Harzianoic acids A and B (Hz-A/B) are two rare cyclobutene-containing sesquiterpenes isolated from a marine strain of the sponge-associated fungus Trichoderma harzianum. They display anticancer and antiviral effects, reducing the entry of hepatitis C virus (HCV) into hepatocarcinoma cells. The large extracellular loop (LEL) of the tetraspanin protein CD81 represents a molecular target for both Hz-A and Hz-B.
The interaction of Hz-A/B with CD81 has been modeled, using structures of the cholesterol-bound full-length protein and a truncated protein corresponding to the LEL portion. The models mimicked the closed and open conformations of the LEL.
The best ligand Hz-B can form stable complexes with the open LEL structure, whereas binding to the closed form is drastically reduced. Key H-bonds between the acid groups of Hz-B and the CD81-LEL domain stabilize the ligand-protein complex. A comparison of the interaction with the homologous tetraspanin CD9, which also presents a dynamic open/closed equilibrium, underlined the marked selectivity of Hz-A/B for CD81 over CD9. The cyclobutane-containing monoterpene grandisol, an insect pheromone, has been identified as a fragment that could be modulated to improve its modest interaction with CD81-LEL.
The modeling docking analysis suggests that Hz-B is a robust CD81 binder, better interacting with the LEL portion of CD81 compared to CD9-LEL. The docking study paves the way to the design of small molecules targeting CD81. The study has implications for a better understanding of CD81 binding properties and the regulation of its activities.
Stroke is the second most common cause of mortality and disability worldwide with ischemic strokes being the predominant type. The advent of neuroprotectants brought hope of improved outcomes and quality of life, but current guidelines, despite numerous trials, have no strong recommendation advising their use. This meta-analysis aims to evaluate the degree of effect and safety of the neuroprotectants cytidine-5’-diphosphocholine (CDP-choline), cerebrolysin, edaravone, and MLC601, in the recovery of patients with cerebral infarcts.
An extensive literature search, through the databases of PubMed, PMC, Cochrane, and Ovid, was done with the keywords “CDP-choline”, “cerebrolysin”, “MLC601”, and “edaravone” each combined with the term “acute ischemic stroke”. Eligible studies included randomized controlled trials of these neuroprotectants administered to patients with acute ischemic strokes. A total of 2,025 studies were found, and after the application of screening criteria, 24 studies were eligible for analysis.
The analysis showed that the functional outcome of patients with acute ischemic strokes improved significantly when receiving neuroprotectants versus placebo supported by an odds ratio = 0.29 (0.09–0.50) with a confidence interval of 95%. The P-values are 0.0022 for the one-tailed test, and 0.0030 for the two-tailed test which express the significant improvement of functional outcomes in patients with acute ischemic strokes taking neuroprotectants.
This study thus supports the use of neuroprotectants in patients with acute ischemic strokes to improve long-term functional outcomes and ultimately quality of life.
Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 has undergone several mutations, and ultimately, Indonesia was designated the Asian epicenter of the pandemic in 2021 due to the emergence of Delta variant SARS-CoV-2. Therefore, this study aimed to determine the characteristics of the Delta variant SARS-CoV-2 gene mutations.
This is a cross-sectional descriptive study to determine the mutation characteristics of the Delta variant SARS-CoV-2 with data collected from patients’ medical records and whole genome sequencing (WGS).
The forty-nine patients who contracted the Delta variant SARS-CoV-2 were mainly aged 31−45 years and female. Four sublineages were identified, namely AY.23 (69.39%), AY.24 (22.45%), B.1.617.2 (6.12%), and AY.62 (2.04%), with fever and malaise being the most common clinical manifestations (79.60%). Furthermore, the spike (S) protein was most frequently mutated (12 mutations), with mutations in the Delta variant SARS-CoV-2 membrane (M) protein, nucleocapsid (N) protein, open reading frame (ORF), and nonstructural protein (NSP) also identified.
The most common Delta variant SARS-CoV-2 sublineage in the current study cohort was AY.23, with the S protein being most frequently mutated. Continuous genomic surveillance is required to contain future outbreaks or infection waves, especially during the COVID-19 pandemic.
Progeroid syndromes are characterized by clinical signs of premature ageing, which may contain several diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cockayne syndrome. These disorders may also exhibit some pathological involvements reminiscent of primary mitochondrial diseases. Emerging evidence has linked mitochondria even to physiological ageing. In addition, alterations in the maintenance pathway of mitochondria have been also deliberated as relevant in age-related diseases. In particular, mitophagy and its regulatory pathway might be key process for the homeostasis of mitochondria. Therefore, chronic DNA damage and/or the activation of poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) could be a threat to the mitochondrial alterations. The PARP1 is an enzyme responding to the DNA damage, which might be also involved in the mitophagy. Interestingly, the PARP1 has been reported to play an important role in the longevity of lifespan, which has attracted growing attention with the social development. This review may provide a rationalized overview of the involvement of mitochondrial oxidative stresses in genetically defined accelerated ageing, progeroid syndromes, physiological ageing, and/or age-related diseases for the innovative therapeutic approaches.
Food production demand has been promoting an increase in the generation of agro-industrial waste. Food industry waste can contain compounds with added value that, if properly extracted and used, can be applied to the development of healthy foods (clean label), nutraceuticals, senior food, cosmetics, etc. The revaluation of by-products from the broccoli industry will make it possible to reduce the large volume of broccoli waste, reducing the cost of waste management and obtaining compounds of interest from them. The aim of this work is the extraction of compounds of interest by means of environmentally sustainable technologies and to characterize the freeze-dried broccoli extracts obtained in each green technology in terms of their characteristic compounds of interest and the study of antimicrobial and antioxidant capacity.
The methods of extraction of compounds of interest from broccoli used in this research are environmentally sustainable technologies, using water as the extraction solvent, including aqueous extraction (AE), enzymatic extraction (EE), and ultrasound-assisted extraction (UAE). After extraction, the freeze-dried broccoli extracts obtained were characterized and the antimicrobial capacity was studied with Listeria and Salmonella strains and the antioxidant capacity was studied with Saccharomyces strains, thus determining which of the techniques is most effective for obtaining a freeze-dried broccoli extract with a high concentration of bioactive compounds.
As a result of the research, different products have been obtained from broccoli waste by means of three green extraction techniques, obtaining products with a high concentration of bioactive compounds with antioxidant and antimicrobial capacity against strains such as Listeria and Salmonella.
The waste generated in the broccoli industry has been revalued to obtain high added value products using environmentally sustainable techniques. Due to their high concentration of bioactive compounds, these products are effective as functional products due to their antioxidant and antimicrobial capacity.
Since the early 1970s, the U.S. Food and Drug Administration (FDA) has received over 800 investigational new drug applications (INDs) for, and pre-INDs pertaining to, research of cannabis or cannabis-derived products. The current data show that applications for research of these products submitted by both academic researchers and commercial developers focus on four major clinical areas: addiction and pain medicine (53%), neurology (19%), immunology and inflammation (14%), and psychiatry (9%). The product types studied have expanded greatly in recent years and include a wide variety of topical, inhalable, injectable, and oral products. In this article, the authors present a breakdown of cannabis and cannabis-derived applications received by the FDA over the past 50 years. The authors also provide a summary of their experience and challenges in reviewing applications for research of cannabis and cannabis-derived products, as well as recommendations for those interested in studying cannabis and cannabis-derived products in human clinical trials. This perspective article includes a discussion on important IND criteria, the pre-IND consultation program, drug master files (DMFs), and various guidance documents and resources. Lastly, the authors provide their perspective for the future of cannabis drug development.
On Feb 2, 2022, Nature published the paper titled “Decade-long leukemia remissions with the persistence of CD4+ CAR T-cells” (Nature. 2022;602:503–9. doi: 10.1038/s41586-021-04390-6). According to the results presented, it could be argued that “chimeric antigen receptor (CAR) T-cells can actually cure patients with chronic lymphocytic leukemia (CLL)”. CAR T-cells remained detectable more than ten years after infusion, and immunoglobulin heavy chain (IGH) rearrangement deep sequencing showed persistent deep molecular remission for both patients (no CLL clonotypes were detectable six months after CAR T-cell infusion and onwards). However, the existing actual disease status of both patients remained unclear, as it was unknown: (1) if CAR T-cells killed all leukemia cells during the initial anti-leukemic response phase, that is, soon after CAR T-cell infusion into both patients; (2) if few CLL cells survived, but persistent CAR T-cells had been able to destroy any leukemia cells before they reach detectable levels. In the first case, both patients could be considered definitely cured; in the second not and their decade-prolonged deep remission could be a consequence of the cytotoxic activity of the functionally active CD4+ CAR T-cells. The first version appears to be stronger and the supporting arguments have been included in a comprehensive commentary article. A new therapeutic intervention may emerge with the potential to fully improve the quality of life of both patients and in addition, ongoing research into CAR T-cells may turn in a new, more effective direction.
The extraction of polyphenols is commonly accomplished using conventional techniques such as solid-liquid and liquid-liquid extraction, which are associated with the use of high quantities of organic solvents, long extraction times, and low selectivity and reproducibility. These limitations have led to the development of innovative extraction technologies. The purpose of this study was to investigate the ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) of polyphenols from partially defatted chia flour (PDCF).
The effect of four factors on the extraction of polyphenols (percentage in relation to the initial weight of PDCF) and on the antioxidant activity [quantified by 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and ferric reducing antioxidant power (FRAP) methods] was investigated and the UAE and MAE processes were optimized using the response surface methodology (RSM).
It was found that MAE improved the extraction yield (polyphenol content and antioxidant activity) in shorter extraction times when compared to UAE.
The application of these alternative green technologies improved the performance of the polyphenol extraction process from PDCF. Overall, both techniques could be used as efficient green alternatives.
The prevalence of skin cancer has increased hastily in the recent decade for both kinds of melanoma and non-melanoma skin cancer. Skin cancers mostly encompass keratinocyte cancers: cutaneous squamous cell carcinoma, basal cell carcinoma, and melanoma. This review discusses the recent advancements in the treatment of skin cancer. In addition to chemotherapy, immunotherapy, targeted therapy, and photodynamic therapy (PDT), there are several other therapies for skin cancer. Additionally, PDT use in combination with chemotherapy, radiation, immunotherapy, and surgery is being actively investigated. This review will specifically address the pathophysiology of skin cancer, diagnostic approaches, and current therapies used in the topical treatment of skin cancers and introduce emerging treatment using nanotechnology that may be beneficial for these indications.
Vagus nerve stimulation (VNS) has gained prominence in the treatment of various clinical disorders such as migraine, depression, and tinnitus. Based on increased scientific knowledge of the VNS and insights into the vagus nerve (VN) function and anatomy/conduction, robust treatment approaches have been developed. There are both noninvasive and invasive VNS (iVNS) techniques. Currently, only iVNS techniques are approved by the US Food and Drug Administration (FDA). In contrast, transcutaneous VNS (tVNS) is a new treatment option that is receiving increasing attention. The tVNS application uses the cutaneous distribution of afferent VN fibers in the auricle, the auricular branch of the VN (ABVN), or in the neck, the cervical branch of the VN (CBVN). However, the tVNS technique has not yet been sufficiently researched in its application and mode of action to be used clinically on a large scale. Moreover, the stimulation parameters of the VN vary widely in different studies. Despite the growing number of research papers on this topic, more coherence in neurostimulation research and neuroanatomical basis is needed. The aim of this review is to highlight new clinical treatment options based on existing clinically applied treatment options. In this article, current clinical applications of tVNS are analyzed and important stimulation parameters are highlighted. Based on this data, useful new tVNS therapies are recommended. The focus will be placed on the study of inflammatory processes associated with cancer and on applications to cardiovascular events such as heart failure.
