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.

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.

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.

Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants, which represents a significant clinical problem, accounting for up to 40% of all childhood blindness. ROP displays a range of severity, though even mild disease may result in life-long visual impairment. This is complicated by the fact that our current treatments have significant ocular and potentially systemic effects. Therefore, disease prevention is desperately needed to mitigate the life-long deleterious effects of ROP for preterm infants. Although ROP demonstrates a delayed onset of retinal disease following preterm birth, representing a potential window for prevention, we have been unable to sufficiently alter the natural disease course and meaningfully prevent ROP. Prevention therapeutics requires knowledge of early ROP molecular changes and risk, occurring prior to clinical retinal disease. While we still have an incomplete understanding of these disease mechanisms, emerging data integrating contributions of maternal/placental pathobiology with ROP are poised to inform novel approaches to prevention. Herein, we review the molecular basis for current prevention strategies and the clinical outcomes of these interventions. We also discuss how insights into early ROP pathophysiology may be gained by a better understanding of maternal and placental factors playing a role in preterm birth.

Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.

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.

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.

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.

Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.

Left ventricular ejection fraction is the critical parameter used for heart failure classification, decision making and assessing prognosis. It is defined as a volumetric ratio and is essentially a composite of arterial and ventricular elastances, but not intrinsic contractility. The clinician should be aware of its numerous limitations when measuring and reporting it. And make a step toward more insightful understanding of hemodynamics.

Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.

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.

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.

Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.

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.

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.

Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.

The currently ongoing coronavirus disease 19 (COVID-19) pandemic has affected globally human health and economy. Research in progress has shown facts associated with this disease and raised questions relevant for disease control and prevention. In this perspective, the collaboration between science and art in visual communication using the artwork “Enseñanza” (“Teaching”) contributes to the representation of the lessons learned from COVID-19 and the way forward. To advance preparedness for current and future pandemics, the authors propose to address international collaborations, support to science, access to food supplies and health services, sustainable development and a “One Health” approach searching a balanced interaction of humanity with nature and a more holistic approach to disease prevention and control.

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.

Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.

The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.

The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.

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.

BCL-X_L is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-X_L 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-X_L is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-X_L inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-X_L for survival. In this review, the authors discuss how BCL-X_L-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-X_L inhibition. The authors summarize the progress in the development of BCL-X_L 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-X_L PROTACs can significantly improve the therapeutic window compared to conventional BCL-X_L 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.

Nonalcoholic fatty liver disease (NAFLD) is a serious condition that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is associated with metabolic syndrome (MetS) and all of its components. According to data, around 25–30% of population has NAFLD. Giving the growing incidence of MetS, obesity and diabetes mellitus type 2, NAFLD related terminal-stage liver disease is becoming prevailing indication for liver transplantation. In order to prevent terminal stage of this disease, it is crucial to determine those that are in risk group, to modify their risk factors and monitor their potential progression. In the absence of other causes of chronic liver disease, the prime diagnosis of NAFLD in daily clinical practice includes anamnesis, laboratory results (increased levels of aminotransferases and gammaglutamil transferases) and imaging methods. The biggest challenge with NAFLD patients is to differentiate simple steatosis from nonalcoholic steatohepatitis, and detection of fibrosis, that is the main driver in NAFLD progression. The gold standard for NAFLD diagnosis still remains the liver biopsy (LB). However, in recent years many noninvasive methods were invented, such as transient elastography (TE). TE (FibroScan®, Echosens, Paris, France) is used for diagnosis of pathological differences of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Investigations in the last years have confirmed that elastographic parameters of steatsis (CAP) and fibrosis (LSM) are reliable biomarkers to non-invasively assess liver steatosis and fibrosis respectively in NAFLD patients. A quick, straightforward and non-invasive method for NAFLD screening in patients with MetS components is TE-CAP. Once diagnosed, the next step is to determine the presence of fibrosis by LSM which should point out high risk patients. Those patients should be referred to hepatologists. LB may be avoided in a substantial number of patients if TE with CAP is used for screening.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver chronic disease worldwide. The pathogenesis of NAFLD is complex and involves many metabolic enzymes and multiple pathways. Posttranslational modifications of proteins (PMPs) added another layer of complexity to the pathogenesis of NAFLD. PMPs change protein properties and regulate many biological functions, including cellular localization, stability, intracellular signaling, and protein function. Lysine acetylation is a common reversible PMP that consists of the transfer of an acetyl group from acetyl-coenzyme A (CoA) to a lysine residue on targeted proteins. The deacetylation reaction is catalyzed by deacetylases called sirtuins. This review summarizes the role of acetylation in NAFLD with a focus on sirtuins 1 and 3.

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.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.

The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.

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.

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.

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.

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.

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.

Technology in diabetes is rapidly evolving, with the aim of helping affected people to safely optimize their blood glucose control. New technologies are now considered as an essential tool for managing glycemia predominantly in people with type 1 diabetes, and clinical trials have demonstrated that in these subjects the use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems are associated with improved glycemic control along with a better quality of life. Literature regarding technologies and type 2 diabetes is relatively lacking, but innovations may have an important role also in the management of these patients. Some studies in adults with type 2 diabetes have shown benefits with the use of CGM in terms of glycemic variability and improved therapeutic adjustments. Clinical trials about CSII and CGM use in type 2 diabetes may have some pitfalls and future studies are needed to assess how these advanced systems could improve clinical outcomes and also ensure cost-effectiveness in this population. In this narrative review, we aim to highlight the most relevant studies on this topic and to focus on the potential role of new technological devices in type 2 diabetes management.

This commentary is the product of a concerted effort to understand the needs, barriers, and gaps in the field of speech and language biomarkers for Alzheimer’s disease (AD). It distills interviews, surveys, and extensive correspondence with global leaders in the areas of dementia research, clinical trials, linguistics, and data analytics into an idealized clinical-study design for the harmonized collection of voice recordings. The ultimate goal of the effort is to democratize the ongoing speech and language analytics efforts by making such rich datasets available to the wider research ecosystem.

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.

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.

Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues.

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.

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.

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.

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.

Silent coronary artery disease (CAD) is one of the manifestations of heart disease that particularly affects subjects with type 2 diabetes mellitus (T2DM). From a clinical point of view, silent CAD represents a constant challenge for the diabetologist, who has to decide whether a patient could or could not be screened for this disease. In the present narrative review, several aspects of silent CAD are considered: the epidemiology of the disease, the associated risk factors, and main studies conducted, in the last 20 years, especially aimed to demonstrate the usefulness of the screening of silent CAD, to improve cardiovascular outcomes in type 2 diabetes.

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.

