on plant-derived prebiotics, highlighting the impact of beneficial gut bacteria and their metabolites. Given their established safety for human consumption, prebiotics represent a promising, low-risk option to improve gut microbiome composition and potentially enhance immunotherapy and clinical outcomes in cancer. Review Fri, 19 Dec 2025 00:00:00 GMT EmilyKay, MahnazKazi, JeremyBurton, Seema NairParvathy, Fri, 19 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002354 https://www.explorationpub.com/Journals/etat/Article/1002355 The evolution of nanocarrier-based drug delivery systems has transformed the paradigm of cancer therapeutics, advancing from conventional cytotoxic formulations to intelligent, adaptive nanosystems capable of precision targeting. Early-generation nanocarriers exploited the enhanced permeability and retention (EPR) effect for passive tumor accumulation, yet their therapeutic efficiency remained constrained by tumor heterogeneity, limited penetration, and off-target toxicity. Emerging nanotechnologies now integrate active targeting, stimuli-responsive components, and biomimetic strategies to achieve spatiotemporal control over drug release and tumor-selective action. These “intelligent” nanocarriers are designed to recognize molecular signatures, respond dynamically to tumor microenvironmental cues such as pH, redox gradients, hypoxia, and enzymatic activity, and even engage in real-time feedback through imaging or biosensing modules. In addition, hybrid and multifunctional platforms—combining liposomes, micelles, dendrimers, polymeric nanoparticles, and inorganic systems—offer programmable functionality and synergistic delivery of chemotherapeutic, gene-editing, and immunomodulatory agents. This review delineates the mechanistic basis of passive and active targeting, highlights recent innovations in stimuli-responsive and biomimetic nanocarriers, and explores translational and regulatory perspectives shaping their clinical journey. By integrating nanotechnology with systems biology and artificial intelligence, next-generation nanocarriers promise to redefine the landscape of precision antitumor therapy. Review Mon, 29 Dec 2025 00:00:00 GMT DilpreetSingh, AkshayKumar, Mon, 29 Dec 2025 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002355 https://www.explorationpub.com/Journals/etat/Article/1002356 Not applicable. Editorial Thu, 22 Jan 2026 00:00:00 GMT MaurieMarkman, Thu, 22 Jan 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002356 https://www.explorationpub.com/Journals/etat/Article/1002357 Machine learning (ML) and deep learning (DL) models applied to electronic health records (EHRs) have substantial potential to improve oncology care across diagnosis, prognosis, treatment selection, and trial recruitment. However, opacity of many high-performing models limits clinician trust, regulatory acceptance, and safe deployment. Explainable artificial intelligence (XAI) methods aim to make model behavior understandable and actionable in clinical contexts. The present perspective summarizes current XAI approaches applied to EHR-based oncology tasks, identifies key challenges in evaluation, reproducibility, clinical utility, and equity, and proposes pragmatic recommendations and research directions to accelerate safe adoption in oncology. Common XAI categories used with EHR data include feature importance/interaction methods, intrinsically interpretable models, attention mechanisms, dimensionality reduction, and knowledge distillation or rule extraction. Tree-based models with SHapley Additive exPlanations (SHAP) explanations dominate recent EHR studies. Other interpretable strategies, such as generalized additive models and rule sets, appear in settings where transparency is prioritized. Gaps include inconsistent reporting, scarce formal evaluation of explanations for clinical utility, limited reproducibility for data and code availability, inadequate external validation, and insufficient consideration of fairness and equity that these issues are particularly important in oncology, where heterogeneity and stakes are high. Overall, integrating XAI with EHR-driven oncology models is promising but underdeveloped, which requires further progress by multi-stakeholder evaluation frameworks, reproducible pipelines, prospective and multicenter validations, and equity-aware design. The field should prioritize clinically meaningful explanations beyond ranking features and study how explanations affect clinician decision-making and patient outcomes. Perspective Wed, 04 Feb 2026 00:00:00 GMT YuhanYang, XiciLiu, Wed, 04 Feb 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002357 https://www.explorationpub.com/Journals/etat/Article/1002358 Glioblastoma (GBM) is a complex condition with a poorly understood pathophysiology and no effective treatment to date. The present article highlights the role of canonical and non-canonical signal transducer and activator of transcription 3 (STAT3) interactions with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the