Self-neuronal regeneration is often limited or nonexistent after neuronal cell damage, making new technologies necessary for treating neurological damage. Although the brain can partially compensate by increasing its plasticity, these compensatory mechanisms can never fully restore the pre-damage state. Analysis of the literature regarding stem cell therapy in case of neurological disorders. Stem cells have shown promise for treating various neurological disorders and disabilities due to their regenerative capacity. Transplanting or administration of different types of stem cells has yielded promising results in animal models and early clinical trials. However, concerns remain regarding their implementation. The type of stem cell used, the optimal method and route of administration, the number of stem cells administered, preconditioning, and the injection schedule all need to be determined. Additionally, the long-term safety of stem cell treatment and the recipient’s age requires further investigation. Despite these concerns, stem cell therapy holds tremendous promise for treating neurological disorders, and continued research and well-designed studies will be crucial for unlocking its full potential.
Asthma is a respiratory disease affecting more than 300 million people around the world. Airflow obstruction and inflammation due to asthma usually involve large airways, but recently small airway involvement (internal diameter < 2 mm) has been shown to represent one of the main determinants of asthma and asthma control. In fact, compared to large airway involvement, small airway dysfunction (SAD) has been demonstrated across all the asthma severity in the majority of patients, as assessed with Global Initiative for Asthma (GINA) steps. Clinically, SAD is associated with, among other features, exercise-induced bronchoconstriction, asthma-related night awakenings, obesity/overweight, more severe airway hyperresponsiveness, worse asthma control, and more severe exacerbations. Impulse oscillometry (IOS), a forced oscillation technique (FOT) requiring less effort than spirometry from the patients, demonstrated to accurately measure SAD in children and adults. The fall in resistance from 5 Hz to 20 Hz (R5–R20), which is the most used index for the resistance of peripheral airways, is how SAD is usually identified by IOS. Other crucial parameters measured by IOS are the reactance at 5 Hz (X5), reflecting elastic recoil of the peripheral airways, the resonant frequency (Fres), which is the frequency at which the inertial properties of the airway and the capacitance of the lung periphery are equal, and the reactance area (AX), reflecting the elastic properties of the lung periphery. In this mini review, the latest findings on the utility of IOS to identify SAD and the associations between SAD and clinical features in adult asthmatic patients were addressed.
It is well known that adolescent patients often have less than optimal outcomes. Adolescence is a time of much transition, physically, emotionally, and socially all of which have effects on asthma management and outcomes. Pubertal changes affect asthma, but mostly it is the move towards independence from the parents, peer pressures, stigma of illness, and adherence issues that cause the issue. It is thus important to learn to treat the patient directly, wherein currently often children are treated through the parent, to ensure success.
Allergy to lipid transfer proteins (LTPs) clinically manifests from oral allergy syndrome (OAS) to anaphylaxis. The risk of systemic symptoms and cross-reactivity make it an important target for allergen immunotherapy. Sublingual immunotherapy (SLIT) with Pru p 3 is effective and safe, but the induction phase (IP) of standard protocol (SP) is time consuming. Rush protocols (RPs) are described without serious adverse effects. The aim was to compare the safety of RP with SP and assess the existence of predictive factors for adverse reactions (ARs).
Retrospective study of patients with LTP syndrome followed at the Food Allergy Unit undergoing SLIT with Pru p 3 between 2012 and 2021. SP has an IP of 4 days and an RP of 2 days. The safety of the IP was assessed by recording the AR.
Fifty-one patients: 41 (73.2% women) in SP group (SPG) and 10 (80% women) in RP group (RPG). Anaphylaxis as a presentation of LTP syndrome was overlapping in both groups (SPG 34.1%, RPG 33.3%). There were 5 (12.2%) ARs in SPG: 3 (60%) OAS, 1 (20%) oropharyngeal tightness, and 1 (20%) uvula edema; and 5 (50%) ARs in RPG: 4 (80%) OAS and 1 (20%) palmar pruritus and cough. All patients completed IP. Mean Pru p 3 specific immunoglobulin E (sIgE) value (kUA/L) of patients with ARs in IP: 6.7 kUA/L in SPG and 5.7 kUA/L in RPG. No group showed significant differences (P > 0.05) between Pru p 3 sIgE value, presence of atopy or greater severity in LTP syndrome presentation, and greater probability of AR/more severe ARs in IP.
ARs in IP were similar in both groups. No association was found between Pru p 3 value, atopy and higher probability of ARs in IP. RP appears to be a safe and less expensive option.
Radiation is a primary therapy in the treatment of thoracic malignancies with clear survival benefits. Consequently, patients with cancer are living longer but may be subject to a wide array of cardiotoxic effects from collateral radiation damage. Ensuing fibrosis can affect any portion of the cardiac parenchyma, increasing the risk for accelerated coronary artery disease, pericardial sequelae such as constrictive pericarditis, valvulopathy, restrictive cardiomyopathy, and a myriad of conduction system abnormalities. Unfortunately, the effects of cardiotoxicity can be subclinical or delayed and there remains an unmet need to standardize management strategies for these patients. Based on current data, it is prudent to consider percutaneous approaches first for coronary and valvular disease and traditional, supportive measures for the remaining sequelae. Every attempt should be made to undergo a complete operative haul due to the increased risks of re-operation if surgery is to be performed. Surrounding the patient with a multidisciplinary heart team is critical.
Transthoracic echocardiography is commonly used to assess coronary artery dilatation in Kawasaki disease (KD). However, existing criteria often miss early abnormalities. This study examines the utility of a new parameter, coronary external diameter index (CEDi), for early diagnosis and monitoring in KD.
CEDi of left main (LM) and right coronary artery (RCA), calculated as the ratio of coronary artery external diameter (i.e., the distance between the outer coronary edges measured in the proximal segment of the artery) and the diameter of the aortic annulus, was evaluated in 34 patients (age 23 mouths ± 13 months) with KD at the hospital admission and after 2 weeks and 8 weeks of treatment. The control group consisted of 210 healthy children aged 20 months ± 13.4 months. Z-score charts for LM and RCA coronary external diameter (CED) were obtained.
Compared with controls, KD patients had a markedly higher mean value of LM CEDi (0.53 ± 0.06 vs. 0.33 ± 0.04; P < 0.0001) and RCA CEDi (0.48 ± 0.05 vs. 0.31 ± 0.04; P < 0.0001) at hospital admission. By ROC analysis, LM CEDi of 0.41, and RCA coronary artery thickness index (CATi) of 0.39 were the best cut-offs to confirm the clinical diagnosis of KD, both exhibiting 100% sensitivity and specificity. Mean LM CEDi and RCA CEDi values decreased significantly (P < 0.0001) after 2 weeks of follow-up and were similar to controls (P = 0.53 and P = 0.12, respectively) 8 weeks after admission.
In patients with KD, CEDi of LM and RCA is an accurate parameter to evaluate coronary artery involvement in the early phase of the illness and during follow-up.
The use of echocardiography, a straightforward and widely available technique, allows for a comprehensive assessment of the patient with hypertrophic cardiomyopathy (HCM) under both resting and stress conditions. The true prevalence of HCM has been redefined over time by this imaging approach, which has also made it feasible to pinpoint parameters that clinicians may use to stratify patients at risk for adverse cardiovascular events. The current and emerging prognostic predictors in HCM, assessed with transthoracic echocardiography at rest and during provocation, are discussed in this review.
Many human cancers carry missense mutations in or deletions of the tumor protein 53 (TP53) tumor suppressor gene. TP53’s product, p53 regulates many biological processes, including cell metabolism. Cholesterol is a key lipid needed for the maintenance of membrane function and tissue homeostasis while also serving as a precursor for steroid hormone and bile acid synthesis. An over-abundance of cholesterol can lead to its esterification and storage as cholesterol esters. The recent study has shown that the loss of p53 leads to excessive cholesterol ester biosynthesis, which promotes hepatocellular carcinoma in mice. Blocking cholesterol esterification improves treatment outcomes, particularly for liver cancers with p53 deletions/mutations that originate in a background of non-alcoholic fatty liver disease.
Immunotherapeutic treatment of autoimmune diseases should aim to inactivate autoaggressive memory T-cells and restore immune tolerance. It is envisaged that three approaches could be used to achieve this goal: stimulation of anti-idiotypic immune responses by vaccination with pathogenic T-cells; administration of suboptimal doses of antibodies (Abs) against two or more surface T-cell markers to provide selective Ab-mediated destruction of activated pathogenic memory T-cells; and induction of oral immune tolerance. The proposal entails the use of T-cell vaccination (TCV) or Ab-based therapy as an initial approach to reduce autoantigenic T-cell sensitization. Subsequently, the implementation of oral immunotherapy (OIT) is recommended to reinstate a consistent immune tolerance.
Solubility prediction is an essential factor in rational drug design and many models have been developed with machine learning (ML) methods to enhance the predictive ability. However, most of the ML models are hard to interpret which limits the insights they can give in the lead optimization process. Here, an approach to construct and interpret solubility models with a combination of physicochemical properties and ML algorithms is presented.
The models were trained, optimized, and tested in a dataset containing 12,983 compounds from two public datasets and further evaluated in two external test sets. More importantly, the SHapley Additive exPlanations (SHAP) and heat map coloring approaches were used to explain the predictive models and assess their suitability to guide compound optimization.
Among the different ML methods, random forest (RF) models obtain the best performance in the different test sets. From the interpretability perspective, fragment-based coloring offers a more robust interpretation than atom-based coloring and that normalizing the values further improves it.
Overall, for certain applications simple ML algorithms such as RF work well and can outperform more complex methods and that combining them with fragment-coloring can offer guidance for chemists to modify the structure with a desired property. This interpretation strategy is publicly available at https://github.com/Pharmacelera/predictive-model-coloring and could be further applied in other property predictions to improve the interpretability of ML models.
The paper aims to review the possibilities of a complex transdisciplinary approach to forming health and longevity. Determinants of productive longevity (DPL) and health culture are reviewed; definitions of health, stress, and eustress, and their roles in active and productive longevity are given. DPL making a decisive contribution to the phenomenon of active longevity are stated and analyzed from the point of view of evidence-based medicine. They are as follows: 1) environmental factors including geographical location, “Blue zones”, and mountain areas, as well as level of the environmental pollution; 2) dietary regimen to support active longevity, including vegetarianism, calorie restriction, fasting, the role of vitamins, biological antioxidants, geroprotectors, and micronutrients; 3) importance of activity and eustress phenomenon, by other words, lifestyle: physical activity, sexual relationship, Qigong and Yoga practices, cognitive activity, sense of humor, and acceptance of age in activities of daily living and survival; 4) genetic and epigenetic particularities as a condition for long-living; 5) level of health care and early diagnostics to prevent age-associated diseases; 6) the role of the state of mind and meditation as well, how it is used for forming health due to Qigong and Yoga natural systems, in religion, and medical practice; 7) motivation for active longevity that significantly increases chances to productive longevity.
The two mainstays of therapy for refractory epilepsy are medication and surgery. Child behavioral and cognitive aspects of epilepsy can be improved by using a specialized dietary regimen such as the ketogenic diet (KD). The purpose of this review is to expand our understanding of KD as a nutritional therapy for children with refractory epilepsy and to provide insight into the physiological aspects of its efficacy as an alternative to anti-seizure medication. Either directly or indirectly, ketones, glucose restriction, and polyunsaturated fatty acids regulate epileptic seizures. For KD to be effective, all three of these components must be present, even though the exact mechanism is unknown. Increasing gamma-aminobutyric acid, mitochondrial biogenesis, and oxidative phosphorylation levels can also serve as a means of promoting stable synaptic function while also decreasing neural activity and excitability. Most side effects of KD are caused by mild metabolic abnormalities such as acidosis, hyperuricemia, hypercholesterolemia, hypocalcemia, and hypomagnesemia. Since medium-chain triglycerides (MCTs) produce more ketones per calorie than long-chain triglycerides, individuals who consume MCTs can consume more carbohydrates and protein. This review demonstrated that KD therapy led to positive outcomes for patients with refractory epilepsy. Further study is needed to evaluate whether less restrictive and easier-to-follow diets, such as the modified Atkins diet and MCT diets, have a similar effect on seizure treatment as the standard KD.