Patients submitted to liver transplantation (LT) are exposed to high risk of cardiovascular (CV) complications which are the main determinants of both short-term and long-term morbidity and mortality in LT. Non-alcoholic fatty liver disease (NAFLD) is a very frequent condition in general population and is associated with a high risk of cardiovascular disease (CVD) which represents the first cause of death of these patients. NAFLD is predicted to become the first indication to LT and nowadays is also frequently detected in patients submitted to LT for other indications. Thus, the risk of CVD in patients submitted to LT is forecasted to increase in the next years. In this review the extent of CV involvement in patients submitted to LT and the role of NAFLD, either recurring after transplantation or as de novo presentation, in increasing CV risk is analysed. The risk of developing metabolic alterations, including diabetes, hypertension, dyslipidemia and weight gain, all manifestations of metabolic syndrome, occurring in the first months after LT, is depicted. The different presentations of cardiac involvement, represented by early atherosclerosis, coronary artery disease, heart failure and arrhythmias in patients with NAFLD submitted to LT is described. In addition, the tools to detect cardiac alterations either before or after LT is reported providing the possibility for an early diagnosis of CVD and an early therapy able to reduce morbidity and mortality for these diseases. The need for long-term concerted multidisciplinary activity with dietary counseling and exercise combined with drug treatment of all manifestations of metabolic syndrome is emphasized.

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.

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.

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.

In recent years, cancer immunotherapy has received unprecedented attention due to the clinical achievements. The applications of biomedical engineering and materials science to cancer immunotherapy have solved the challenges caused by immunotherapy to a certain extent. Among them, cell-derived vesicles are natural biomaterials chosen as carriers or immune-engineering in view of their many unique advantages. This review will briefly introduce the recent applications of cell-derived vesicles for cancer immunotherapy.

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.

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.

Atopic dermatitis (AD) is characterized by skin barrier disruption, type 2 immune dysregulation, chronic pruritus, and abnormal colonization by Staphylococcus aureus (S. aureus). Tapinarof, an aryl hydrocarbon receptor modulator, has been demonstrated to attenuate the development of AD in clinical studies. Recently, we found that tapinarof upregulated the expression of filaggrin and loricrin, which are essential proteins in skin barrier functions. Paradoxically, tapinarof induced interleukin (IL)-24 secretion by normal human keratinocytes. IL-24 is produced by T helper 2 lymphocytes and keratinocytes following stimulation by type 2 cytokines, and IL-24 is upregulated in the skin of patients with AD. Furthermore, IL-24 contributes to skin barrier disruption and hyperplasia in AD, and it may exacerbate skin inflammatory responses, itch, and S. aureus infection. In this review, we summarized the current findings regarding the detrimental role of IL-24 in AD, thereby suggesting that co-treatment of tapinarof with therapeutics that block IL-24 signaling may represent a promising strategy for managing AD.

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.

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.

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.

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.

Interleukin (IL)-22 is produced from immune cells such as T helper (Th)22 cells, Th17/22 cells, and group 3 innate lymphoid cells. IL-22 signals via the IL-22 receptor 1 (IL-22R1) and the IL-10 receptor 2 (IL-10R2). As the IL-22R1/IL-10R2 heterodimer is preferentially expressed on border tissue between the host and the environment, IL-22 is believed to be involved in border defense. Epidermal keratinocytes are the first-line skin barrier and express IL-22R1/IL-10R2. IL-22 increases keratinocyte proliferation but inhibits differentiation. Aryl hydrocarbon receptor (AHR) is a chemical sensor and an essential transcription factor for IL-22 production. In addition, AHR also upregulates the production of barrier-related proteins such as filaggrin in keratinocytes, suggesting a pivotal role for the AHR-IL-22 axis in regulating the physiological skin barrier. Although IL-22 signatures are elevated in atopic dermatitis and psoriasis, their pathogenic and/or protective implications are not fully understood.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug reaction, which can affect multiple organs. Patients with DRESS syndrome and hepatic manifestations may present alterations ranging from mild hepatitis to acute liver failure. The diagnosis might be difficult, and the management of these patients is challenging. This report analyzes a series of five cases reporting the clinical presentation, which ranged from acute hepatitis to liver failure, and discussed their treatment.

Nucleolin (NCL) is a multifunctional nucleolar phosphoprotein harboring critical roles in cells such as cell proliferation, survival, and growth. The dysregulation and overexpression of NCL are related to various pathologic and oncological indications. These characteristics of NCL make it an ideal target for the treatment of various cancers. AS1411 is a synthetic quadruplex-forming nuclease-resistant DNA oligonucleotide aptamer which shows a considerably high affinity for NCL, therefore, being capable of inducing growth inhibition in a variety of tumor cells. The high affinity and specificity of AS1411 towards NCL make it a suitable targeting tool, which can be used for the functionalization of therapeutic payload-delivery nanosystems to selectively target tumor cells. This review explores the advances in NCL-targeting cancer therapy through AS1411-functionalized delivery nanosystems for the selective delivery of a broad spectrum of therapeutic agents.

The limitations of current cancer treatments have stimulated the application of nanotechnology to develop more effective and safer cancer therapies. Remarkable progress has been made in the development of nanomedicine to overcome issues associated with conventional cancer treatment, including low drug solubility, insufficient targeting, and drug resistance. The modulation of nanoparticles allows the improvement of drug pharmacokinetics, leading to improved targeting and reduced side effects. In addition, nanoparticles can be conjugated to ligands that specifically target cancer cells. Furthermore, strategies that exploit tumor characteristics to locally trigger drug release have shown to increase targeted drug delivery. However, although some clinical successes have been achieved, most nanomedicines fail to reach the clinic. Factors that hinder clinical translation vary from the complexity of design, incomplete understanding of biological mechanisms, and high demands during the manufacturing process. Clinical translation might be improved by combining knowledge from different disciplines such as cell biology, chemistry, and tumor pathophysiology. An increased understanding on how nanoparticle modifications affect biological systems is pivotal to improve design, eventually aiding development of more effective nanomedicines. This review summarizes the key successes that have been made in nanomedicine, including improved drug delivery and release by polymeric nanoparticles as well as the introduction of strategies that overcome drug resistance. In addition, the application of nanomedicine in immunotherapy is discussed, and several remaining challenges addressed.

Immunity is continuously evolving by evolutionary mechanisms shaped by pathogenic stimuli of different kinds. Man-made nanomaterials (NMs) have been developed in the last decades and represent a novel challenge for our immune system, especially when applied to medical science. Toxicological studies of such nanoparticles (NPs) revealed that size, shape, and surface chemistry are key parameters to understand their noxious effects on cellular mechanisms. Less is known on the immune reactions to NMs since prolonged exposure data are not so detailed as the results for acute administration. The importance of immunity to biocompatible NPs is underlined by their increasing use as drug or gene delivery carriers in common pharmaceutical preparations and vaccines. In the latter case, the immunomodulatory properties of NMs allow their use also as efficient adjuvants to enhance the innate immune response. In the current manuscript, the authors discuss the main concepts in this fast-growing field by restricting our view to NMs with consolidated application in biomedicine.

Vascular aging, aortic stiffness and hypertension are mechanistically interrelated. The perspective presented here will focus mainly on the molecular mechanisms of age-associated increases in the stiffness of the vascular smooth muscle cell (VSMC). This review will highlight the mechanisms by which the VSMC contributes to disorders of vascular aging. Distinct functional sub-components of the vascular cell and the molecular mechanisms of the protein-protein interactions, signaling mechanisms and intracellular trafficking processes in the setting of the aging aorta will be detailed.