modulation of the mitochondrial melatonergic pathway in GBM microenvironment pathophysiology. The capacity of STAT3 and NF-κB to interact to upregulate the mitochondrial melatonergic pathway is suppressed systemically over the course of aging, thereby attenuating the capacity to achieve inflammation resolution. The suppressed capacity to induce the mitochondrial melatonergic pathway systemically is partly driven by the dramatic 10-fold decrease in pineal melatonin over aging. The attenuation of pineal melatonin in the first half of sleep over aging and aging-accelerating conditions disinhibits the effects of cortisol in the second half of sleep. This decrease in the melatonin/cortisol ratio alters the nature of night-time dampening and resetting in preparation for the coming day by altering cellular and intercellular homeostatic interactions. Aging and aging-accelerating conditions, by impacting the night-time melatonin/cortisol ratio, also suppress the capacity of the vagal nerve to resolve inflammation. This further contributes to systemic changes that influence GBM pathoetiology and ongoing pathophysiology. Aging-associated changes in night-time dampening and resetting provide a novel framework on which many previously disparate bodies of data on GBM pathophysiology can be collated. This has numerous future research, prevention, and treatment implications. Review Fri, 13 Feb 2026 00:00:00 GMT GeorgeAnderson, Fri, 13 Feb 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002358 https://www.explorationpub.com/Journals/etat/Article/1002359 Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior, often resulting in ossicular erosion, hearing loss, labyrinthine fistula, and, rarely, intracranial complications. Surgical excision remains the primary management strategy; however, recurrence is common due to persistent microenvironmental drivers. Recent mechanistic studies—including single-cell transcriptomics, spatial proteomics, and epigenetic profiling—reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation via RANKL and activin A, epithelial plasticity with partial epithelial-to-mesenchymal transition (EMT), and a dysbiotic, biofilm-forming microbiome. Emerging evidence further implicates oxidative stress, RNA and epigenetic modifications, miRNA dysregulation, and immune cell infiltration as central modulators of lesion chronicity and bone resorption. Collectively, these processes establish a self-sustaining pro-osteolytic microenvironment that drives bone erosion and postoperative recurrence. Cholesteatoma recapitulates several features of malignant lesions—hyperproliferation, local invasion, and stromal/immune cell recruitment—yet remains fundamentally benign, lacking metastatic potential and genomic instability. Its aggression is ecological rather than genetic, highlighting the potential for microenvironment-directed, precision-based strategies. Adjunctive approaches may include local delivery of modulatory agents, targeted interference with inflammatory, proteolytic, osteoclastogenic, and microbial axes, and biomarker-guided patient stratification. Preclinical and early-phase experimental studies assessing target engagement, radiologic stabilization, and molecular surrogates of efficacy could inform safer, mechanism-driven interventions that complement surgery, reduce recurrence, and preserve hearing. Integrating molecular pathobiology with clinical strategy positions cholesteatoma as a model for benign yet locally aggressive, microenvironment-driven disease, providing a roadmap for translational therapies with direct relevance to surgical practice. Mini Review Wed, 25 Feb 2026 00:00:00 GMT PinelopiSamara, MichailAthanasopoulos, IoannisAthanasopoulos, Wed, 25 Feb 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002359 https://www.explorationpub.com/Journals/etat/Article/1002360 Background: Docetaxel is a cornerstone chemotherapy for metastatic hormone-sensitive and castration-resistant prostate cancer. Although the standard triweekly regimen is widely used, weekly and biweekly schedules are often employed to improve tolerability, particularly in elderly or frail patients. The comparative efficacy and safety of these dosing strategies remain unclear. This study aimed to systematically compare weekly, biweekly, and triweekly docetaxel regimens using a network meta-analysis. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to February 2025. Randomized controlled trials and observational retrospective studies comparing weekly, biweekly, and triweekly docetaxel regimens were included. Outcomes assessed were prostate-specific antigen (PSA) response rate, time to treatment failure or progression, and adverse events. A frequentist random-effects network meta-analysis was conducted using R software. Results: Eleven studies involving 1,238 patients were included. PSA response rates did not differ significantly among regimens; triweekly docetaxel showed a numerically lower response compared with weekly dosing (RR = 0.79, 95% CI 0.52–1.22; I2 = 41.1%). Time to treatment failure was significantly longer with triweekly dosing compared with weekly dosing (mean difference = 10.91 months, 95% CI 6.94–14.87; I2 = 96.8%). Biweekly and triweekly regimens were associated with significantly higher hepatotoxicity compared with weekly dosing (RR = 3.71 and RR = 3.21, respectively; I2 = 0%). Vomiting was more frequent with triweekly docetaxel (RR = 2.47, 95% CI 1.31–4.63). No significant differences were observed for overall adverse events, hematologic toxicity, neuropathy, fatigue, febrile neutropenia, nausea, anorexia, or diarrhea. Discussion: Docetaxel dosing schedules show comparable PSA response rates. Triweekly dosing prolongs time to treatment failure but is associated with greater toxicity, whereas weekly dosing offers better tolerability. Treatment decisions should balance efficacy and safety based on individual patient characteristics. Systematic Review Fri, 27 Feb 2026 00:00:00 GMT ShreeRath, FatimaSajjad, Khawaja AbdulRehman, ZaryabBacha, Ahmad OmarSaleh, UmairHayat, UmamaAlam, WaseefUllah, FareedaBrohi, OsamaAhmad, MuzamilKhan, AmarLal, Fri, 27 Feb 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002360 https://www.explorationpub.com/Journals/etat/Article/1002361 Breast cancer is a leading cause of cancer death in women worldwide. One of the major causes of death from breast cancer is metastatic disease, which results from the malignant cells invading and migrating through blood vessels to distant sites. Several studies have shown that metastasis is facilitated by haemostatic proteins. Breast cancer is characterized by a haemostatic imbalance, which is tilted more to a procoagulant state with resultant thrombotic complications. These elements that are involved in thrombosis also play key roles in different aspects of breast cancer growth, including cancer proliferation and progression, cancer survival, angiogenesis, and metastasis. Some of these elements include platelets, endothelial cells, coagulation factors, and fibrinolytic proteins. There is a close relationship between cancer and many of the haemostatic elements. They are usually increased in metastatic breast cancer and have found use as predictive and prognostic markers. Some have been validated in breast cancer. Due to their seemingly active roles in breast cancer progression, some of the haemostatic proteins are being developed as diagnostic tools in the management of breast cancer. They are equally seen as potential targets for the development of novel therapies in breast cancer or repurposing drugs in current use for the same gain. This review highlights the role haemostatic proteins play in breast cancer progression, and their diagnostic and therapeutic relevance. Review Mon, 09 Mar 2026 00:00:00 GMT Ogochukwu O.Izuegbuna, Mon, 09 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002361 https://www.explorationpub.com/Journals/etat/Article/1002362 Aim: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options and poor survival outcomes. Prognostic models developed in Western cohorts rarely assess algorithmic fairness. This study aimed to develop and internally validate a clinically interpretable Cox survival model for TNBC using baseline diagnostic variables and to evaluate its fairness according to ISO/IEC TR 24027:2021 guidelines in a Middle East and North Africa (MENA) cohort. Methods: A total of 138 TNBC patients were included after merging two institutional datasets and removing variables with > 25% missingness. Baseline features comprised age, tumor size, lymph node involvement, tumor grade, Ki-67, type of surgery, metastasis at diagnosis, chemotherapy, and radiotherapy. A Cox proportional hazards (CoxPH) model with six clinically established predictors was fitted to reduce overfitting. Model performance was assessed through five-fold stratified cross-validation using Harrell’s concordance index (C-index), receiver operating characteristic area under the curve (AUROC), and calibration curves. Fairness was evaluated using demographic parity, equality of opportunity, predictive equality, and equalized odds metrics following ISO/IEC TR 24027:2021. Results: During follow-up, 34 patients (24.6%) died. Metastasis at diagnosis, high tumor grade, and radical mastectomy were significantly associated with mortality. The CoxPH model achieved a C-index of 0.80 [SE = 0.04; 95% confidence interval (CI): 0.72–0.87] and an AUROC of 0.81 (95% CI: 0.72–0.90). Calibration plots showed strong agreement between predicted and observed survival probabilities, with a modest overall bias of –8.8%. Fairness assessment revealed small but notable disparities in false-positive rates across age groups and surgical categories, while lymph node status and other variables showed no significant bias. Conclusions: This study presents a robust and fairness-aware survival prediction model for TNBC using routinely available clinical features. The model demonstrates strong discrimination, good calibration, and quantifiable fairness across patient subgroups, offering a clinically interpretable and ethically aligned tool