Mitral valve prolapse (MVP) is a relatively common mitral valvulopathy and the most common cause of isolated primary mitral regurgitation (MR) requiring surgical repair. It affects about 1–3% of the general population. Although MVP is viewed as a benign condition, the association between MVP and sudden cardiac death (SCD) has been proven. Patients with MVP have a three times higher risk of SCD than the general population. The underlying mechanisms and predictors of arrhythmias, which occur in patients with MVP, are still poorly understood. However, some echocardiographic features such as mitral annulus disjunction (MAD), bileaflet MVP (biMVP), and papillary muscle (PM) fibrosis were frequently linked with increased number of arrhythmic events and are referred to as “arrhythmogenic” or “malignant”. Arrhythmogenic MVP (AMVP) has also been associated with other factors such as female sex, polymorphic premature ventricular contraction (PVC), abnormalities of T-waves, and Pickelhaube sign on tissue Doppler tracing of the lateral part of the mitral annulus. Cardiac magnetic resonance (CMR) imaging and speckle tracking echocardiography are new tools showing significant potential for detection of malignant features of AMVP. This paper presents various data coming from electrocardiography (ECG) analysis, echocardiography, and other imaging techniques as well as compilation of the recent studies on the subject of MVP.
Astrocytes not only support neuronal function with essential roles in synaptic neurotransmission, action potential propagation, metabolic support, or neuroplastic and developmental adaptations. They also respond to damage or dysfunction in surrounding neurons and oligodendrocytes by releasing neurotrophic factors and other molecules that increase the survival of the supported cells or contribute to mechanisms of structural and molecular restoration. The neuroprotective responsiveness of astrocytes is based on their ability to sense signals of degeneration, metabolic jeopardy, and structural damage, and on their aptitude to locally deliver specific molecules to remedy threats to the molecular and structural features of their cellular partners. To the extent that neuronal and other glial cell disturbances are known to occur in affective disorders, astrocyte responsiveness to those disturbances may help to better understand the roles astrocytes play in affective disorders. The astrocytic sensing apparatus supporting those responses involves receptors for neurotransmitters, purines, cell adhesion molecules, and growth factors. Astrocytes also share with the immune system the capacity to respond to cytokines released upon neuronal damage. In addition, in response to specific signals, astrocytes release unique factors such as clusterin or humanin that have been shown to exert potent neuroprotective effects. Astrocytes integrate the signals above to further deliver structural lipids, remove toxic metabolites, stabilize the osmotic environment, normalize neurotransmitters, provide antioxidant protection, facilitate synaptogenesis, and act as barriers to contain varied deleterious signals, some of which have been described in brain regions relevant to affective disorders and related animal models. Since various injurious signals that activate astrocytes have been implicated in different aspects of the etiopathology of affective disorders, particularly in relation to the diagnosis of depression, potentiating the corresponding astrocyte neuroprotective responses may provide additional opportunities to improve or complement available pharmacological and behavioral therapies for affective disorders.
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a survival rate below fifty percent. Addressing meager therapeutic options, a series of small molecule inhibitors were screened for antitumor efficacy. The most potent analog, acryl-3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD; A-DiFiD), demonstrated strong cellular JUN proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (JUN, c-Jun) antagonism. c-Jun, an oncogenic transcription factor, promotes cancer progression, invasion, and adhesion; high (JUN) mRNA expression correlates with poorer HNSCC survival.
Four new small molecules were generated for cytotoxicity screening in HNSCC cell lines. A-DiFiD-treated HNSCC cells were assessed for cytotoxicity, colony formation, invasion, migration, and adhesion. Dot blot array was used to identify targets. Phospho-c-Jun (p-c-Jun) expression was analyzed using immunoblotting. The Cancer Genome Atlas (TCGA) head and neck cancer datasets were utilized to determine overall patient survival. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets interfaced with University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) were analyzed to determine protein levels of c-Jun in HNSCC patients and correlate levels with patient.
Of the small molecules tested, A-DiFiD was the most potent in HNSCC lines, while demonstrating low half-maximal drug inhibitory concentration (IC50) in non-malignant Het-1A cells. Additionally, A-DiFiD abrogated cell invasion, migration, and colony formation. Phospho-kinase in vitro array demonstrated A-DiFiD reduced p-c-Jun. Likewise, a time dependent reduction in p-c-Jun was observed starting at 3 min post A-DiFiD treatment. TCGA Firehose Legacy vs. recurrent and metastatic head and neck cancer reveal a nearly 3% DNA amplification in recurrent/metastatic tumor compared to below 1% in primary tumors that had no lymph node metastasis. CPTAC analysis show higher tumor c-Jun levels compared to normal. Patients with high JUN expression had significantly reduced 3-year survival.
A-DiFiD targets c-Jun, a clinical HNSCC driver, with potent anti-tumor effects.
Coronavirus disease 2019 (COVID-19) became pandemic on 11th March 2020 and it deeply stressed the healthcare system. Cancer patients represent a vulnerable population, so many recommendations have been approved to ensure optimal management. Clinical research was notably impacted by COVID too. This review aims to analyze the challenges occurred during a pandemic for the management of enrolled patients (enrollment, use of telemedicine visits, study procedures) and for the clinical trials system (from feasibility to selection visit, site initiation visit, monitorings, use of e-signature, deviations and discontinuations).
The studies included in the present review were selected from PubMed/Google Scholar/ScienceDirect databases.
During the first phase of pandemic many clinical trials were suspended in accrual and, as the pandemic progressed, recommendations were established to guarantee the safety and the continuity of care of enrolled patients. In addition, lot of new strategies was found during the pandemic to reduce the negative consequences on clinical trial performance and to guarantee new opportunities of care in the respect of good clinical practice (GCP) in a bad scenario.
Among all modifiers, investigators would prefer to maintain the positive ones such as pragmatic and simplified trial designs and protocols, reducing in-person visits when not necessary and to minimizing sponsor and contract research organizations (CROs) visits.
Oncology patients are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to hospital contact and an immunological system that can be compromised by antineoplastic therapy and supportive treatments. Certain similarities have been described in the physiopathology of coronavirus disease 2019 (COVID-19) and lung cancer (LC) that may explain the higher probability of these patients of developing a more serious disease with more frequent hospitalizations and even death, especially with the addition of smoking, cardiovascular and respiratory comorbidities, old age and corticosteroids use. Pre-existing lesions and cancer therapies change the normal architecture of the lungs, so diagnostic scales such as COVID-19 Reporting and Data System (CO-RADS) are of vital importance for a correct diagnosis and patient homogenization, with a high inter-observer correlation. Moreover, anticancer treatments have required an adaptation to reduce the number of visits to the hospital [hypofractionated radiotherapy (RT), larger intervals between chemotherapy cycles, delay in follow-up tests, among others]. In a way, this has also caused a delay in the diagnosis of new cancers. On the other hand, vaccination has had a positive impact on the mortality of these patients, who maintain a similar seroprevalence to the rest of the population, with a similar impact in mortality.
The clinical manifestations of COVID-19 which mainly involve the respiratory system may however affect also cardiovascular system. There are a lot and still increasing numbers of reports revealing cardiovascular complications of COVID-19, which may occur in the acute phase as well as during longer follow-up period. The most clinically important diseases include: pulmonary embolism (PE), myocarditis, and acute coronary syndromes (ACS) as well as arrhythmias with the very common atrial fibrillation (AF) and pericarditis. In this review, cardiac imaging options in patients with and after coronavirus infection are presented, showing potential utility for expanding and improving the full and accurate diagnosis of potential complications. Echocardiography, magnetic resonance imaging, and computed tomography (CT) are considered in turn, highlighting their best advantages in patients affected by COVID.
Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.
This study aimed to establish a learning system using an artificial neural network (ANN) to predict the effects of vitamin D supplementation on the serum levels of vitamin D, inflammatory factors, and total antioxidant capacity (TAC) in women with breast cancer.
The data set of the current project was created from women with breast cancer who were referred to the Shafa State Hospital of Patients with Cancers in Ahvaz city, Iran. Modeling was implemented using the data set at the serum levels of vitamin D, tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β), and TAC, before and after vitamin D3 supplement therapy. A prediction ANN model was designed to detect the effects of vitamin D3 supplementation on the serum level changes of vitamin D, inflammatory factors and TAC.
The results showed that the ANN model could predict the effect of vitamin D3 supplementation on the serum level changes of vitamin D, TNF-α, TGF-β1, and TAC with an accuracy average of 85%, 40%, 89.5%, and 88.1%, respectively.
According to the findings of the study, the ANN method could accurately predict the effect of vitamin D3 supplementation on the serum levels of vitamin D, TNF-α, TGF-β1, and TAC. The results showed that the proposed ANN method can help specialists to improve the treatment process more confidently in terms of time and accuracy of predicting the influence of vitamin D supplementation on the factors affecting the progression of breast cancer (https://www.irct.ir/ identifier: IRCT2015090623924N1).
To study factors associated with the development of calcium pyrophosphate (CPP) arthritis and the severity phenotype.
Transversal case-control study. Cases had to be confirmed by both X-ray chondrocalcinosis and CPP crystals in synovial fluid. Controls had neither chondrocalcinosis nor CPP crystals in synovial fluid. Patients and controls with hemochromatosis or primary hyperparathyroidism were not included. Mutations of hemochromatosis genes (HFE), magnesium (Mg), calcium (Ca), phosphate, iron (Fe), transferrin saturation, ferritin, parathyroid hormone (PTH), and calcifediol levels were studied.
Three hundred patients and 300 sex and age matched controls were compared. Lower serum Mg (sMg) and higher ferritin levels were found among patients. Hypomagnesemia (HypoMg) and HFE mutations were more frequent among patients. Involvement of over one joint was observed in 199 (66.4%) patients whereas persistent joint inflammation was retrieved in 154 (51.4%) of the patients. Initial analysis showed that the frequency of polyarticular and inflammatory phenotypes seemed to be progressively overrepresented in patients with HFE mutations. Further bivariate and multivariate analysis adjusted for the time from onset disclosed that the presence of genotypes with C282Y mutations was associated with polyarticular disease (hazard risk 3.501, 95% confidence interval 1.862–6.581, P < 0.001). Although C282Y mutations also seemed to be associated with inflammatory patterns, the association did not reach statistical significance (P = 0.173).
Low sMg and high ferritin levels are associated with CPP arthritis (CPPA). In patients without hemochromatosis, HFE mutations, and specifically C282Y mutations seem to associate with the polyarticular disease phenotype, and plausibly with the chronic inflammatory phenotype.
Rheumatoid arthritis (RA) is an inflammatory arthritis that affects synovial joints, and it is not surprising that the temporomandibular joint (TMJ), a synovial joint, is also affected. However, TMJ is rarely the first affected joint in the course of RA. Often, RA patients come to the physician with more focus on complaints in other peripheral joints. Therefore, asking TMJ complaints and symptoms, and TMJ examination in RA patients is often neglected by doctors too, because they focus more on other joints. This neglect may cause serious damage to the joints and cause disability. Examination of TMJs, which is a crucial component of vital activities such as nutrition and speech, should be added to the routine. Also, further studies may be focused on adding TMJ assessment to disease activity scales and health assessment questionnaires.
Soy whey is a byproduct of tofu production and is being discarded after tofu preparation. However, soy whey is a rich source of phytochemicals, minerals, and protein. The present study was conducted to utilize soy whey for the development of nutraceutical-rich orange juice beverages.