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.

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.

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.

The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism.

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.

Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic.

As the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a new virus, the current knowledge on the immunopathogenesis of this newly emerged SARS-CoV-2 is beginning to unravel with intensive ongoing global research efforts. Although a plethora of new studies have been published in a short space of time describing how the virus causes disease and incurs insults on the host immune system and the underlying immunopathogenic mechanisms remain to be elucidated. Thus, the discussion in this review is based on the most current knowledge on the immunopathogenesis of SARS-CoV-2 that has emerged in the past 12 months. The main objective is to shed light on the most current concepts in immunopathological aspects of the lung, bloodstream, and brain caused by the SARS-CoV-2, which has led to the current pandemic resulting in > 100 million infections and > 2 million deaths, and ongoing.

Arginase-1 (Arg1) and the inducible nitric oxide synthase 2 (NOS2) compete for the common substrate L-arginine, semi-essential amino acid, and central intestinal metabolite. Both enzymes exhibit various, sometimes opposing effects on immune responses, tissue regeneration, or microbial growth and replication. In sub-mucosal tissues of patients suffering from inflammatory bowel disease (IBD), similar as in experimental colitis, the expression and activity of both enzymes, Arg1 and NOS2 are more prominent than in respective controls. Accordingly, the metabolism of L-arginine is altered in IBD patients. Thus, L-arginine represents a promising medical target for clinical intervention in these devastating diseases. Previous studies primarily focused on the host side of L-arginine metabolism. Initial reports using Arg1 inhibitors generated conflicting results in murine colitis models. Subsequently, only the generation of conditional Arg1 knockout mice allowed reliable functional analyses of Arg1 and the L-arginine metabolism in the immune system. Utilizing cell-specific conditional Arg1 knockouts, we have recently reported that Arg1, surprisingly, hampered the resolution of experimental colitis due to the restriction of the intraluminal availability of L-arginine. Reduced levels of L-arginine restrained the compositional diversity of the intestinal microbiota and subsequently the mutual metabolism between the microbiota and the host. Thus, the intraluminal microbiota represents a potential therapeutic target for L-arginine metabolism aside from host-dependent L-arginine consumption.

Some have said that it is inappropriate and perhaps impossible to consider wave and Windkessel phenomena simultaneously. For 50 years, arterial hemodynamics has been dominated by the frequency-domain “impedance analysis” in which it was assumed that all variations in aortic pressure and flow were caused only by forward- and backward-going waves. This paper is a review of the results of incorporating the effects of Frank’s Windkessel. We have taken the view that measured aortic pressure is the sum of a Windkessel component and forward-going and backward-going wave components. When the Windkessel component is initially subtracted out, the pattern of propagation and reflection of wave components becomes clear. Furthermore, this analysis obviates the implications of impedance analysis that have not been explained satisfactorily.

Immunotherapy is a unique approach to treat cancer that targets tumours besides triggering the immune cells. It attempts to harness the supremacy and specificity of immune cells for the regression of malignancy. The key strategy of immunotherapy is that it boosts the natural defence and manipulates the immune system at both cellular and molecular levels. Long-lasting anti-tumour response, reduced metastasis, and recurrence can be achieved with immunotherapy than conventional treatments. For example, targeting cytotoxic T-lymphocyte antigen-4 (CTLA4) by monoclonal antibody is reported as an effective strategy against cancer progression in vivo and chimeric antigen receptor (CAR) modified T-cells are known to express a stronger anti-tumour activity. CTLA4 and CAR are, therefore, beneficial in cancer immunotherapy; however, in clinical settings, both are expensive and cause adverse side effects. Nanomaterials have augmented advantages in cancer immunotherapy, besides their utility in effective delivery and diagnostics. In particular, materials based on lipids, polymers, and metals have been sought-after for delivery technologies. Moreover, the surface of nanomaterials can be engineered using ligands, antigens, and antibodies to target immune cells. In this sense, checkpoint inhibitors, cytokines, agonistic antibodies, surface receptors, and engineered T-cells are promising to regulate the immune system against tumours. Therefore, emerging nanomaterials that can be used for the treatment of cancer is the prime focus of this review. The correlation of mode of administration and biodistribution of various nanomaterials is reviewed here. Besides, the acute and chronic side effects and outcome of clinical trials in the context of cancer immunotherapy are discussed.

The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

Skin is the largest organ of the body having multifunctional activities. It has a dynamic cellular network with unique immunologic properties to maintain defensive actions, photoprotection, immune response, inflammation, tolerogenic capacity, wound healing, etc. The immune cells of the skin exhibit distinct properties. They can synthesize active vitamin D [1,24(OH)₂D₃] and express vitamin D receptors. Any difficulties in the cutaneous immune system cause skin diseases (psoriasis, vitiligo, atopic dermatitis, skin carcinoma, and others). Vitamin D is an essential factor, exhibits immunomodulatory effects by regulating dendritic cells’ maturation, lymphocytes’ functions, and cytokine production. More specifically, vitamin D acts as an immune balancing agent, inhibits the exaggeration of immunostimulation. This vitamin suppresses T-helper 1 and T-helper 17 cell formation decreases inflammatory cytokines release and promotes the maturation of regulatory T cells and interleukin 10 secretion. The deficiency of this vitamin promotes the occurrence of immunoreactive disorders. Administration of vitamin D or its analogs is the therapeutic choice for the treatment of several skin diseases.

Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.

Obesity and metabolic syndrome are conditions at high risk for the development of complications such as type 2 diabetes mellitus, atherosclerotic cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). The growing prevalence of NAFLD has recently raised attention in the clinical practice, due to the worsening prognosis observed in the affected patients. Sex hormones abnormalities, commonly found in subjects suffering from obesity and metabolic syndrome, have been recently hypothesized to be directly involved in the physiopathology of obesity-related comorbidites; however, their role in the pathogenesis of NAFLD remains unclear. In this review of the available literature, a summary of the knowledge about the role of sex steroids abnormalities in the risk of developing NAFLD was performed, mentioning the possible clinical implications for therapy.

The pathogenic basis behind some of the most prevalent neurodegenerative diseases in advanced societies, known as proteinopathies, deals with alterations in protein homeostasis. Despite the broad diversity of clinical symptoms, they share a remarkably common feature that is the serious neuronal loss in several disease-specific brain regions due to the presence of toxic aggregations of misfolded proteins. So far, research efforts have been insufficient to decipher the exact molecular mechanisms that trigger the conformational change from a functional healthy protein to its pathological version. This is a sine qua non condition to progress in developing new approaches and treatments for these diseases for which there is no cure. Currently, it is well accepted that perturbations in gut microbiota composition negatively impact a wide range of brain processes via the gut-brain axis which increases host susceptibility to neurodegenerative disorders. In this context, modulate the microbial ecosystem colonizing the gastrointestinal tract may be a promising therapeutic approach in the management of proteinopathies. This review aims to provide an updated view of the role that gut microbiota poses in the pathogenesis of Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, the most common neurodegenerative proteinopathies, and of the possibility of translating this knowledge into effective and safe clinical microbiota-based interventions, especially those designed to afford neuroprotection.