to support TNBC risk stratification and decision-making in the MENA region. Original Article Fri, 20 Mar 2026 00:00:00 GMT MehrshadAlirezaei Farahani, FatemeSadeghipour, Hamid RezaMarateb, MaryamSoltan, AzarNaimi, MarjanMansourian, Fri, 20 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002362 https://www.explorationpub.com/Journals/etat/Article/1002363 Aim: Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core NURD remodeling complex ATPase that plays a crucial role as a gene repressor. Its overexpression has been reported in several cancers. In papillary thyroid carcinomas (PTCs), CHD4 is overexpressed and associated with aggressive features of the tumor, such as proliferation, migration, and epithelial-mesenchymal transition (EMT). We previously showed in PTCs that NADPH oxidase NOX4 expression is positively regulated by BRAFV600E mutation, which is the most aggressive alteration in PTCs. In this retrospective study, we wondered whether there is a link between CHD4 and NOX4 protein expression in malignant thyroid tissues. Methods: We explored CHD4 protein expression by immunostaining analysis in 86 human thyroid tissues: 44 thyroid tumor tissues [28 classical forms of PTCs (C-PTCs), 13 follicular variants of PTCs (F-PTCs), and three anaplastic thyroid carcinomas (ATCs)] and 42 of their normal adjacent tissues (NATs). The detection of BRAFV600E mutation was performed using Sanger sequencing and digital droplet PCR. Statistical analyses were conducted using GraphPad Prism 8 software. Various tests were used to assess the statistical relevance of different correlations, such as the chi-square test, Fisher’s exact test, and the Pearson correlation coefficient. A p-value of less than 0.05 indicates statistical significance. Results: The CHD4 protein expression analysis with already published data from our group (BRAFV600E status and NOX4 expression) reveals a highly significant level of CHD4 protein expression in C-PTCs compared to F-PTCs and ATC. Importantly, 70% of C-PTCs-BRAFV600E overexpress CHD4 at the protein level, confirming the positive correlation between the CHD4 expression and BRAFV600E mutation. Furthermore, a high level of CHD4 is associated with the presence of capsular breach and vascular emboli, affirming the involvement of CHD4 in thyroid tumor aggressiveness. Interestingly, we showed for the first time, to our knowledge, a positive correlation between CHD4 and NOX4 protein expression in malignant thyroid tissues. Conclusions: The results of this study suggest that CHD4 could be used as a complementary molecular marker to improve the diagnosis and the management of PTCs-BRAFV600E. Original Article Thu, 26 Mar 2026 00:00:00 GMT SalmaFenniche, MohamedOukabli, YassireOubaddou, AllaouiMohamed, Mohamed RedaElochi, AbirAlghuzlan, AbdelilahLaraqui, NadiaDakka, YoussefBakri, CorinneDupuy, Rabii AmezianeEl Hassani, Thu, 26 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002363 https://www.explorationpub.com/Journals/etat/Article/1002364 Aim: Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes. Methods: 3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels. Results: 3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy-D-glucose (2DG), a glycolytic inhibitor, depleted ATP dose-dependently (30–300 μM) and prevented those increases both at the protein and transcriptional levels. This was also observed in 3D spheroids upon TGF-β transient siRNA-mediated silencing or when TGF-βR1 kinase activity was inhibited by galunisertib. Transcriptomic profiling revealed shared upregulation of apoptosis-related (BCL2, CASP7, FAS, FASLG, GADD45A) and autophagy-related (ATG7, ATG16L1, IRGM, PIK3C3, ULK1) genes in response to TGF-β or upon 3D spheroid formation. 2DG, transient silencing of TGF-β, or galunisertib treatment prevented these increases. Conclusions: 3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer. Original Article Tue, 31 Mar 2026 00:00:00 GMT MaellisPayet-Desruisseaux, AlainZgheib, Bogdan AlexandruDanalache, MichelDesjarlais, BorhaneAnnabi, Tue, 31 Mar 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002364 https://www.explorationpub.com/Journals/etat/Article/1002365 Aim: Intravesical Bacillus Calmette–Guérin (BCG) is the standard therapy for non-muscle invasive bladder cancer (NMIBC); however, many patients experience recurrence or progression. We examined how urinary immune signals and the urinary microbiome change across BCG and are related to outcomes. Methods: In this single-center prospective cohort study, adults with NMIBC underwent transurethral resection of bladder tumor (TURBT), followed by BCG induction. Urine was collected before TURBT, before BCG, after BCG induction, and three months later. Urine sediment mRNA (PD-L1, PD-L2, CD33, and CD204) was quantified using TaqMan ΔCt. The urinary microbiome was profiled using 16S rRNA gene sequencing, and diversity, composition, and taxon balance were evaluated using nonparametric tests, PERMANOVA, repeated-measures correlations, and mixed-effects models. We analyzed the relationship between the