The soy whey and orange juice were produced and beverage samples were developed from them. The samples were evaluated for physicochemical, rheological, antioxidant, and sensory properties to evaluate the optimum percentage of soy whey that can be utilized for beverage development.
The protein content increased from 0.45% to 1.65% with an increase in soy whey from 0% to 50%. The pH of the beverage samples was in the range of 4.27–4.77 with the total soluble solids (TSSs) of 5.75–6.0 for various beverage samples. The lightness (L*), redness (+a*), and yellowness (+b*) of beverage samples range between 31.57–49.04, 1.21–0.54, and 25.37–39.63 respectively. The vitamin C content of the beverage samples was 56.30 mg/L, 52.75 mg/L, 36.97 mg/L, 26.35 mg/L, and 22.87 mg/L for A, B, C, D, and E beverages respectively. The 1, 1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), reducing power ranges of beverage samples range between 91.2–96.23%, 0.521–0.994%, and 0.204–0.859% respectively, and total phenolic content (TPC) ranges between 112 mg gallic acid equivalents (GAE)/100 mL and 181 mg GAE/100 mL of beverage samples. The beverage samples presented a shear thinning property with a flow index (n) ranging between 0.2371–0.8214. The consistency coefficient of the beverage samples ranges between 0.0405 Pa∙Sn and 0.0041 Pa∙Sn. The control, 20%, and 30% soy whey-containing beverage samples showed higher sensory properties.
The beverage samples with 0%, 20%, and 30% showed improved DPPH and FRAP percent activity and higher overall acceptability compared to 40% and 50% soy whey-containing beverage samples.
Infection and suppuration of chronic wounds reduce the effectiveness of their treatment with a course of antibiotics and antiseptics combined with frequently renewed dressings. Therefore, daily short-term procedures of cleaning wounds from purulent-necrotic masses by mechanical methods, including the use of cleansing solutions and necrophage fly larvae, are also part of the general practice of chronic wound treatment. But even they do not always provide rapid healing of chronic wounds. In this connection, it is suggested to supplement the treatment of chronic wounds with preparations dissolving dense pus and wound dressings made in the form of warm moist compresses creating a local greenhouse effect in the wounds. Solutions of 3% hydrogen peroxide and 2–10% sodium bicarbonate heated to a temperature of 37°–45°С, possessing alkaline activity at рН 8.4–8.5 and enriched with dissolved carbon dioxide or oxygen gas (due to overpressure of 0.2 atm were suggested as pyolytic drugs. The first results of the use of pyolytics and warm moist dressings-compresses in the treatment of chronic wounds demonstrate a wound-healing effect. It is suggested to consider sanitizing therapy with pyolytics and warm moist wound dressings-compresses as an alternative to the use of modern cleansing solutions and artificial introduction of larvae of the necrophage fly into the purulent masses of chronic wounds to dissolve dense pus and accelerate the healing process.
The patient is a 58-year-old male who presented with chief complaints of right-sided numbness, tingling, and loss of temperature sensation in the upper and lower extremities. The patient’s symptoms began around the face and right corner of the mouth [maxillary/mandibular (V2/V3) distribution] before descending to the arm, trunk, and followed by the lower leg and foot. His home medication regimen included lisinopril, atorvastatin, long and short-acting insulin, and amlodipine. During the interview, the patient admitted to abstinence from his medications. Upon examination, the patient was found to have a loss of hot and cold touch on the right side and expressed 2+ reflexes (brisk response; normal) on both upper and lower extremities. In the initial work-up of the patient, he received a computed tomography (CT) scan which demonstrated an area of potential ischemic infarct of one of the left sided pontine perforator arteries. Immediately at that time he was given a loading dose of 325 mg aspirin and started on 81 mg daily. Because of the patient’s symptoms and risk factors, he was hospitalized for further additional work-up and eventually discharged on dual antiplatelet therapy. This case is intriguing as both neuroradiological reading and neurological examination helped with localization of the lesion and changing the treatment strategy of the patient. With a pontine perforator ischemic event, the harms of treatment with thrombolytics would have outweighed the benefits. This interprofessional work between neuroradiology, internal medicine, and neurology ensured that the patient received the best care for his specific ailments.
Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy.
Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented.
First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line.
This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD.
This case report demonstrates the successful induction of apexogenesis in an extensively carious lower right first molar with immature roots through the use of stepwise excavation and calcium-enriched mixture (CEM) cement as an indirect pulp capping material. The patient, an 8-year-old boy, presented with pain and carious pulp exposure. The initial treatment involved removing soft dentin and applying CEM cement as an indirect pulp cap. The patient experienced pain relief after 24 h, and subsequent follow-up appointments showed complete healing and maturation of the tooth. The case highlights the potential of indirect pulp treatment with CEM cement and emphasizes the importance of regenerative biomaterials in promoting healing and dentin bridge formation. Further clinical work and research are recommended to explore the efficacy of this treatment approach.
Oral cancer is the most common carcinoma of head and neck cancers. The majority of oral cancers are oral squamous cell carcinoma (OSCC). Among the various etiological factors, oral microbes—bacteria are also associated with pathogenesis of OSCC. But only few studies have been done associating the presence of oral bacteriome with OSCC. The main aim of this review is to focus on association of microbes with OSCC, the pathogenesis, variation in bacteriome profiling in different geographic conditions, their role in pathogenesis of OSCC, and different samples and methods that are used to study their association with habits and tumour node metastasis (TNM) staging. To conclude, the imbalance in the oral bacteriome could be considered an etiological factor for OSCC. Since the bacteriome profiling varies greatly with geographic location and even in an individual in different locations of the oral cavity, it advocates more research. The study on identifying bacteria associated with OSCC will also enable their use as diagnostic markers and preventive management of OSCC.
The Mediterranean dietary pattern, where extra virgin olive oil (EVOO) takes the central spot, is related to longer life expectancy and lower risk of a number of non-communicable diseases, including cardiovascular, diabetes, dementias, and cancer. Positive effect of olive oil on a broad spectrum of diseases, including diabetes mellitus type 2 (DMT2), is usually attributed to its fatty acid content (e.g., oleic acid). Yet, in the last two decades researchers confirmed that, the phenolic compounds (e.g., oleuropein) also significantly alter on glycaemic regulation. Other unprocessed parts of olive plant (fruit and leaves) showed positive impact on glycaemic variability among individuals living with DMT2. The present review focuses on the available research findings on the effect of olive oil, fruits, and leaves on DMT2 treatment. Specifically, the focus is on polyphenols and fats of olive oil, fruits, and leaves with regard to their antidiabetic biological activities.
Epidemiological studies have reported an association between obesity/metabolic syndrome (MetS) and male reproductive disorders. Endocrine dysfunctions, direct testicular damage, chronic low-grade inflammation, and insulin resistance (IR) are involved in the occurrence of male obesity secondary hypogonadism (MOSH) which in turn alters the metabolic imbalance, creating a sort of vicious circle. Since IR and chronic inflammation state play a pivotal role in MOSH, low-calorie and low-carbohydrate diet protocols may be administered in obese men to improve their metabolic and hormonal profile. The ketogenic diet (KD) has been reported to determine positive effects on body weight, IR, cardio-metabolic risk, hypothalamic-pituitary-testicular (HPT) axis, and prostate with possible improvement of plasma androgens levels, sexual function (SF), and male fertility. This review aims to evaluate the effectiveness of KD on testicular function. Emerging evidence reports that very low-calorie KD (VLCKD) may revert MOSH by restoring HPT axis function and testosterone (T) levels. Moreover, VLCKD could improve SF, prostate health and lower urinary tract symptoms (LUTSs) in overweight/obese male patients. VLCKD may also positively impact spermatogenesis although evidence is still poor. Future studies are warranted to clarify the effectiveness of KD on testicular and prostate gland function.
Protein therapeutics are extensively used in the treatment of autoimmune diseases, but a subset of patients appears to be refractory to these treatments, mainly due to the development of an immune response to the drug. A better understanding of the mechanism underlying the therapeutic drug’s failure becomes fundamental for the development of new and more effective treatments. Unfortunately, there are few cases where the exact mechanisms through which drugs bypass immunological tolerance and provoke immunogenicity have been studied. In this context, peptide epitope identification gained increasing importance in investigating the molecular mechanism of therapeutic drug’s immune responses. Despite peptide identification and use to monitor anti-drug antibody (ADA) profiles is a promising research field, their use is far away from a wide application both at the research and at the commercial level. Herein it is reported a compilation of studies in which peptides are directly involved in anti-drug immune responses, becoming the molecular key step for a better understanding of refractory reactions in therapeutic drugs. An overview on T-cell and B-cell peptide recognition is given, showing the growing potential and advantages of peptides when used in the field of refractoriness to drugs. This review includes studies describing antigenic peptides that enable enhanced ADA detection directly in patients’ sera, as well as the proof of concept that asses the use of peptides instead of proteins, to facilitate the identification of neutralizing ADA.
Familial achalasia (FA) is a very rare condition. This work aims to evaluate its prevalence, characterize its clinical profile in a large series, and assess the efficacy and safety of pneumatic dilation (PD) in this context.
A total of 817 patients with achalasia were collected over a period of 20 years (1990–2010). All cases of FA: isolated or associated to Allgrove syndrome, were looked for in both parents and siblings.
In this study, 18 families with FA were identified n = 41 patients (5%). Two members were affected in each family, in 14 families, three members per family in three others, and for the remaining family 04 members. All cases of achalasia were observed in siblings and parent to child transmission was unfound. Achalasia was associated to Allgrove syndrome in 15 families. It was isolated in 3 families. Consanguinity was found in 89% of patients, and death at a young age in the siblings was recorded in 27% of cases. Achalasia was present before the age of 5 years in 75% of cases. There was no difference between the two groups for age, age at onset, sex and the presence of the cardinal signs of achalasia. A total of 102 dilations were performed. Only one session in 31% of cases, two in 38%, three in 17% and more than three sessions in 14%. The long-term success rate of PD was low.
FA manifests almost exclusively in childhood. It is rarely isolated; most often falls under Allgrove syndrome. Alacrima is the earliest sign that should lead to the diagnosis. The long-term success rate of PD is rather low. This requires recourse to multiple sessions of PD or Heller’s cardiomyotomy which may be the best initial approach.
This study aims to analyze the efficacy and safety of benzbromarone as uricosuric, in a real-life clinical setting of a retrospective hospital-based gout cohort.
Data from gout patients were retrieved from the digital hospital dossiers. Demographics, clinical variables, and laboratory parameters were collected at baseline and 6 months. Efficacy was measured by reaching a serum uric acid (sUA) target < 0.30 mmol/L at 6 months, and the fractional excretion of uric acid (FeUA) was used as a parameter with a potential predictor value.
Data from 98 gout patients were analyzed. Patients were 70 (± 12) years of age, and 90% were male. After 6 months of treatment, 68 out of 98 patients (69%) reached a sUA level < 0.30 mmol/L (5 mg/dL). In patients with a FeUA < 4.5%, so-called low excretors, the FeUA increase was most impressive from 3.2% (± 1.0%) to 12.1% (± 6.9%) after 6 months of benzbromarone treatment (mean increase +8.9% [95% confidence interval (CI): +6.5 to +11.5%], P < 0.001). In non-low excretors, FeUA was on average 7.3% (± 5.1%) and increased to 9.7% (± 6.1%): a mean +2.1% change (95% CI: –2.2 to +6.6%). The increase differed insignificantly in low versus non-low excretors: P > 0.05. Four patients stopped benzbromarone treatment because of a progressive decline in renal function, a condition that was already present before benzbromarone was initiated. Remarkably 38% of patients is still using benzbromarone after 3.8 (± 3.4) years of treatment.