Since the identification and cloning of the cannabinoid receptor 2 (CB₂R), several studies focused on the characterization of its physiological and pathological role. Initially, CB₂R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB₂R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB₂R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB₂R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB₂R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders.

Central pontine myelinolysis (CPM) is a rare manifestation of osmotic demyelination syndrome (ODS) which involves the pons and causes significant morbidity and mortality. CPM usually occurs in the setting of rapid correction of severe chronic hyponatremia. A rare case of CPM due to hyperglycemia in a 27-year-old man with type 1 diabetes is reported. During the patient’s hospitalization, his plasma glucose level showed a wide variability ranging from 38 mg/dL to 530 mg/dL; while plasma sodium level was constantly normal. At computed tomography (CT) scans, areas of hypodensity with a hyperdense ring were identified in the anterior part of the pons. At magnetic resonance imaging (MRI) scan, pontine abnormalities compatible with CPM were observed. According to laboratory tests, we concluded that CPM resulted from rapid and wide shifts in osmolar gradient owing to variability in plasma glucose levels. While universally recognized in several clinical settings, CPM is rarely observed in diabetic patients. Our report supports the notion that hyperosmolarity per se plays a key role in the pathogenesis of CPM, which may occur independently of sodium abnormalities.

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.

The term non-alcoholic fatty liver disease (NAFLD) appears unfitting both in adults and in children. As obesity and metabolic syndrome play a relevant pathogenic role, an international group of adults’ liver disease experts has proposed to rename this condition metabolic (dysfunction)-associated fatty liver disease (MAFLD). While this new more appropriate and useful definition has mostly been met with good reactions in adults, it may present a tangled path in pediatrics. Here we further stress the recommendations of the North American and the European Societies for Pediatric Gastroenterology, Hepatology and Nutrition that a hyperechogenic liver in a child affected by obesity or overweight with chronically elevated liver enzymes should not be assumed to have NAFLD only. Especially in those patients who are not in the classic age range or who have particularly severe laboratory anomalies, other genetic, metabolic (inborn errors of metabolism, IEM), endocrine, intestinal and hepatic pediatric-onset conditions, should in fact be excluded, particularly when response to a weight loss trial is not available. The term pediatric fatty liver disease (PeFLD) with three subtypes [1. contextual diagnosis of an IEM; 2. metabolic (dysfunction)-associated fatty liver; 3. unknown cause of fatty liver] has recently been proposed aiming to separate true MAFLD from IEM and/or the other above mentioned conditions, which may be rare when considered individually but represent a large group when considered collectively. Although the cost-effectiveness ratio of this attitude is still indeterminate, it is likely that the advantage of the early identification of a specifically treatable pediatric-onset liver disease associated to/mimicking MAFLD would be rewarding.

Submucosal esophageal hematoma is an uncommon clinical complication of anticoagulation. Current literature is scarce regarding presentation and management in acute submucosal hematomas in critically ill patients. Patients often present with retrosternal chest pain, making the diagnosis challenging due to overlap with common presentations of cardiopulmonary disorders. A high degree of suspicion is necessary in sedated patients. Several factors contribute to its etiology, and diagnosis often requires invasive techniques like endoscopy. However, management is usually supportive and aimed at its underlying cause. This is a case of a 68-year-old female who developed submucosal esophageal hematomas following anticoagulation for subarachnoid hemorrhage-related delayed neurological deficits in the intensive care unit.

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.

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.

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.

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca²⁺, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca²⁺-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dysfunction during the progression of heart failure.

Acute aortic syndromes, including aortic dissection (AD), are rare. The AD detection risk score (ADDRS) and associated investigation pathway were developed to reduce missed diagnosis of AD. The methodology for its development was sub-optimal and it has not been robustly validated in the emergency department chest pain population. Recent research suggests that it will drive over-investigation and that the risks of missed diagnosis may not be in balance with the risks of the testing strategy. There are serious doubts about whether the score and investigation pathway are fit for purpose.

Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 spread globally and creates an alarming situation. Following the SARS-CoV-2 paradigm, therapeutic efficacy is achieved via repurposing several antiviral, antibacterial, and antimalarial drugs. Innate and adaptive immune cells work close to combat infection through the intricate production of antibodies (Abs) and inflammatory cytokines. As an essential component of the immune system, Abs play an important role in eliminating viruses and maintaining homeostasis. B lymphocytes (B cells) are effector cells, stringent to produce neutralizing Abs to combat infection. After recognizing SARS-CoV-2 antigens by a surface receptor called B cell receptors (BCRs) on the plasma membrane, the BCRs transmembrane signal transduction and immune activation results in Ab production and development of immune memory. Thus, it ensures that plasma B cells can quickly start an intricate immune response to generate efficient protective Abs to clear the pathogen. Nevertheless, considering therapeutic challenges in the context of the new coronavirus pandemic, this review addresses the molecular mechanism of the immune activation and function of novel SARS-CoV-2 specific B cells in the production of SARS-CoV-2 specific Abs. Additionally, these studies highlighted the Ab-mediated pathogenesis, the intriguing role of nano-scale signaling subunits, non-structural proteins during COVID-19 infection, and structural insights of SARS-CoV-2 specific Abs.

Head and neck squamous cell carcinoma (HNSCC) is a relatively widespread cancer with high mortality rates. Many patients with locally advanced disease are treated with combinations of surgery, radiation, and chemotherapy, while others are considered incurable and develop recurrent/metastatic (R/M) disease. Despite these treatment modalities, the 5-year survival rate of HNSCC has remained at 50% due to limited treatment options in patients with recurrent disease. Immunotherapy has been shown to induce durable responses in R/M patients, but only a minority of patients currently respond. A major hurdle in tumor immunotherapy is identifying the non-responders and markers to predict resistance in patients who at first responded to the therapy. In HNSCC patients, the tumor microenvironment (TME) assumes a vital role to either diminish or augment immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. In this review, the impact of TME on the efficiency of immunotherapy, addressing the factors that mediate therapy resistance are highlighted. The composition of the TME encompassing the immunosuppressive cells including myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), mesenchymal stem cell (MSC), cancer-associated fibroblast (CAF), and tumor-associated macrophages (TAMs) and intrinsic factors like hypoxia, reactive oxygen species (ROS), extracellular matrix (ECM), angiogenesis, and epithelial-mesenchymal transition (EMT), how this debilitates immunosurveillance, and also discuss existing and potential strategies aimed at targeting these cellular and molecular TME components are reviewed. Understanding the interactions between the TME and immunotherapy is not only important in dissevering the mechanisms of action of immunosuppression but also offers scope for developing newer strategies to improve the competence of current immunotherapies.