urinary microbiome and prognosis. Results: Twenty-three patients were analyzed; ten recurrences, eight progressions, and three deaths were observed. Relative to baseline, CD33 increased after BCG and after three months; PD-L2 increased immediately after BCG and returned to baseline by three months; PD-L1 and CD204 increased after BCG. Shannon alpha-diversity was unchanged, but total read count was higher at three months, with stable beta-diversity and dispersion. Higher PD-L1 expression was associated with lower Actinobacteria abundance in the bladder cancer microenvironment. A higher post-BCG Firmicutes/Bacteroidetes ratio was associated with worse prognosis, with the clearest signal for progression-free survival (PFS) observed in the univariate Cox models. Higher post-BCG Corynebacterium and Enterobacteriaceae abundance was associated with better PFS. Conclusions: BCG was associated with higher urinary PD-L1/PD-L2 and myeloid marker transcripts, while overall community structure remained stable. These exploratory data support that pre-BCG microbial features may be related to early response, and post-BCG profiles may reflect durability and survival. Urine immune-microbiome profiling could be a feasible, noninvasive adjunct for monitoring and risk stratification in NMIBC. Original Article Tue, 14 Apr 2026 00:00:00 GMT YukiOda, MakitoMiyake, NobutakaNishimura, TakutoShimizu, TakuyaOwari, KotaIida, YasushiNakai, NobumichiTanaka, KiyohideFujimoto, Tue, 14 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002365 https://www.explorationpub.com/Journals/etat/Article/1002366 Aim: This study aimed to evaluate the real-world efficacy and safety of lorlatinib in patients with anaplastic lymphoma kinase (ALK)-rearranged metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior ALK tyrosine kinase inhibitor (TKI). Methods: The dataset included 82 subjects with metastatic NSCLC, who received lorlatinib upon compassionate use program or routine treatment between January 2017 and May 2025. All patients involved in this study responded to a prior ALK inhibitor for at least 4 months and switched to the above drug due to disease progression. Results: The overall objective response rate (ORR) was 64.6%, with the disease control rate (DCR) of 96.3%. Among 65 patients with brain metastases, the intracranial ORR and DCR were 66.2% and 96.9%, respectively. After a median follow-up of 82.7 months, the median progression-free survival (PFS) was 66.7 months (95% CI, 40.5–75.0 months), while the median overall survival (OS) was not reached (NR) (95% CI, NR–NR). Patients who had benefited from prior ALK TKI for more than 12 months achieved significantly longer PFS (NR vs. 34.0 months; p = 0.013) and OS (NR vs. 39.4 months; p = 0.002). Multivariate analysis showed that prior response to ALK TKI of less than 12 months was an independent negative predictor of survival (PFS: p = 0.039, OS: p = 0.027). Treatment-related adverse events (AEs) were reported in 75.6% of patients, with 8.1% experiencing grade 3 or higher toxicity; no treatment-related AEs led to permanent discontinuation of lorlatinib. Conclusions: This real-world dataset demonstrates an unusually pronounced benefit from lorlatinib in selected patients who progressed on early-generation TKIs, especially in long-term responders to prior therapy. However, the observed outcomes should be interpreted within the context of patient selection. The enrichment for prior responders limits the generalizability to unselected post-TKI populations, including those with primary resistance. Original Article Thu, 16 Apr 2026 00:00:00 GMT Sergey V.Orlov, Konstantin K.Laktionov, Aram A.Musaelyan, Elena V.Reutova, Svetlana V.Odintsova, Magaripa A.Urtenova, Valeria A.Kuzmina, Vladislav I.Tiurin, Alexandra E.Lomakova, Evgeny N.Imyanitov, Thu, 16 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002366 https://www.explorationpub.com/Journals/etat/Article/1002367 Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that typically arise from the pleura but may occur in various extrathoracic sites. Primary intraparenchymal pulmonary SFTs without pleural attachment are exceptionally uncommon and often pose diagnostic and therapeutic challenges. We report the case of a middle-aged female patient presenting with progressive dyspnea and a large mass in the left lower lobe on imaging. Computed tomography revealed a well-circumscribed, hypervascular mass occupying the left lower lobe. Bronchoscopic and percutaneous biopsies were nondiagnostic, and surgical resection was pursued. Intraoperatively, the tumor was found to arise from the lung parenchyma without pleural involvement. Histopathological examination demonstrated a spindle-cell neoplasm with the typical “patternless pattern,” and immunohistochemistry confirmed nuclear STAT6 positivity, establishing the diagnosis of SFT. The postoperative course was uneventful apart from a transient pulmonary embolism, which was successfully treated. The patient was discharged in good condition and is under regular radiologic