Using the uricosuric benzbromarone in real-life gout patients proved effectivity in lowering sUA levels within 6 months by increasing FeUA significantly. Particularly low excretors benefit from benzbromarone treatment manipulating this mode of action. Determining FeUA in gout patients may further help to find the patient profile benefiting the most from benzbromarone treatment.
Changes in strategies in the coronavirus disease 2019 (COVID-19) crisis and the imposing of restrictions have isolated many vulnerable patients including those with hepatocellular carcinoma (HCC) from routine medical care. This study investigated how the COVID-19 pandemic is affecting the diagnosis and treatment of HCC.
An extensive search was conducted in the PubMed, Scopus, and Web of Science databases by using the appropriate keywords: COVID-19, hepatocellular carcinoma, hepatocellular cancer, and MeSH. Studies in English related to the purpose of the study were included in the analysis, and review studies, case reports, letters to editors, comments, and reports were excluded. The quality of the studies was assessed by the “Adapted Newcastle-Ottawa Quality Assessment Scales” checklist. The Endnote X7 software has been used for managing items.
The final qualitative analysis consisted of 27 articles. During the COVID-19 crisis, HCC diagnosis decreased from 20% to 34.13% compared to pre-crisis. The impact of the COVID-19 pandemic on HCC treatment encompasses a wide range of aspects. Generally, delays in treatment for patients with HCC ranged from more than one month for 21.5% of patients in France, to two months for 26% of patients in Italy, up to 30% in Austria, and 66.7% in Asia-Pacific countries.
According to the findings, developing and implementing appropriate diagnostic and therapeutic strategies and developing low-cost and high-precision screening programs among high-risk populations seem to be effective in reducing the impact of the COVID-19 pandemic on HCC management.
Cannabis use for sleep-related problems is on the rise; however, little is known about the cannabis products people are using for sleep or the perceived effects of cannabis in comparison to more conventional sleep aids. Therefore, the aim of this study was to examine the products cannabis users prefer to use for sleep as well as their experiences with cannabis relative to more conventional sleep aids.
De-identified archival data from a Strainprint® survey of 1,216 individuals who use cannabis for sleep were analyzed.
Participants predominantly reported smoking joints or vaping flower as their methods of administration, and seeking tetrahydrocannabinol (THC), cannabidiol (CBD), and the terpene myrcene in the cannabis they use for sleep. Only a small minority reported using cannabis in conjunction with conventional sleep aids. Comparisons of the self-reported effects of cannabis to conventional sleep aids revealed that participants reported feeling more refreshed, focused, better able to function, fewer headaches, and less nausea the morning after using cannabis for sleep than after using more conventional sleep aids or no sleep aids. However, they indicated they were more sleepy, anxious, and irritable in the mornings following the use of cannabis relative to other sleep aids. Participants were more likely to report red eyes and thirst and less likely to report nausea, anxiety, paranoia, and racing heart as side effects of cannabis relative to other sleep aids.
Knowledge gained from this survey will provide health professionals with a better understanding of why people are using cannabis for sleep and may help guide future more controlled research.
Post-translational modifications (PTMs) of alpha-synuclein (α-syn) can alter protein aggregation propensity to affect α-syn oligomer and fibril formation. The inflammatory response in Parkinson’s disease (PD) is mediated by microglia, astrocytes, T cells, B cells, macrophages, and neutrophils, which respond to α-syn aggregates in an attempt to clear synucleinopathy and restore brain homeostasis. This review focuses on the effects of PTMs on α-syn aggregation and cell-specific immune responses to α-syn aggregates in the context of PD.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in December 2019 quickly escalated to pandemic levels and had a severe impact on public health. There are 761 million confirmed coronavirus disease 2019 (COVID-19) cases, with over 6.88 million deaths worldwide till March 2023. Severe cases of the disease caused critical respiratory failure followed by multiorgan involvement. Clinical escalation of COVID-19 has been correlated with markedly increased plasma inflammatory markers [e.g., C-reactive protein (CRP)] and pro-inflammatory cytokine levels [e.g., interleukin (IL)-6, tumor necrosis factor-α (TNF-α)]. Therapeutic options have mostly utilized corticosteroids, antivirals (e.g., remdesivir), and monoclonal antibody-based immunomodulation (e.g., tocilizumab). These existing treatments have adverse side effects, inadequate efficacy, and limitations in administering to patients with comorbidities and other underlying diseases. Monoclonal antibody-based therapies and some of the antivirals are very costly. Many phytochemicals have previously reported anti-inflammatory, antiviral, and antioxidant properties. Studying the effectiveness of such phytochemicals against COVID-19 and identifying new plant-derived molecules with antiviral properties have been a focus since the SARS-CoV-2 outbreak. This review article has documented in vitro, in vivo, and clinical studies encompassing 28 different phytochemicals belonging to various chemical groups (e.g., polyphenols, alkaloids, terpenes) that show anti-COVID-19 activity. These findings suggest that multiple phytochemicals can interfere with virus entry and replication inside the host cell. Many of them can protect from cytokine storm by acting on intracellular signalling pathways in addition to inhibiting virus multiplication. Phytochemicals may prove useful in alleviating post-COVID complications associated with kidney injury, and central nervous system complications, as well. Plant-derived compounds are usually cheaper and have fewer side effects. But, developing new formulations with better absorption and bioavailability remains a priority. This review informs the readers of the current status and indicates the ongoing research in this highly relevant field.
Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5–6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.
The present coronavirus disease 2019 (COVID-19) pandemic scenario has posed a difficulty for cancer treatment. Even under ideal conditions, malignancies like small cell lung cancer (SCLC) are challenging to treat because of their fast development and early metastases. The treatment of these patients must not be jeopardized, and they must be protected as much as possible from the continuous spread of the COVID-19 infection. Initially identified in December 2019 in Wuhan, China, the contagious coronavirus illness 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finding inhibitors against the druggable targets of SARS-CoV-2 has been a significant focus of research efforts across the globe. The primary motivation for using molecular modeling tools against SARS-CoV-2 was to identify candidates for use as therapeutic targets from a pharmacological database. In the published study, scientists used a combination of medication repurposing and virtual drug screening methodologies to target many structures of SARS-CoV-2. This virus plays an essential part in the maturation and replication of other viruses. In addition, the total binding free energy and molecular dynamics (MD) modeling findings showed that the dynamics of various medications and substances were stable; some of them have been tested experimentally against SARS-CoV-2. Different virtual screening (VS) methods have been discussed as potential means by which the evaluated medications that show strong binding to the active site might be repurposed for use against SARS-CoV-2.
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.
A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.
Parkinson’s disease (PD) is a complex, chronic neurodegenerative disorder with predominately sporadic etiology. Intricate genetic-environmental interactions lead to the hallmarks of the disease: degeneration of dopaminergic neurons and the deposition of α-synuclein aggregates. The aim of this study was to establish a novel primary patient cell model as an in vitro screen to study α-synuclein processing for drug screening.
Primary patient olfactory neuroepithelial-derived cells (ONS) were exposed to α-synuclein and examined for cytotoxicity, processing, and solubility over 48 h. Epigallocatechin gallate (EGCG), which is known to destabilise α-synuclein fibrils, was used to investigate the solubilisation of α-synuclein in the model system.
Exposure to 0.1 μmol/L α-synuclein preformed fibrils was not toxic to ONS over 48 h. ONS processing of α-synuclein was observed to be different in PD cells by their increased accumulation in the cytoplasm. Processing deficits in the PD ONS were confirmed by immunoblotting with an increase in sodium dodecyl sulfate (SDS)-insoluble α-synuclein after 48 h.
The data has illustrated the utility of primary patient ONS as a model system to understand the processing of α-synuclein. Considerable differences in α-synuclein processing were identified in PD ONS. Furthermore, the data suggests that primary patient ONS are a viable in vitro drug screening platform for α-synuclein pathology in PD.
Allergen-specific immunotherapy (AIT) is a proven efficacy treatment for allergic rhinitis (AR), asthma, and Hymenoptera venom allergy, but its use in food allergy (FA) is still under investigation. Because some efficacy and safety concerns still remain, biologic drugs, including omalizumab and dupilumab, have been studied as an adjunctive therapy to AIT for these conditions. In this article, the evidence supporting the use of monoclonal antibodies (mAbs) as an add-on therapy to AIT for FA, AR, asthma, and Hymenoptera venom allergy has been reviewed. The review will delve into the mechanisms of action of different mAbs, their efficacy, and how they can be integrated into personalized medicine approaches to treat allergic diseases. Furthermore, future research areas will be considered. Evidence suggests that omalizumab in combination with AIT may be a beneficial option for respiratory allergies or food desensitisation, especially during the escalation or build-up phase, when adverse events are more frequent. Currently, there is a small number of well-structured clinical trials in Hymenoptera venom allergy, and the available data consist mainly of single-case reports that provide information of limited value. Dupilumab has been studied as adjunctive therapy in patients with respiratory and FAs. Clinical trials are ongoing to evaluate the efficacy of dupilumab as monotherapy or as an adjunct to oral immunotherapy (OIT) in peanut allergy. Other studies are investigating the use of dupilumab in patients with multiple FAs and as an adjunct to milk OIT. Overall, mAbs have the potential to improve outcomes in various allergic conditions when used as an add-on to AIT, especially during the build-up phase. Further research is needed to fully understand their optimal dosing and duration of treatment, as well as to identify which patients may benefit the most from these therapies.
The present study aims to analyze the impact on cognitive recovery of an interdisciplinary treatment for acute and severe psychiatric patients.
The present research is a naturalistic observational study of 130 adults (mean age of 47.68 years, 68% women). Clinical severity was assessed using Brief Psychiatry Rating Scale (BPRS), Montgomery-Asberg Depression Rating Scale (MADRS), and Hamilton Anxiety Rating Scale (HARS). Functional performance was evaluated using the Functioning Assessment Short Test (FAST), and cognitive impairment by applying the Montreal Cognitive Assessment (MoCA). Patients were clustered into four diagnostic groups (non-affective psychosis, bipolar, depressive, and personality disorders) and had individualized psychopharmacological treatment. They receive a transdiagnostic group program including several interventions that have shown evidence of beneficial effects over the different cognitive domains impaired in mental illness (attention, speed of processing, memory, working memory, reasoning, and problem-solving), as well as social cognition domains (emotion processing and social skills), in combination with psychoeducation and some strategies oriented to achieve healthy lifestyle routines (balanced diet, physical exercise, sleep hygiene, and smoking and alcohol cessation).
All clinical scales scores were improved after the end of treatment compared with those achieved at admission (BPRS, MADRS, and HARS scores below the cut-off point for establishing a case diagnosis). MoCA scores improved after the end of treatment concerning admission, both in the total score and in the differentiated cognitive domains, excluding orientation, which remained unchanged in the whole of the sample studied. No statistical significance was found in any comparisons between different diagnostic groups. No correlation between MoCA scores and BPRS, MADRS, or HARS scores at admission or discharge was found.
These results show that the interdisciplinary therapeutic intervention can be effective for recovering cognitive impairment associated with mental disorders, irrespective of the diagnosis.
Bell’s palsy is a rapid unilateral peripheral paralysis of cranial nerve VII whose etiology is varied, most commonly associated with an acute infectious or inflammatory demyelinating process. Nerve injury can result in edema because of increased permeability of vascular structures, which can sometimes be seen as a locus of enhancement of magnetic resonance imaging (MRI). Bell’s palsy is typically considered a clinical diagnosis and the specificity and sensitivity of imaging have been poorly studied. Herein is describe a case of a 73-year-old male who presented to the emergency department with left-sided facial droop and no other focal neurological abnormalities. With a history of a Janus kinase 2 (JAK2) mutation and the new initial facial drooping, acute cerebrovascular insult was high on the differential. Initial labs and computerized tomography (CT) head were inconclusive, but MRI showed pronounced enhancement of the left distal internal carotid artery (ICA) with contiguous enhancement of the labyrinthine, geniculate, and tympanic segments of the left facial nerve. Diagnosing Bell’s palsy can be a challenge as there are numerous postulated etiologies stemming from trauma, infection, and neoplasm; with infection (particularly viral) postulated to be the most likely source. Though MRI is currently not validated as a tool in expediting Bell’s palsy diagnosis, findings such as the enhancement seen here provide some insight into the benefit of MRI as a diagnostic modality in some cases. This case is unique both for the diagnostic dilemma between stroke and Bell’s palsy and the potential for MRI imaging to help guide clinical decision-making into treatment.