Understanding the interactions of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with humans is deeply grounded in immunology, from the diagnosis to pathogenesis, from the clinical presentations to the epidemiology, prevention, and treatment. However, the difficulty of capturing the complex and changeable array of immunological concepts and incorporating them into the strategies of control of the SARS-CoV-2 pandemic poses significant hindrances to establish optimal public health policies. The contribution of immunology to the control of the pandemic is to shed light on the features and mechanisms of the protective immunity elicited by SARS-CoV-2 infection and vaccines. Do they induce effective protective immunity? How? For how long? What is the effect of vaccination on individuals who were previously infected? To appropriately answer these questions, it is necessary to get rid of the outdated notion of a naïve, static, and closed immune system, which leads to misconceptions about susceptibility, specificity, immunological memory, and protective immunity. The present essay discusses these issues based on current immunological concepts.

There are various types of skin immune responses including inflammatory skin diseases and skin malignancy. Macrophages and fibroblasts are skin resident cells that had been overlooked in terms of immunological research targets. In this review, cross talk among macrophages, fibroblasts, and migratory immune cells in skin diseases such as atopic dermatitis (AD), contact hypersensitivity, psoriasis, systemic sclerosis, melanoma, and cutaneous T-cell lymphoma is described. Macrophages are important in AD by antigen-presenting phagocytosis, production of inflammatory cytokines, removal of apoptotic cells, and mediating clusters between dendritic cells (DCs) and T cells. They are also increased in lesional skin of psoriasis, especially in stable plaques, and an increased ratio of M1/M2 macrophages and tumor necrosis factor-α production by macrophages are essential for development of psoriasis. The progression of skin malignancy is mediated by macrophages through promotion of tumor survival pathways via expression of cytokines and growth factors, interaction with regulatory T cells (Tregs) and myeloid-derived suppressor cells, and suppression of function of tumor-infiltrating T cells by immunosuppressive cytokines and programmed death-ligand (PD-L)1. Fibroblasts play important roles in development and maintenance of AD lesions through expression of CC chemokine ligand (CCL)17, CCL11, CCL26, C-X-C motif chemokine ligand (CXCL)12, CCL19, and periostin, interacting with T helper (Th)2 cells, natural killer T (NKT) cells, DCs, and keratinocytes. They also play important roles in psoriasis, expressing interleukin (IL)-8 and vascular endothelial growth factor, production of fibronectin, and changes in the proteomic profiles. Fibroblasts have a critical role in the progression skin malignancy via expression of cytokines, suppression natural killer (NK) functions, and establishment of Th2-dominant microenvironment. Thus, cross talk among macrophages, fibroblasts, and migratory immune cells including T cells, DCs, and NK cells in skin diseases is important and those skin-resident cells are attracting therapeutic targets in the near future.

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.

With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.

There have been significant developments in the design of nanostructured scaffolds for eliciting robust immune responses named vaccine. The technique is to produce strong immune responses is to manipulate the appearance of a pathogen. Subsequently pathogens such as viruses and bacteria often demonstrate of multiple copies of ligands on their surfaces, the immune system is predominantly sensitive towards multivalent presentations of antigens. Consequently, when designing a vaccine, it is beneficial to garnish a nanostructured surface with multiple copies of an antigen so it can effectively act as an immune booster. Different methods are there for the development of the vaccine, from them most of the techniques are well developed and reported and some of in the developing state. This review focuses primarily on cellular and non-cellular vaccines, the whole cells or cellular proteins either as the source of antigens or the platform in which to deliver the antigens. Purpose of this review, understand and discussion on the various vaccine platforms which will contribute noteworthy information to vaccine research and development (R and D).

Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4⁺ T-cells, but also CD8⁺ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8⁺ and CD4⁺ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease.

Spinal cord injury (SCI) induces several destructive events that develop immediately after the primary insult. These phenomena increase tissue damage; that is why, numerous therapeutic approaches are studied in order to neutralize these destructive mechanisms. In line with this, several studies indicate that after injury, neural tissue could be protected by an adaptive immune response directed against self-antigens. Immunization with neural-derived peptides (INDP) reduces secondary degeneration of neurons after spinal cord insult and promotes a significant motor recovery. The combination of antioxidants or other immunomodulatory peptides after SCI can improve the protective effect induced by INDP. INDP in acute SCI is a promising strategy, so further studies should be addressed to be able to formulate the best strategy.

Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP₂), and phosphatidylinositol 3,4,5-trisphosphate (PIP₃). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP₂ and PIP₃ can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP₂ and PIP₃ carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP₂ and PIP₃ signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP₂ and PIP₃ signaling, in the context of neuronal health and disease.

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.

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.

Both innate and adaptive immune cells exist in the skin, predominantly in the dermis layer. Recent studies have focused on how and which circadian rhythms contribute to maintain good health. Over recent years, we have gained a better understanding of the molecular mechanisms that control biological clocks and circadian rhythms. Circadian rhythms maintain homeostasis by providing day and night information to various physiological functions of our body. However, excessively high immune system activity can lead to a risk of developing autoimmune or allergic diseases. Recently, increasing numbers of studies with human and mouse models have been conducted to investigate the mechanisms underlying circadian regulation of the skin homeostasis. In this review, circadian regulation in the skin will be discussed from different points of view. Skin is referred as the largest organ of the body and is directly exposed to the external environment, including large changes in diurnal temperature, light, and pathogens. Immune cells as well as skin cells are the ones protecting us from these stimulants. Associations of the circadian system and these cells have been revealed in many ways, however, the specific roles of the peripheral clocks in these cells remain unknown. Circadian regulation in the skin diseases is discussed specifically in atopic dermatitis and other skin allergic symptoms as well as psoriasis.

Pregnancy increases the risk of common vascular events and also the rarer events like aortic dissection (AD)/aortic rupture and this is even more pronounced in patients with predisposing aortopathies. AD was found to occur in 0.0004% of all pregnancies, and it is more pronounced in patients with underlying connective tissue disorders. The normal hemodynamic changes on a weak aorta will lead to AD and/or rupture, more so with increase in the period of gestation. Hence the haemodynamic and hormonal changes during pregnancy make pregnancy itself a risk factor for AD. It is advised that women with Marfan syndrome who are planning pregnancy should go through prophylactic aortic repair if the diameter of the ascending aorta exceeds 4 cm. Pre-pregnancy counselling is very important in these patients and must include complete history taking, including family history, physical examination and advanced aortic imaging. There is a general consensus among various authors advising against surgery during pregnancy in stable patients due to increased maternal and fetal morbidity but it is justified if the condition is refractory to medical management or in life threatening stage like acute AD. Though the incidence of aortopathy in pregnancy is rare, there is a high maternal and fetal mortality associated with this condition.

Recently, Arrese and Colleagues have published a review article entitled, “Insights into Nonalcoholic Fatty-Liver Disease (NAFLD) Heterogeneity” (Semin Liver Dis. 2021;41:421–34. doi: 10.1055/s-0041-1730927). This milestone publication clearly and exhaustively explains the multitude of pathogenic pathways involved in the development and progression of disease eventually conducive to heterogeneous clinical phenotypes and different disease outcomes. The present commentary first briefly discusses the biological grounds of NAFLD heterogeneity and then illustrates the work by Arrese et al. In conclusion, the presently adopted nomenclatures appear inadequate in rendering the complexity of disease in the individual patient. In order to adopt the principles of personalized care, what remains to be done is to propose and validate a simple and accurate classification system. This should give full consideration to the principal disease modifiers and should shape a scheme to be adopted in both clinical practice and in the research arena. Care should be taken to not neglect the systemic nature of disease.