surveillance. SFTs of the lung are rare and often mimic more common pulmonary tumors radiologically. Histologic confirmation with STAT6 immunohistochemistry is crucial for accurate diagnosis. Complete surgical excision remains the mainstay of treatment. Given the risk of late recurrence—especially in large tumors—long-term imaging follow-up is mandatory. This case highlights the importance of considering SFT in the differential diagnosis of large pulmonary masses, the critical role of STAT6-based histopathologic confirmation, and the necessity for prolonged surveillance even after complete resection. Case Report Wed, 22 Apr 2026 00:00:00 GMT VasileiosLeivaditis, KonstantinosGrapatsas, FranceskMulita, SofoklisMitsos, EfstratiosKoletsis, AthanasiosPapatriantafyllou, EliasLiolis, AdmirMulita, PeriklisTomos, ManfredDahm, Wed, 22 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002367 https://www.explorationpub.com/Journals/etat/Article/1002368 Background: Targeted radioligand therapy (TRT) is an emerging theranostic modality in oncology. While well established in neuroendocrine and prostate cancers, its role in small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) remains investigational. This systematic review summarizes current evidence evaluating TRT in lung cancer. Methods: A Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-guided systematic review of PubMed, Embase, and Scopus (2000–November 2025) was conducted. Original studies evaluating TRT in SCLC or NSCLC were included. Primary outcomes were tumor response, disease-control rate, and treatment-related toxicity. Secondary outcomes included progression-free survival, overall survival, and dosimetry. Risk of bias was assessed using the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool. Results: From 2,453 records, 15 studies were included, reporting 358 lung cancer patients, of whom 105 received TRT. Disease-control rates reached up to 78% in mixed NSCLC/SCLC cohorts. In SCLC, somatostatin receptor-targeted peptide receptor radionuclide therapy demonstrated heterogeneous disease control (0–50%), with [177Lu]Lu-labeled agents showing more favorable outcomes than [90Y]Y-based therapy. The most favorable outcomes were a median progression-free survival of 11.9 months and an overall survival of 16 months in responders. In NSCLC, fibroblast activation protein (FAP)-targeted agents such as [177Lu]Lu-FAP-2286 demonstrated partial metabolic responses, including a 44.4% response rate and 78% disease control in a mixed cohort. Severe toxicities were infrequent. Discussion: TRT is a promising but experimental option for advanced lung cancer. Early efficacy signals exist for strong somatostatin receptor (SSTR)-targeted therapy in SCLC and FAP-targeted therapy in NSCLC, but evidence remains limited. Prospective trials with standardized protocols and dosimetry are needed to define TRT’s role in lung cancer treatment. Systematic Review Mon, 27 Apr 2026 00:00:00 GMT SerinMoghrabi, SaadRuzzeh, KamalAl-Rabi, AhmedAbdlkadir, Mohammed J.Al-Jaghbeer, NouraldeenAlzorgan, Ula AlRasheed, MohammadAlqudah, AkramAl-Ibraheem, Mon, 27 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002368 https://www.explorationpub.com/Journals/etat/Article/1002369 This commentary discusses the FDA’s drug approvals in 2025, with a particular focus on cancer therapies and the role of companion diagnostics (CDx). Cancer has emerged as the leading therapeutic area, accounting for 35% of all new drug approvals, largely driven by targeted therapies, with kinase inhibitors representing nearly half of these drugs. Many of the drugs have received orphan drug designations and/or have utilized the Accelerated Approval Program. A key finding was the widespread adoption of the drug-diagnostic co-development model, in which a CDx assay is developed along with the drug and used for patient selection in clinical trials. However, a significant challenge is the frequent lack of concurrent drug and CDx assay approvals. The absence of an analytically and clinically validated CDx assay may pose a challenge for healthcare providers in accurately identifying eligible patients, potentially delaying access to appropriate therapy. The FDA’s cancer drug approvals for 2025 highlight an ongoing commitment to precision medicine, with several new targeted treatments, such as antibody-drug conjugates and kinase inhibitors, where CDx assays play an important role in identifying the appropriate patient population. Commentary Mon, 27 Apr 2026 00:00:00 GMT Jan TrøstJørgensen, Mon, 27 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002369 https://www.explorationpub.com/Journals/etat/Article/1002370 The treatment paradigm for advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations is undergoing a significant transition. While third-generation tyrosine kinase inhibitors (TKIs) like osimertinib have long served as the frontline standard, the emergence of heterogeneous resistance mechanisms requires more robust therapeutic strategies. This review evaluates the clinical impact of the