Renal cell carcinoma (RCC) is one of the most life-threatening urinary malignancies displaying poor response to radiotherapy and chemotherapy. Although in the recent past there have been tremendous advancements in using targeted therapies for RCC, despite that it remains the most lethal urogenital cancer with a 5-year survival rate of roughly 76%. Timely diagnosis is still the key to prevent the progression of RCC into metastatic stages as well as to treat it. But due to the lack of definitive and specific diagnostic biomarkers for RCC and its asymptomatic nature in its early stages, it becomes very difficult to diagnose it. Reliable and distinct molecular markers can not only refine the diagnosis but also classifies the tumors into thier sub-types which can escort subsequent management and possible treatment for patients. Potential biomarkers can permit a greater degree of stratification of patients affected by RCC and help tailor novel targeted therapies. The review summarizes the most promising epigenetic [DNA methylation, microRNA (miRNA; miR), and long noncoding RNA (lncRNA)] and protein biomarkers that have been known to be specifically involved in diagnosis, cancer progression, and metastasis of RCC, thereby highlighting their utilization as non-invasive molecular markers in RCC. Also, the rationale and development of novel molecular targeted drugs and immunotherapy drugs [such as tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs)] as potential RCC therapeutics along with the proposed implication of these biomarkers in predicting response to targeted therapies will be discussed.
The sequential phosphorylation of mitogen-activated protein (MAP) kinases MEK-ERK is the most relevant cellular signaling pathway. This study quantified the parallel in vivo regulation of brain phosphorylation-MEK1/2 (p-MEK1/2) to p-ERK1/2 by mechanistically different cannabinoid 2 (CB2) receptor ligands, i.e., direct (and endogenous) agonists and inverse agonists.
Groups of Swiss albino CD1 IGS male adult mice were treated (i.p.) with the CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, 1 h, n = 8) or the CB2 inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, 1.5 h, n = 8–9), and 0.9% NaCl (2 mL/kg, 1 h, n = 4–10) as vehicle control. Transgenic male mice overexpressing cortical CB2 receptors [messenger RNA (mRNA) and protein] on a Swiss ICR congenic background (CB2xP) and the corresponding littermates age-matched wild-type (WT) controls were used. Protein forms (total MEK and ERK p-kinases) were resolved by electrophoresis [sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) minigels] followed by immunoblotting standard procedures.
The selective CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, i.p., 1 h) modestly decreased MEK (17%, n = 8) and upregulated ERK (25%, n = 8) activities. The endogenous CB2 agonists (acting on promoted overexpressed receptors) decreased MEK (44%, n = 9) and upregulated ERK (67%, n = 10) activities. The inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, i.p., 1.5 h) increases MEK activity (27%, n = 8) without significantly altering that of ERK (5%, n = 9).
Acute treatments of mice with mechanistically different CB2 receptor ligands (i.e., direct agonists, endogenous agonists, and inverse agonists) resulted in disruption of MEK (p-MEK/total-MEK ratio) to ERK (p-ERK/total-ERK ratio) signals in the brain cortex. This striking disruption of MEK to ERK parallel regulation in the cannabinoid CB2 receptor system in the brain could be relevant to the postulated role of CB2 receptors in various central nervous system (CNS) diseases.
Apolipoprotein E (ApoE) isoforms, especially the ApoE4 isoform, are genetic risk factors for Alzheimer’s disease (AD). Moreover, the APOE ε4 haplotype has a dose-dependent association with an increased risk of amyloid-related imaging abnormalities (ARIA) in individuals receiving disease-modifying therapy for AD. Therefore, the importance of APOE genotyping or proteotyping has been highlighted. Here, the authors developed fully automated chemiluminescence enzyme-immunoassay kit for ApoE4 and Pan-ApoE, and evaluated their diagnostic concordance with the APOE genotyping.
One hundred seventy-eight specimens were analyzed using the Lumipulse® G ApoE4 and Pan-ApoE for the ApoE proteotype and evaluated its diagnostic concordance with the APOE genotype.
The ApoE4 kit specifically detected the ApoE4 concentration in plasma samples, and the polymorphism could be classified clearly by the ratio of ApoE4 and Pan-ApoE amount in plasma.
The combination of Pan-ApoE and ApoE4-specific chemiluminescent enzyme immunoassay (CLEIA) assay is useful for predicting APOE ε4 allele status.
As the average lifespan has increased, memory disorders have become a more pressing public health concern. However, dementia in the elderly population is often neglected in light of other health priorities. Therefore, expanding the knowledge surrounding the pathology of dementia will allow more informed decision-making regarding treatment within elderly and older adult populations. An important emerging avenue in dementia research is understanding the vascular contributors to dementia. This review summarizes potential causes of vascular cognitive impairment like stroke, microinfarction, hypertension, atherosclerosis, blood-brain barrier dysfunction, and cerebral amyloid angiopathy. Also, this review address treatments that target these vascular impairments that also show promising results in reducing patient’s risk for and experience of dementia.
The pathogenesis of primary biliary cholangitis (PBC) is particularly complicated as both intrinsic and extrinsic factors are implicated. Several forms of cellular death, both programmable and non-programmable, operate leading biliary epithelial cells (BECs) to elimination. The precise role of critical pathways like autophagy, apoptosis, senescence, and their interplay has not been fully clarified. Therefore, in this review, data on these important mechanisms are presented and their implication in PBC is discussed. The interplay of the three mechanisms is examined and the factors that drive them are analyzed. Moreover, the upstream drivers of autophagy, apoptosis, and senescence are presented. They include the loss of the protective bicarbonate umbrella in BECs due to the reduction of activity of the anion exchanger 2 (AE2) with the resultant activation of the intracellular soluble adenylyl cyclase (sAC). The role of toxic bile acids is also presented. A sequence of events is proposed including involvement of the gut-liver axis and the possible role of ferroptosis. Finally, a brief account of the initial trigger of the disease is given.
One of the greatest challenges in the study of coronavirus disease 2019 (COVID-19) has been to establish the determining factors in the severity of the disease. Through extensive research efforts, a crucial factor responsible for disease control or exacerbation in COVID-19 has been identified—the regulation of the immune response. The abnormal release of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α) has been extensively studied in the context of the altered immune response observed in severe cases of COVID-19. However, recent attention has turned towards the excessive release of IL-17 and the increased presence of T helper 17 (Th17) cells, the main secretory cells of this cytokine. These factors have garnered interest due to their potential involvement in the cytokine storm observed in severe cases of COVID-19. In this review, it will be delved into the intricate mechanisms by which IL-6 contributes to the differentiation of Th17 cells, resulting in an increase in the population of Th17 cells. Moreover, it will be explored the proportional relationship between the increase of these lymphocytes and the release of IL-17 and other chemokines, which all together play a key role in promoting the chemotaxis and activation of neutrophils. Ultimately, this cascade of events culminates in the generation of tissue damage by neutrophils. Additionally, therapeutic options targeting these lymphocytes and cytokines are explored, providing insights into potential avenues for intervention.
Bone formation is a complex process that occurs throughout life, and is normally limited to the skeletal system. In bone formation, osteoprogenitor cells follow several developmental stages, including differentiation in osteoblasts, proliferation, matrix maturation, and mineralization. The mechanisms involved in the mineralization process of bone, such as in the new bone formation, are extremely complex and have been under intense investigation for many years. Bone formation follows two distinct processes, intramembranous and endochondral ossification; both are regulated by signaling pathways involving numerous genes. Disturbance of these signaling pathways may cause a large spectrum of skeletal diseases characterized by new bone formation and bone growth anomalies. This review will only focus on the key genetic pathways involved in heterotopic bone formation. Wingless/integrated (Wnt), hedgehog (HH), and transforming growth factor beta (TGFβ)/bone morphogenetic protein (BMP) signaling pathways are described and illustrated; their relation with new bone formation is demonstrated through their involvement in bone formation disorders.
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease of unknown origin. Although it mainly affects joints, it can have extra-articular manifestations, with the lung being one of the most affected organs. The estimated incidence of diffuse interstitial lung disease (ILD) is 4 cases to 4.5 cases/1000 patient-years. The most common forms are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP; 44–46% and 33–44%, respectively), although there have been reports of cases involving all the histopathologic forms described for the disease. RA-ILD is associated with specific risk factors, such as male sex, older age, smoking, and positive rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) levels. The clinical course of ILD ranges from asymptomatic forms to rapidly progressive disease in a minority of cases. It has been estimated that the risk of death is up to 3-fold higher in patients with RA-ILD than in those without ILD, making RA-ILD the second most common cause of death after cardiovascular disease. Treatment of RA has improved considerably in recent years with the advent of biologics; however, the use of these agents has been restricted in patients with ILD owing to safety concerns. Many doubts continue to surround the treatment of patients with RA-ILD. Therefore, the objective of this review is to examine the current management of affected patients in terms of diagnosis, treatment, and follow-up.
The study aims to evaluate the incidence of recurrent thromboses in patients with primary antiphospholipid syndrome (PAPS) and its association with the presence of different antiphospholipid antibodies (aPLs) and known thrombogenic risk factors.
This retrospective study included 52 patients. The median age of the patients was 38.5 years [31.5; 43.5], and the duration of the disease was 9.0 years [3.1; 13.0]. aPLs, including IgG/IgM/IgA antibodies to cardiolipin (aCLs), IgG/IgM/IgA anti-beta2-glycoprotein I (anti-β2-GPI), IgG anti-domain I-β2-GPI (anti-β2-GPIDI) antibodies, IgG/IgM antibodies to the phosphatidylserine/prothrombin complex (aPS/PT), and other thrombosis risk factors were included for analysis.
Recurrent thrombosis was reported in 34 (65%) out of 52 patients and 18 (35%) did not have it. The main reason for the recurrence of thrombosis was the lack of anticoagulant therapy: in 18 (52.9%) out of 34 patients with recurrent thrombosis. Three patients were taking warfarin at the time of thrombosis recurrence, but target international normalized ratio (INR) levels were not achieved. Other patients with recurrent thrombosis were taking direct oral anticoagulants (DOACs). The risk of recurrent thrombotic events with positive IgG aCL was 10.33 (P = 0.002) and 21 (P = 0.007) times higher were examined in enzyme-linked immunoassay (ELISA) and chemiluminescent assay (CLA), respectively. The risk of thrombosis was 4.58 times higher in patients who were IgA aCL-positive (P = 0.01). Compared with other antibodies, with positive IgG values of anti-β2-GPI and IgG aPS/PT by ELISA, a lower probability of thrombosis recurrence was observed: 7.56 and 7.25, respectively. A high risk of recurrent thrombosis [odds ratio (OR) = 32.0] was observed in IgG anti-β2-GPI (CLA). The combination of IgG aCL with IgG anti-β2-GPI and with IgG anti-β2-GPIDI is more informative with respect to the risks of thrombosis recurrence compared to double positivity for aCL with anti-β2-GPI (OR = 20.71 vs. OR = 10.18). Triple positivity for IgG aCL with IgG anti-β2-GPI and with IgG aPS/PT also shows better results compared to positivity for aCL with anti-β2-GPI (OR = 6.06 vs. OR = 5.79). Among other risk factors, arterial hypertension (AH) and obesity were significant in relation to the recurrence of thrombosis. AH occurred in 22 (42%) of 52 patients with PAPS. AH was associated with recurrent thrombosis in PAPS patients: 18 (53%) out of 34 with recurrent thrombosis had AH versus 4 out of 18 without recurrent thrombosis (P = 0.003).