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.

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.

Familial early-onset Alzheimer’s disease (AD) is more probable in individuals coming from mothers diagnosed with AD than from fathers diagnosed with AD. Studies in animal models have shown maternal imprinting due to the transmission to the embryo of altered material in the ovum. In the case of transgenic animals harboring a mutated form of the human amyloid precursor protein (APP), offspring from crosses with wild-type (WT) fathers and transgenic mothers display more abnormalities than offspring from crosses with transgenic fathers and WT mothers. Expression of the mutated APP in the ovum may lead to alterations that may be genetic and/or epigenetic in the nuclear and/or the mitochondrial DNA. These modifications that are transmitted to the new living beings affect more mitochondrial proteins and, therefore, the mitochondrial function may be affected in adulthood by trends present in the ovum.

Excessive reactive oxygen species (ROS) may cause oxidative stress which is involved in aging and in the pathogenesis of various human diseases. Whereas unregulated levels of the ROS may be harmful, regulated basal level of ROS is even necessary to support cellular functions as a second messenger for homeostasis under physiological conditions. Therefore, redox medicine could develop as a new therapeutic concept for human health-benefits. Here, we introduce the involvement of ROS on the crossroads of stemness, senescence, and carcinogenesis in a stem cell and cancer cell biology. Amazingly, the anti-proliferative (APRO) family anti-proliferative proteins characterized by immediate early growth responsive genes may also be involved in the crossroads machinery. The biological functions of APRO proteins (APROs) seem to be quite intricate, however, which might be a key modulator of microRNAs (miRNAs). Given the crucial roles of ROS and APROs for pathophysiological functions, upcoming novel therapeutics should include vigilant modulation of the redox state. Next generation of medicine including regenerative medicine and/or cancer therapy will likely comprise strategies for altering the redox environment with the APROs via the modulation of miRNAs as well as with the regulation of ROS of cells in a sustainable manner.

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.

Viral vectors have been frequently applied for vaccine development. It has also been the case for vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to tackle the coronavirus disease 2019 (COVID-19) pandemic. A multitude of different viral vectors have been mainly targeting the SARS-CoV-2 spike (S) protein as antigen. Intramuscular injection has been most commonly used, but also intranasal administration has been tested. Adenovirus vector-based vaccines are the most advanced with several vaccines receiving Emergency Use Authorization (EUA). The simian ChAdOx1 nCoV-19 vaccine applied as a prime-boost regimen has provided 62.1–90% vaccine efficacy in clinical trials. The Ad26.COV2.S vaccine requires only one immunization to provide protection against SARS-CoV-2. The rAd26-S/rAd5-S vaccine utilizes the Ad26 serotype for the prime immunization followed by a boost with the Ad5 serotype resulting in 91.2% vaccine efficacy. All adenovirus-based vaccines are used for mass vaccinations. Moreover, vaccine candidates based on vaccinia virus and lentivirus vectors have been subjected to clinical evaluation. Among self-replicating RNA viruses, vaccine vectors based on measles virus, rhabdoviruses, and alphaviruses have been engineered and tested in clinical trials. In addition to the intramuscular route of administration vaccine candidates based on influenza viruses and adenoviruses have been subjected to intranasal delivery showing antibody responses and protection against SARS-CoV-2 challenges in animal models. The detection of novel more transmissible and pathogenic SARS-CoV-2 variants added concerns about the vaccine efficacy and needs to be monitored. Moreover, the cause of recently documented rare cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) must be investigated.

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.

According to the Global Cancer Observatory (GLOBOCAN) 2020, colorectal carcinoma (CRC) was the second leading cause of cancer death globally. Current literature utilizes reported databases such as Surveillance, Epidemiology, and End Results (SEER) to better understand the epidemiology of CRC. The global cancer observatory’s “Cancer Tomorrow” data visualization tools were used to predict the future incidence and mortality of colorectal cancers until 2030 as a guided tool to look over ways to reduce incidence by controlling risk factors of CRC. The total number of CRC is expected to rise by 2030, with a percent change of 17.3%. The expected percent change in colon cancer is more than rectal cancer (19.8% vs. 11.6%). The estimated number of deaths secondary to CRC is expected to increase in 2030, an estimated percent change of 22.2%. The incidence and mortality rate was higher in men vs. women; however, the gap seems to be closing on trend analysis. Major risk factors for CRC include familial syndromes, family history, race, gender, obesity, diet, alcohol, and smoking. Risk can be reduced by exercise and dietary changes, fiber intake, vitamin D, calcium, and minerals. Individualized screening based on age, gender, and additional risk factors could be an option that needs further comparative data to propose a definitive benefit over established screening guidelines.

Antenatal screening for hepatitis B surface antigen seropositivity is widely adopted to identify pregnant women with chronic hepatitis B virus (HBV) infection in order to target their newborn infants for combined passive-active neonatal immunization to prevent the maternal-to-child transmission of HBV. It is less certain whether the presence of chronic HBV infection in these largely asymptomatic women could impact their pregnancy outcome. There is now gathering information in the literature, though sometimes conflicting, on the obstetric implications of chronic HBV infection. The conflicting data is most probably related to confounding factors such as the immunological phase of chronic HBV infection, viral genotype and activity, presence of hepatic inflammation and other co-existing liver disorders such as non-alcoholic fatty liver disease, and coinfection with other virus such as hepatitis C virus and micro-organisms, which are usually not examined, but which could have made significant influence on the occurrence of many of the pregnancy complications and adverse fetal and neonatal outcome. For pregnancy complications, the evidence suggests association with increased gestational diabetes mellitus, preterm birth, intrahepatic cholestasis of pregnancy, caesarean delivery, and postpartum haemorrhage, probably increased placental abruption and prelabour rupture of the membranes, and no effect or a reduction in the hypertensive disorders of pregnancy, especially preeclampsia. For perinatal outcome, there may be increased miscarriage and fetal malformations, and increase in both low birthweight and large-for-gestational age/macrosomic infants, as well as increased intrauterine fetal demise/stillbirth and fetal distress. However, most studies have not elaborated on the mechanisms or explanations of many of the adverse outcomes. Taken together, maternal chronic HBV infection increases the risk of adverse obstetric outcome overall, but further prospective studies are warranted to elucidate the reasons and mechanisms of, and with a view to mitigating, these adverse obstetric outcomes.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; βCoV), the causative agent of coronavirus disease 2019 (COVID-19), causes severe lower respiratory tract infections and acute respiratory failure syndrome (ARDS). Deaths due to the ongoing COVID-19 pandemic for more than a year are still seen worldwide. Therefore, vaccine trials have gained importance. The discovery of the genome and protein structure of SARS-CoV-2 in a short time allowed the development of nucleic acid-based vaccines (mRNA and DNA vaccines), vector vaccines, inactivated virus vaccines, protein-based vaccines, virus-like particle vaccines, and live attenuated virus vaccines. Many companies, universities, and institutes around the world continue to develop effective vaccines against SARS-CoV-2. In this review, the structural features, classification, genome, and intracellular entry of SARS-CoV-2 coronaviruses, stimulation of the immune system and immunity, COVID-19 vaccine types, and the latest status of clinical trials of these vaccines have been reviewed.