MARIPOSA trial, which demonstrated the superior efficacy of combining the bispecific antibody amivantamab with lazertinib. Beyond improving progression-free and overall survival, this dual-inhibition approach fundamentally alters the clonal evolution of the disease by suppressing common escape routes, such as MET amplifications and secondary EGFR mutations. Furthermore, we explore the diversifying landscape of second-line interventions, including the rise of antibody-drug conjugates (ADCs) like Sac-TMT and patritumab-deruxtecan, dual PD-1/VEGF inhibitors, and novel fourth-generation TKIs. By integrating preclinical insights on drug-tolerant persister cells with late-phase clinical data, this article outlines a future for EGFR-mutant NSCLC management defined by precision sequencing and the proactive mitigation of molecular resistance. Mini Review Tue, 28 Apr 2026 00:00:00 GMT Carminia MariaDella Corte, CaterinaDe Rosa, FaizUl Haq, FlorianaMorgillo, Tue, 28 Apr 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002370 https://www.explorationpub.com/Journals/etat/Article/1002371 Aim: The aim of this study is to investigate the molecular and functional features underlying the clinical heterogeneity between oligometastatic (OM) and polymetastatic (PM) colon cancer. Methods: We performed a genotype-phenotype analysis in a homogeneous cohort of 127 patients with metastatic colon cancer (mCC) profiled using the same next-generation sequencing platform (TruSight Oncology® 500). OM disease was defined as the presence of one to three metastatic lesions per involved organ, involving no more than two organs overall, with all lesions measuring < 70 mm in maximum diameter and no single lesion > 25 mm. Molecular alterations, microsatellite instability (MSI), tumor mutational burden (TMB), and overall survival (OS) were analyzed. Gene Ontology (GO) enrichment and Phenolyzer network analyses were applied to explore functional differences between prognostically distinct molecular subgroups. Results: OM patients showed a striking survival advantage compared with PM patients [median OS not reached versus 29 months; hazard ratio (HR): 0.20, P < 0.0001], validating the clinical distinction between the two phenotypes. PM disease was significantly enriched for RAS mutations, whereas OM disease was associated with MSI-high status and elevated TMB. Canonical driver alterations were largely shared between groups, and Phenolyzer analysis revealed similar core oncogenic networks centered on adenomatous polyposis coli (APC), tumor protein p53 (TP53), and epidermal growth factor receptor (EGFR). In contrast, GO analysis demonstrated selective enrichment in PM tumors for molecular functions related to ATP binding, nucleotide binding, and protein kinase activity, consistent with enhanced bioenergetic demand and signaling intensity. Conclusions: These findings support refined biological stratification of mCC and the exploration of personalized, metastasis-directed strategies, potentially incorporating immunological modulation in OM disease. Original Article Thu, 14 May 2026 00:00:00 GMT RobertoSirica, CarminePicone, FrancescoSabbatino, NadiaPetrillo, MarcoCascella, MariachiaraSantorsola, VincenzaGranata, MonicaIanniello, RaffaellaRuggiero, LuisaCircelli, GiulianaCiappina, MassimilianoBerretta, GiovanniSavarese, AlessandroOttaiano, Thu, 14 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002371 https://www.explorationpub.com/Journals/etat/Article/1002372 Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. Consequently, standard hormone and HER2-targeted therapies are ineffective, necessitating reliance on chemotherapy, immunotherapy, antibody-drug conjugates (ADCs), and poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA-mutated cases. TNBC exhibits rapid growth, a high risk of early recurrence, and disproportionately affects younger women, Black women, and BRCA1 mutation carriers. Standard management typically involves neoadjuvant chemotherapy followed by surgery and potential radiation. However, TNBC treatment remains challenging due to its severe biological heterogeneity, high metastatic potential, and the toxicity associated with systemic therapies. This review discusses the current understanding of TNBC biology, highlighting the urgent need for advanced diagnostics, integrated molecular subtyping, and personalized targeted therapies. Review Fri, 15 May 2026 00:00:00 GMT AlhasanAlobaidi, VikrantRai, Fri, 15 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002372 https://www.explorationpub.com/Journals/etat/Article/1002373 In 2013, more than a decade ago, the “Recalcitrant Cancer Research Act of 2012” was signed into law in the USA. Recalcitrant cancers are among the leading causes of global cancer morbidity and mortality. At the inception of the act, priority was placed on lungs and pancreatic cancers. Despite the tremendous advancement achieved in the research and treatment of said ‘recalcitrant cancers’ in the form of developing novel or modified small molecule and antibody drugs, modest improvement