Recurrent thrombosis in antiphospholipid syndrome (APS) is largely associated with IgG aCL, IgG anti-β2-GPI, IgG anti-β2-GPIDI, IgG aPS/PT, and IgA aCL positivity. AH was a significant risk factor for recurrent thrombosis.
The etiology of recurrent spontaneous abortion (RSA) is extremely complex, as there are 40–50% of patients with unexplained miscarriages, known as unexplained RSA (URSA). URSA affects approximately 1–2% of females of childbearing age and has a massive impact on the physical and mental conditions of both patients and their families. The pathogenesis of the disease remains unclear, making its treatment complicated. In recent years, considerable progress has been made in the exploration of the URSA immune balance mechanism and it has been universally acknowledged that a balanced immune response (as abnormal immunity) may be the root cause of poor pregnancy outcomes. This review discussed and summarized the effects of immune cells and blocking antibodies (BAs) on URSA based on the current state of knowledge in this area. Additionally, molecular genetics also plays an essential role in the incidence rate of URSA since the role of genetic polymorphism in the pathogenesis of URSA has been thoroughly studied. Nonetheless, the outcomes of these studies are inconsistent, particularly across populations. This paper reviewed previous studies on URSA and maternal genetic polymorphism, focusing on and synthesizing the most important findings to date, and providing diagnostic recommendation for URSA patients with clinical symptoms.
Immunosenescence encompasses multiple age-related adaptations that result in increased susceptibility to infections, chronic inflammatory disorders, and higher mortality risk. Macrophages are key innate cells implicated in inflammatory responses and tissue homeostasis, functions progressively compromised by aging. This process coincides with declining mitochondrial physiology, whose integrity is required to sustain and orchestrate immune responses. Indeed, multiple insults observed in aged macrophages have been implied as drivers of mitochondrial dysfunction, but how this translates into impaired immune function remains sparsely explored. This review provides a perspective on recent studies elucidating the underlying mechanisms linking dysregulated mitochondria homeostasis to immune function in aged macrophages. Genomic stress alongside defective mitochondrial turnover accounted for the progressive accumulation of damaged mitochondria in aged macrophages, thus resulting in a higher susceptibility to excessive mitochondrial DNA (mtDNA) leakage and reactive oxygen species (ROS) production. Increased levels of these mitochondrial products following infection were demonstrated to contribute to exacerbated inflammatory responses mediated by overstimulation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and cyclic GMP-ATP synthase (cGAS)-stimulator of interferon genes (STING) pathways. While these mechanisms are not fully elucidated, the present evidence provides a promising area to be explored and a renewed perspective of potential therapeutic targets for immunological dysfunction.
Vaccines are prophylactic medical products effectively used against infectious diseases. Although a high amount of vaccine studies are conducted at the preclinical stage, the number of approved vaccines is less than 10%. Development of vaccines from the research stage to the approval of administrative institutions takes about 5 years to 10 years conventionally. However, this period of time for vaccine development is not convenient during public health emergencies because an effective vaccine is required in a short time to restrict the speed of high mortality and morbidity. The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had its catastrophic effects worldwide quickly. Therefore, an atypical process was followed for the development of COVID-19 vaccines. Great effort was spent in terms of cooperation among the governmental institutions, academia, and medical companies as well as a high amount of budget was allocated to develop effective vaccines against COVID-19. As of March 2023, the numbers of COVID-19 vaccines in clinical and preclinical development were 183 and 199, respectively. An emergency use authorization (EUA) process was applied to accelerate the approval of the vaccines. Consequently, vaccinations could be started in less than a year, which decelerated the speed of the pandemic. Although EUA caused hesitancy among some people questioning the safety and efficacy of the vaccines, the vast majority of the population was vaccinated. Currently, more than 5.5 billion people (about 70% of the world population) have received 13.38 billion doses of 11 different COVID-19 vaccines, and 73% of the doses were Comirnaty manufactured by Pfizer/BioNTech.
The Global Initiative for Asthma (GINA) provides the most comprehensive and frequently updated guidelines for the management of asthma. The primary aim of guidelines is to bridge the gap between research and current medical practice by presenting the best available evidence to aid clinical decision-making, thereby improving patient outcomes, quality of care, and cost-effectiveness. Guidelines are particularly useful in situations where scientific evidence is limited, multiple treatment options exist, or there is uncertainty about the best course of action. However, due to variations in healthcare system structures, many countries have developed their own local guidelines for the management of asthma. Adoption of GINA recommendations into local guidelines has been uneven across different countries, with some embracing the changes while others continue to follow older approaches. This review article will explore the impact of the noteworthy changes in GINA guidelines, particularly in the 2019 version, on local guidelines and some of the challenges associated with implementing them.
Modification of the C-terminus of a peptide to improve its properties, particularly after constructing the peptide chain, has great promise in the development of peptide therapeutics. This study discusses the development of a late-stage diversification method for synthesizing peptide acids and amides from hydrazides which can serve as a common precursor.
Peptide hydrazides were synthesized solely by using conventional solid-phase peptide synthesis (SPPS). Hydrazides were subjected to oxidation by potassium peroxymonosulfate (Oxone) to afford carboxylic acids. Azidation of hydrazides using sodium nitrite (NaNO2) under acidic conditions, followed by the addition of β-mercaptoethanol (BME), could also be used to generate carboxylic acids. For the preparation of peptide amides, azides that can be prepared from hydrazides were reacted with ammonium acetate (NH4OAc) or tris(2-carboxyethyl)phosphine (TCEP)∙hydrochloride (HCl) to develop the products through ammonolysis or a Staudinger reaction, which produces iminophosphorane from an azide and a phosphine. The antimicrobial activity of modelin-5 derivatives synthesized from the corresponding hydrazides was evaluated by the colony count of Escherichia coli (E. coli) after treatment with the peptides.
Oxone oxidation yielded the corresponding acids rapidly although oxidation-prone amino acids were incompatible. Azidation and subsequent treatment with BME afforded peptide acids an acceptable yield even in sequences containing amino acids that are prone to oxidation. Both methods for conversion of hydrazides to amides were found to afford the desired products in good yield and compatibility. The conditions that were developed were adapted to the synthesis of modelin-5 derivatives from the corresponding hydrazides, yielding late-stage production of the desired peptides. The amides of the resulting peptide showed more potent activity against E. coli than the acid form, and the most potent activity was observed from the hydrazide.
The developed protocols allow hydrazides to be converted to acids or amides, enabling late-stage diversification of peptide C-terminal residues.
Life is the highest form of adaptation to the environment which is based on energy metabolism. To maintain life, the neuromuscular system must constantly interact with the environment. The striatal muscles are the main energy consumer and their access to energy fuel is mainly limited by the brain’s needs. In the state of wakefulness, the brain must continuously process streams of sensory signals and respond to them with motor actions. At the same time, the brain to be efficient must memorize the sensory-movement relationships. Brain memory networking requires additional energy allocation, and due to limited systemic energy resources, the processes of memorization are completed during the sleep phase when the inactive muscular system allows allocating the energy fuel to the brain functions such as memory trace formation and the removal of the activity-dependent waste products. Both physiological processes can be completed during sleep only, and consequently, chronic sleep disorder leads to pathological changes in brain functioning and escalation of neurodegenerative processes. Consequently, sleep disorders become the main cause of dementia which is the prodrome of Alzheimer’s disease.
Self-replicating RNA viruses such as alphaviruses, flaviviruses, paramyxoviruses, and rhabdoviruses have been engineered as expression vectors for vaccine development. The prominent feature of self-replicating RNA viruses is their RNA-dependent RNA polymerase activity, which generates massive self-amplification of RNA in the cytoplasm of infected host cells leading to extreme levels of transgene expression. Infectious diseases have been targeted by overexpression of surface proteins of pathogens as antigens for vaccine development. Moreover, overexpression of tumor-associated antigens and immunostimulatory genes has been the basis for cancer vaccines. Proof-of-concept of robust antigen-specific immune responses and protection against challenges with lethal doses of infectious agents have been demonstrated. Likewise, vaccine development against various cancers has elicited strong immune responses and resulted in tumor regression and eradication, cure, and prolonged survival in animal tumor models. Good safety and immune responses have been achieved in clinical trials. The ERVEBO® vaccine, based on the vesicular stomatitis virus, has been approved for immunization against the Ebola virus disease.
Diabetes mellitus has become increasingly more common and diagnosed within the global population. Coupled with the continued prevalence of substance use, there are some distinct considerations for users suffering (knowingly or unknowingly) from type 1 or type 2 diabetes. The various different types of drugs of abuse including central nervous system stimulants, depressants, and hallucinogens present varying direct and indirect complications for diabetes based on their physiological and psychological effects ranging from non-compliance with medication to an increased risk of hypoglycaemia, hyperglycaemia, and/or ketoacidosis. This perspective highlights these issues supported by the drug history and toxicological findings in patients undergoing drug rehabilitation in the United Arab Emirates (UAE) demonstrating the use of alcohol, amphetamines, benzodiazepines, cannabis, opiates/opioids (especially tramadol), pregabalin, and synthetic cannabinoids. Physicians and drug clinic professionals should be aware of the contraindications of substance use and diabetes with a view to educating patients and healthcare professionals within such clinical settings.
Green propolis is collected by Apis mellifera from the flowers and buds of Baccharis dracunculifolia. It has several chemical compounds that confer anti-inflammatory, antimicrobial, healing, and antioxidant biological activities. To report a series of clinical cases in the treatment of oral mucositis (OM) in patients with cancer undergoing radiotherapy in the head and neck region. Rapid treatment of OM means restoring quality of life to patients and lowering the cost of cancer treatment for public health. There male patients with oral carcinoma undergoing radiotherapy treatment were followed between August 2018 and April 2019. The patients presented themselves to the clinics in the Faculty of Dentistry of Federal University of Minas Gerais with erythematous and ulcerated coalescing lesions with purulent fibrin pseudomembranes in the oral mucosa, classified as grade IV OM according to the World Health Organization. The patients complained about the inability to eat, drink, and speak, which caused the radiotherapy interruption. After completing the clinical forms, anamnesis, and proper oral hygiene of each patient, a mucoadherent gel containing 5% propolis was prescribed for daily use, with a 3 time-a-day application every 8 h. After 7 days of use, there was an 80% lesion reduction, with total remission after 15 days of its application. The rapid response with total remission of lesions seems to be related to the chemical composition of propolis. Clinical and cellphone monitoring of patients, weekly and daily, respectively, were essential for successful treatment. The patients were monitored for one year, being encouraged to make constant use of the gel to control hyposalivation caused by changes in the salivary glands during radiotherapy.
Transmitted primarily by Aedes aegypti (Ae. aegypti) and Aedes albopictus (Ae. albopictus), arboviral diseases pose a major global public health threat. Dengue, chikungunya, and zika are increasingly prevalent in Southeast Asia. Among other arboviruses, dengue and zika are becoming more common in Central and South America. Given human encroachment into previously uninhabited, often deforested areas, to provide new housing in regions of population expansion, conceptualizing built urban environments in a novel way is urgently needed to safeguard against the growing climate change-driven threat of vector-borne diseases. By understanding the spread from a One Health perspective, enhanced control and prevention can be achieved. This is particularly important considering that climate change is likely to significantly impact the persistence of ponded water where mosquitoes breed due to increasing temperature and shifting rainfall patterns with regard to magnitude, duration, frequency, and season. Models can incorporate aquatic mosquito stages and adult spatial dynamics when habitats are heterogeneously available, thereby including dispersal and susceptible-exposed-infected-recovered (SEIR) epidemiology. Coupled with human population distribution (density, locations), atmospheric conditions (air temperature, precipitation), and hydrological conditions (soil moisture distribution, ponding persistence in topographic depressions), modeling has improved predictive ability for infection rates. However, it has not informed interventional approaches from an urban environment perspective which considers the role of ponds/lakes that support green spaces, the density of population that enables rapid spread of disease, and varying micro-habitats for various mosquito stages under climate change. Here, for an example of dengue in Vietnam, a preventive and predictive approach to design resilient urban environments is proposed, which uses data from rapidly expanding metropolitan communities to learn continually. This protocol deploys computational approaches including simulation and machine learning/artificial intelligence, underpinned by surveillance and medical data for validation and adaptive learning. Its application may best inform urban planning in low-middle income countries in tropical zones where arboviral pathogens are prevalent.