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.

Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.

The maternal syndrome preeclampsia is triggered by syncytiotrophoblast (STB) stress; the heterogeneity of the syndrome is caused by the different pathways leading to this STB stress. Inflammation plays a pivotal role in the pathogenesis of preeclampsia. While, the immune system at large is therefore intimately involved in the causation of this heterogeneous syndrome, the role of the adaptive immune system is more controversial. The classic paradigm placed preeclampsia as the disease of the nulliparous pregnant women. Up to the later part of the 20th century, human reproduction, particularly in Western societies, was characterised by a low rate of pre-marital sex, and the great majority of children being born within one stable sexual relationship. More prolonged periods of regular sexual intercourse within a stable relationship have been demonstrated to reduce the risk of preeclampsia and fetal growth restriction. Primarily animal studies have indeed shown that repetitive sperm exposure leads to partner specific mucosal tolerance. Societal changes made partner change over the reproductive period of individual women extremely common. For the adaptive immune system of multiparous women, being pregnant in a new sexual relationship (primipaternity) would represent being faced with a new “hemi-allograft”. In these pregnancies, potential couple-specific immune “maladaptation” could lead to the superficial cytotrophoblast invasion of the spiral arteries, known to be associated with early-onset preeclampsia. Having a new pregnancy in a different relationship does indeed increase the risk for this type of preeclampsia. Large epidemiologic population studies identified prolonged birth interval but not “primipaternity” as a risk factor for preeclampsia in multiparous women. This apparent contradiction is explained by the fact that the great majority of preeclampsia cases in these population studies involve term preeclampsia. In late-onset preeclampsia, the far more common phenotype of the syndrome, STB stress is not caused by lack of proper spiral artery modification, but involves maternal genetic predisposition to cardiovascular and metabolic disease, with in particular obesity/metabolic syndrome representing major players. Partner or couple specific issues are not detectable in this disease phenotype.

The testis is designated as one of the immune previleged sites in the body and harbours a unique immunoregulatory environment, which is important for preventing an immune response against sperm antigens which otherwise are recognized as “foreign” by the immune system. The blood-testis barrier along with the unique immune cells repertoire and various immunoregulatory & immunosuppressive factors secreted by the Leydig cells, Sertoli cells and peritubular cells act in concert to maintain the tolerogenic environment in the testis. Abberations in immunotolerant mechanisms in the testis can lead to generation of anti-sperm antibodies that have an association with male infertility. It can also lead to inflammatory conditions of the male reproductive tract manifested as epididymitis and orchitis, generally due to bacterial or viral infections. In addition, non-infectious epididymitis and orchitis, having autoimmune origin have also been reported in males. While the immune privilege status of human testis protects the germ cells from an immune attack, it can also make the testis a succeptible reservoir for viruses such as human immunodeficiency virus-1, Zika virus and severe acute respiratory syndrome coronavirus-2, all of which have adverse consequences on male reproduction.

Non-alcoholic fatty liver disease (NAFLD) as the most common chronic liver disease poses a significant impact on public healthcare and economic risk worldwide. As a multifactorial disease, NAFLD is usually associated with many comorbidities such as obesity, insulin resistance, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. Without effectively preventive intervention, the advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). However, there is no approved therapeutic treatment. Excessive fat accumulation in the liver is the hallmark of NAFLD, which can lead to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Dysfunction of two organelles also induces the upregulation of reactive oxygen species (ROS), activation of the unfolded protein response (UPR), and disruption of calcium transport, which promote NAFLD progression. Herein, this review summarized the current understanding of the roles of mitochondrial dysfunction and ER stress in the pathogenesis of NAFLD. Specifically, this review focused on the key molecules associated with the ER-mitochondria communication and different treatment options by targeting ER stress and mitochondrial dysfunction to treat NAFLD or NASH. Clinical trials to evaluate the therapeutic efficacy of representative agents, such as natural products, metabolites, and modulators of stress, have been reviewed and analyzed. Overall, recent findings suggest that targeting ER stress and mitochondrial dysfunction holds a promise for NAFLD treatment.

Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers—cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)]—has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also been proved useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

Vaccination against coronavirus disease 2019 (COVID-19) is one of the most effective tools to curb the pandemic. Multiple vaccine candidates based on different platforms are available for emergency use presently. However, in common all the vaccines target spike protein, which is a dominant immunogen of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). Adequate immunogenicity and efficacy are demonstrated by many of the vaccines in clinical phase III trials. The emergence of the new variant of concern is believed to be associated with less susceptibility to the post-infection or post-vaccination mounted immunity. It is a global concern currently threatening the progression of the vaccination drive. Nevertheless, the results of the presently available phase III clinical trials promote COVID-19 vaccination to prevent disease severity and COVID-19 related deaths. Cross-immunity towards the new variants of concern especially against the South African variant is yet to be explored and managed adequately.

Coronavirus disease 2019 (COVID-19) emerges as an expeditiously growing pandemic, in the human population caused by the highly transmissible RNA virus severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). Prognosis of SARS-CoV-2 infection predominantly occurs at the angiotensin-converting enzyme 2 receptor and transmembrane protease serine type 2 positive (ACE2 + TMPRSS2)⁺ epithelial cells of the mucosal surface like nasal, oral mucosae, and/or the conjunctival surface of the eye where it has interacted along with the immune system. The primary host response towards the pathogen starts from an immune microenvironment of nasopharynx-associated lymphoid tissue (NALT) and mucosa-associated lymphoid tissue (MALT). The presence of exhausted lymphocytes, lymphopenia, pneumonia and cytokine storm is the hallmark of COVID-19. The multifaceted nature of co-morbidity factors like obesity and type 2 diabetes and its effects on immunity can alter the pathogenesis of SARS-CoV-2 infection. Adipose tissue is a crucial endocrine organ that secretes a plethora of factors like adipokines, cytokines, and chemokines that have a profound impact on metabolism and augments the expression of mucosal pro-inflammatory cytokines, like tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and the interleukin-12 (IL-12)/IL-23. Mucosal immunization could be a superior approach to activate mucosal and systemic immune responses against pathogenic invasion at mucosal surface entry ports. Mucosal vaccines are also able to generate strong systemic humoral immunity—required to neutralize any virus particle that dodges the primary immune response. To develop an efficient vaccine against mucosal pathogens, considering the designing of the delivery route, immunomodulatory features, and adjuvants are very important. In this article, we further provide evidence to understand the significant role of mucosal immunity, along with secretory and circulating immunoglobulin A (IgA) antibodies in generating a novel mucosal vaccine against COVID-19. Moreover, along with mucosal vaccines, we should look for combination treatment strategies with plant bioactive molecules. Glycan-binding lectins against viral proteins for targeted activation of mucosal immune response are one of such examples. This might play a promising role to halt this emerging virus.