has been recorded for patients’ survival. Also, current mortality and morbidity for recalcitrant cancers keep increasing. Similarly, rare cancers only enjoy very meager research and drug development efforts globally. Consequently, very limited advancement has been made towards therapeutic development targeting rare cancers. Hence, the current situation calls for re-strategizing research efforts and exploring different treatment modalities towards combating recalcitrant and rare cancers. On this note, RNA therapeutics strategy holds a unique and vital prospect because of its propensity to target coding and non-coding RNA transcripts in the biological system. Moreover, RNA therapeutics such as lncRNAs and circRNAs have been established to even modulate protein expressions and biological phenotypic activity through RNA-protein interactions. Therefore, the current review aimed at summarizing existing literature, clinical trials, and elucidating the important prospect of RNA therapeutics in mitigating the recalcitrant and rare cancers menace. Review Thu, 21 May 2026 00:00:00 GMT Afeez AdekunleIshola, Nalini DeviVerusingam, BashirLawal, Thu, 21 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002373 https://www.explorationpub.com/Journals/etat/Article/1002374 Chemotherapy has profoundly shaped modern oncology, evolving from early cytotoxic approaches to biologically informed strategies. In glioblastoma (GBM), the highly aggressive primary brain tumor, precision medicine does not rely on the identification of a single crucial oncogenic driver but integrates biologically informed stratification strategies to predict treatment response, resistance, and therapy-induced adaptation. This review recapitulates the historical milestones of chemotherapeutic development in neuro-oncology, with particular emphasis on GBM. As the main chemotherapeutic agent currently used in GBM, temozolomide (TMZ) initially represented a major therapeutic breakthrough; however, its clinical use has progressively unveiled the biological and clinical limitations of conventional cytotoxic paradigms. While TMZ exerts antitumor activity through DNA damage–induced apoptosis, accumulating experimental evidence indicates that it may also elicit adaptive responses, ultimately supporting tumor progression and therapy resistance. By integrating historical milestones with recent molecular understanding, this review highlights how improved knowledge of therapy-induced adaptations may inform emerging precision medicine strategies in GBM, underscoring the need for tailored treatments to overcome tumor heterogeneity and adaptive responses. Review Fri, 22 May 2026 00:00:00 GMT AlessiaCiafarone, PaolaPalumbo, Fri, 22 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002374 https://www.explorationpub.com/Journals/etat/Article/1002375 Endocrine resistance in estrogen receptor-positive (ER+) breast cancer has undergone a fundamental reconceptualization over the past decade. The discovery that activating mutations in the ESR1 gene encoding ERα emerge under aromatase inhibitor (AI) selection pressure and drive ligand-independent receptor activation established a shift from empirical treatment sequencing to molecularly guided intervention. This review provides a synopsis of the structural biology underlying constitutive ER activation, the evolutionary dynamics of ESR1-mutant clones detectable through circulating tumor DNA (ctDNA), and the clinical evidence demonstrating that early molecular detection can trigger therapeutic switches that alter disease trajectory. The regulatory approval of elacestrant for ESR1-mutant disease and randomized trial data showing progression-free survival (PFS) benefit from ctDNA-guided endocrine switching (PADA-1, SERENA-6) position ESR1 genotyping as a dynamic biomarker with direct therapeutic implications. We examine the integration of oral selective ER degraders (SERDs) into treatment algorithms, the role of co-occurring alterations in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and emerging directions, including machine learning approaches to ctDNA kinetics and adaptive trial designs that treat clonal evolution as an actionable target. The convergence of structural mechanisms, liquid biopsy technology, and biomarker-driven drug development provides a framework for precision oncology in endocrine-resistant breast cancer. While these advances are substantial, important challenges remain, including the lack of mature overall survival (OS) data from interception trials, cost and accessibility barriers to serial ctDNA monitoring in diverse global healthcare settings, the unresolved question of optimal therapeutic sequencing in patients with concurrent ESR1 and PI3K pathway alterations, and the need to distinguish clinically actionable low-variant allele frequency (VAF) ESR1 calls from background noise in liquid biopsies. Review Tue, 26 May 2026 00:00:00 GMT ThaisMartinez, SamanthaWegner, Hisham F.Bahmad, Tue, 26 May 2026 00:00:00 GMT https://www.explorationpub.com/Journals/etat/Article/1002375