Tissue-resident macrophages play critically important roles in host homeostasis and pathogenesis of diseases, with the functions of phagocytosis, metabolism, and immune modulation. Recently, two research studies accomplished by a collaborated group of researchers showed that there are two populations of liver resident Kupffer cells (KCs), including a major cluster of differentiation 206 low expression (CD206^low)endothelial cell-selective adhesion molecule negative (ESAM⁻) population (KC1) and a minor CD206^highESAM⁺ population (KC2). Both KC1 and KC2 express KC markers, such as C-type lectin domain family 4 member F (CLEC4F) and T-cell membrane protein 4 (Tim4). In fatty liver, the frequency of KC2 was increased, and those KC2 expressed some markers like liver sinusoidal endothelial cells (LSECs), such as CD31 and ESAM. In addition, KC2 population had a relatively higher expression of CD36, as fatty acid transporter, which was implicated in the production of reactive oxygen species (ROS) and lipid peroxidation. Furthermore, this collaborated group also showed that KC2 can cross-present hepatocellular antigens to prime antiviral function of CD8⁺ T cells by sensing interleukin-2 (IL-2) in hepatitis B virus (HBV) replication-competent transgenic mice. Increasing evidence shows that targeting hepatic macrophages can prevent and reverse non-alcoholic fatty liver disease (NAFLD), with a new suggested name metabolic dysfunction-associated fatty liver disease (MAFLD) to include metabolic dysfunction-associated fatty liver diseases, such as viruses and alcohol. In summary, differentiating specific populations of hepatic macrophages is critically important for the treatment of MAFLD or NAFLD, and their overlaps. Markers specifically expressed on sub-types of hepatic macrophages may be applied for liver disease diagnosis.

This article is a tribute and homage to Gerard Chaouat who invited me to contribute this article. My years in France have remained very memorable to me. Reviewed briefly is the vaccine that was made against human chorionic gonadotropin (hCG) to prevent unwanted pregnancy in sexually active women. It has now been developed as a genetically engineered recombinant vaccine and passed onto industry for its production under good manufacturing practices (GMP) conditions for confirmatory trials. The trials have received the approval of the Drugs Controller General of India. The trials have started but have been interrupted by the coronavirus disease 2019 (COVID-19) pandemic. This vaccine is likely to have another highly beneficial application in the treatment of cancers expressing ectopically hCG.

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

The foetus expressing paternal antigens ought to be “rejected” by the maternal immune system. However, the immunological relationship of the mother and the foetus does not follow the rules of transplantation immunology. Maternal immune functions are re-adjusted during pregnancy, to create a tolerant environment for the developing foetus. Progesterone and its downstream mediator; the progesterone induced blocking factor (PIBF) are important in this process. The mRNA transcribed from the PIBF1 gene contains 18 exons, and codes for a 90 kDa protein. The 90 kDa form is associated with the centrosome and plays a role in cell cycle regulation, while smaller isoforms produced by alternative spicing are secreted, and bind to the glycosylphosphatidylinositol (GPI) anchored PIBF receptor. Upon ligation, the former forms a heterodimer with the alpha chain of the interleukin-4 (IL-4) receptor and activates the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, via which, PIBF induces increased production of T helper2 (Th2) cytokines. PIBF regulates natural killer (NK) cytotoxicity, by inhibiting perforin release from the cytoplasmic granules of NK cells. During normal human pregnancy, the serum concentrations of PIBF increase with gestational age, and lower than normal serum levels predict spontaneous pregnancy termination. Depletion of PIBF during the peri-implantation period in mice, results in lower implantation and increased resorption rates, together with increased decidual and peripheral NK activity, downregulation of the genes implicated in T cell activation in CD4⁺ cells, and Th1 differentiation of the T cells. PIBF is expressed in rapidly proliferating immature cells as well as several tumours, and regulates invasion. The PIBF gene has been identified in the chromosomal region 13q21-q22—which is a common site for somatic deletions in a variety of malignant tumours. These data suggest that PIBF might be involved in tumorigenesis.

The processes of cancer and embryonic development have a partially overlapping effect. Several transcription factor families, which are highly conserved in the evolutionary history of biology, play a key role in the development of cancer and are often responsible for the pivotal developmental processes such as cell survival, expansion, senescence, and differentiation. As an evolutionary conserved and ubiquitously expression protein, CCCTC-binding factor (CTCF) has diverse regulatory functions, including gene regulation, imprinting, insulation, X chromosome inactivation, and the establishment of three-dimensional (3D) chromatin structure during human embryogenesis. In various cancers, CTCF is considered as a tumor suppressor gene and plays homeostatic roles in maintaining genome function and integrity. However, the mechanisms of CTCF in tumor development have not been fully elucidated. Here, this review will focus on the key roles of CTCF in cancer evolution and development (Cancer Evo-Dev) and embryogenesis.

Cutaneous homeostasis is maintained by dynamic cellular communications between different cell types in the skin through interactions with various mediators, including cytokines, chemokines and antimicrobial peptides/proteins (AMPs). Keratinocytes, as the major cell type of the epidermis, not only form a passive physical barrier, but also actively participate in the pathogenesis of many, if not all, inflammatory skin diseases. Keratinocytes highly interact with immune cells to shape, amplify or regulate inflammatory responses, thus triggering and/or sustaining these inflammatory skin diseases. In this review, crosstalk between keratinocytes and immune cells is summarized, and its contributions to two major inflammatory skin disorders including psoriasis and atopic dermatitis are highlighted.

Pseudoexfoliation (PXF) syndrome is an important public health concern requiring individual population level analysis. Disease prevalence differs by geographic location and ethnicity, and has environmental, demographic, genetic, and molecular risk factors have been demonstrated. Epidemiological factors that have been associated with PXF include age, sex, environmental factors, and diet. Genetic and molecular components have also been identified that are associated with PXF. Underserved populations are often understudied within scientific research, including research about eye disease such as PXF, contributing to the persistence of health disparities within these populations. In each population, PXF needs may be different, and by having research that identifies individual population needs about PXF, the resources in that population can be more efficiently utilized. Otherwise, PXF intervention and care management based only on the broadest level of understanding may continue to exacerbate health disparities in populations disproportionally burdened by PXF.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a fundamental role in regulating endothelial function and vascular tone in the physiological conditions of a vascular system. However, oxidative stress has detrimental effects on human health, and numerous studies confirmed that high ROS/RNS production contributes to the initiation and progression of cardiovascular diseases. The antioxidant defense has an essential role in the homeostatic functioning of the vascular endothelial system. Endogenous antioxidative defense includes various molecules and enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. Together all these antioxidative enzymes are essential for defense against harmful ROS features. ROS are mainly generated from redox-active compounds involved in the mitochondrial respiratory chain. Thus, targeting antioxidative enzymes and mitochondria oxidative balance may be a promising approach for vascular diseases occurrence and treatment. This review summarized the most recent research on the regulation of antioxidative enzymes in vascular diseases.

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.

Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.