Brain development, a complex process, consisting of several phases, starting as early as two weeks after conception, and continuing through childhood till early adolescence, is crucial for the development of properly functioning body systems, behavioral traits, and neurocognitive abilities. Infancy and childhood are recognized as important periods for initial brain formation, however in later stages of life, such as childhood and adulthood, experiences, together with environmental exposures, can still influence brain physiology. The developing brain is particularly susceptible to epigenetic changes with many factors being proposed as modifiers by directly impacting DNA methylation as well as histone and chromatin modifications within genes implicated in development. These factors include: maternal stress and diet, exposure to pollutants, sleep quality, as well as dietary habits. Evidence indicates exposures to environmental threats can lead to inappropriate neurological, metabolic, and endocrine functioning often mediated by epigenetic mechanisms with symptoms manifesting themselves as early as childhood or in later stages of life. Therefore, the main aim of this review is to evaluate the current studies focused on negative environmental exposures and their consequences on the developing brain directed by epigenetic mechanisms.
To evaluate the prevalence, associated factors, and the impact of diffuse idiopathic skeletal hyperostosis (DISH) in patients with gout.
Patients with gout entering into an inception cohort were evaluated for either spinal or peripheral hyperostosis from January 2022 to April 2023. Age, gender, along with comorbid conditions associated to gout and DISH were analyzed, including the presence either axial or peripheral hyperostosis and associated calcium pyrophosphate arthritis (CPPA).
The prevalence of DISH was 25.6% (31/121) patients, neat peripheral joint hyperostosis affecting 51.6% (16/31). CPPA was also present in 11.6% (14/121) patients. Only older age and male gender were independently associated to the presence of DISH. The presence of hyperostosis in peripheral joints was not associated to a worse initial evaluation of the severity of gout.
The presence of DISH in patients with gout seems to be related mostly to aging. Conditions apparently associated to DISH in gout patients seem therefore to be related to aging.
Artificial intelligence (AI) is a new field of science in which computers will provide decisions-supporting tools to help doctors make difficult clinical choices. Recent AI applications in otolaryngology include head and neck oncology, rhinology, neurotology, and laryngology. The aim of this systematic review is to describe the potential uses of AI in head and neck oncology with a special focus on the surgical field.
The authors performed a systematic review, in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, in the main medical databases, including PubMed, Scopus, and Cochrane Library, considering all original studies published until February 2023 about the role of AI in head and neck cancer surgery. The search strategy included a combination of the following terms: “artificial intelligence” or “machine learning” and “head and neck cancer”.
Overall, 303 papers were identified and after duplicate removal (12 papers) and excluding papers not written in English (1 paper) and off-topic (4 papers), papers were assessed for eligibility; finally, only 12 papers were included. Three main fields of clinical interest were identified: the most widely investigated included the role of AI in surgical margins assessment (7 papers); the second most frequently evaluated topic was complications assessment (4 papers); finally, only one paper dealt with the indication of salvage laryngectomy after primary radiotherapy.
The authors report the first systematic review in the literature concerning the role of AI in head and neck cancer surgery. An increasing influx of AI applications to clinical problems in otolaryngology is expected, so specialists should be increasingly prepared to manage the constant changes. It will always remain critical for clinicians to use their skills and knowledge to critically evaluate the additional information provided by AI and make the final decisions on each patient.
Antiphospholipid syndrome (APS) is defined as an autoimmune and prothrombotic disorder in patients with the persistent presence of antiphospholipid antibodies (aPLs). In the classification criteria, aPL expresses lupus anticoagulant (LA) activity, which is detected by prolongation of coagulation assays. The LA detection algorithm is a sequential flow including screening tests, mixing tests, and confirmatory tests to differentiate between LA-positive and other anticoagulant abnormalities. Two types of assays are used, like dilute Russell’s viper venom time (dRVVT) and activated partial thromboplastin time (APTT) because no single test is sensitive to all LAs. The anticoagulant drugs prescribed for the prevention and treatment of thrombosis disorders can interfere with the assays, and it is important to know the effects of these drugs in the assays. Especially, new generation anticoagulant drugs, called direct oral anticoagulants (DOACs), affect the results. In this review, the following points are discussed: i) LA detection flow and data interpretation, ii) the principles of coagulation assays proposed and their characteristics, and iii) the effects of anticoagulant drugs in LA detection.
Breast cancer (BC) is a leading cause of cancer-related deaths in women worldwide where the process of metastasis is a major contributor to the mortality associated with this disease. Metastasis suppressor genes are a group of genes that play a crucial role in preventing or inhibiting the spread of cancer cells. They suppress the metastasis process by inhibiting colonization and by inducing dormancy. These genes function by regulating various cellular processes in the tumor microenvironment (TME), such as cell adhesion, invasion, migration, and angiogenesis. Dysregulation of metastasis suppressor genes can lead to the acquisition of an invasive and metastatic phenotype and lead to poor prognostic outcomes. The components of the TME generally play a necessary in the metastasis progression of tumor cells. This review has identified and elaborated on the role of a few metastatic suppressors associated with the TME that have been shown to inhibit metastasis in BC by different mechanisms, such as blocking certain cell signaling molecules involved in cancer cell migration, invasion, enhancing immune surveillance of cancer cells, and promoting the formation of a protective extracellular matrix (ECM). Understanding the interaction of metastatic suppressor genes and the components of TME has important implications for the development of novel therapeutic strategies to target the metastatic cascade. Targeting these genes or their downstream signaling pathways offers a promising approach to inhibiting the spread of cancer cells and improves patient outcomes.
Sarcopenia and skeletal muscle density (SMD) have been shown to be both predictive and prognostic marker in oncology. Advanced lung cancer inflammation index (ALI) has been shown to predict overall survival (OS) in small cell lung cancer (SCLC). Computed tomography (CT) enables skeletal muscle to be quantified, whereas body mass index (BMI) cannot accurately reflect body composition. The purpose was to evaluate the prognostic value of modified ALI (mALI) using CT-determined third lumbar vertebra (L3) muscle index beyond original ALI and see the interaction between sarcopenia, SMD, neutrophil-lymphocyte ratio (NLR), ALI and mALI at baseline and post 4 cycles of chemotherapy and their effects on OS and progress free survival (PFS) in patients with advanced non-SCLC (NSCLC).
This retrospective study consisted of a total of 285 advanced NSCLC patients. The morphometric parameters such as SMD, skeletal muscle index (SMI) and fat-free mass (FFM) were measured by CT at the L3 vertebra. ALI was defined as BMI × serum albumin/NLR and mALI was defined as SMI × serum albumin/NLR.
Sarcopenia was observed in over 70% of patients across all BMI categories. Patients having sarcopenia suffered from a higher incidence of chemotherapeutic drug toxicities but this was not found to be statistically significant. Concordance was seen between ALI and mALI in the pre-treatment setting and this was statistically significant. A significant proportion of patients with poor ALI (90.9%), poor pre-chemotherapy mALI (91.3%) and poor post-chemotherapy mALI (89%) had poor NLR and each of them was statistically significant.
In both univariate and multivariate analyses, this study demonstrated the statistical significance of sarcopenia, SMD, and mALI as predictive factors for OS. Additionally, sarcopenia and SMD were also found to be statistically significant factors in predicting PFS. These biomarkers could potentially help triage patients for active nutritional intervention for better outcomes.
Despite consistent progress in prompt diagnosis and curative therapies in the last decade, lung cancer (LC) continues to threaten mankind, accounting for nearly twice the casualties compared to prostate, breast, and other cancers. Statistics associate ~25% of 2021 cancer-related deaths with LC, more than 80% of which are explicitly caused by tobacco smoking. Prevailing as small and non-small cell pathologies, with respective occurring frequency of nearly 15% and 80–85%, non-small cell LCs (NSCLCs) are prominently distinguished into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes. Since the first use of epidermal growth factor receptor (EGFR) inhibitor gefitinib for NSCLC treatment in 2002, immense progress has been made for targeted therapies with the next generation of drugs spanning across the chronological generations of small molecule inhibitors. The last two years have overseen the clinical approval of more than 10 therapeutic agents as first-line NSCLC medications. However, uncertain mutational aberrations as well as systemic resistant responses, and abysmal overall survival curtail the combating efficacies. Of late, immune checkpoint inhibitors (ICIs) against various molecules including programmed cell death-1 (PD-1) and its ligand (PD-L1) have been demonstrated as reliable LC treatment targets. Keeping these aspects in mind, this review article discusses the success of NSCLC chemo and immunotherapies with their characteristic effectiveness and future perspectives.
From attributing mutations to cancers with the advent of cutting-edge genetic technology in recent decades, to re-searching the age-old theory of intrinsic metabolic shift of cancers (Warburg’s glycolysis), the quest for a precise panacea for mainly the metastatic cancers, remains incessant. This review delineates the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway driven intricate oncogenic cues, budding from the metabolic (glycolytic) reliance of tumour cells, branching into metastatic emergence of malignancies. Strong AGE-RAGE concomitance in metastasis, chemo-resistance and cancer resurgence adversely incite disease progression and patient mortality. At the conjunction of metabolic and metastatic shift of cancers, are the “glycolytically” generated AGEs and AGE-activated RAGE, instigating aberrant molecular pathways, culminating in aggressive malignancies. AGEs as by-products of metabolic insurgence, modify the metabolome, epigenome and microbiome, besides coercing the inter-, intra- and extra-cellular micro-milieu conducive for oncogenic events like epithelial-mesenchymal transition (EMT). AGE-RAGE synergistically elicit ATP surge for surplus energy, autophagy for apoptotic evasion and chemo-resistance, insulin-like growth factor 1 (IGF-1) for meta-inflammation and angiogenesis, high mobility group box-1 (HMGB1) for immune tolerance, S100 proteins for metastasis, and p53 protein attenuation for tumour suppression. AGEs are pronouncedly reported in invasive forms of breast, prostate, colon and pancreatic cancers, higher in patients with cancer than healthy counterparts, and higher in advanced stage than localized phase. Hence, the investigation of person-specific presence of AGEs, soluble RAGE and AGE-activated RAGE can be advocated as impending bio-markers for diagnostic, prognostic and therapeutic purposes, to predict cancer risk in patients with diabetes, obesity, metabolic syndrome as well as general population, to monitor prognosis and metastasis in patients with cancer, and to reckon complications in cancer survivors. Furthermore, clinical reports of exogenous (dietary) and endogenous (internally formed) AGEs in cancer patients, and contemporary clinical trials involving AGE-RAGE axis in cancer are underlined with theranostic implications.
The biorecognition unit of an electrochemical biosensor requires molecules that are immobilised to serve as a bridge between the recognition unit and the transducing surface. Unique materials that enhance immobilisation of biorecognition molecules and improve electrochemical signal transduction are important in overcoming challenges based on the sensitivity of biosensors. In this regard, the electrochemical properties (EPs) of hydroxyapatite (HAp) material for the direct immobilisation of cells was investigated.
Snail shell HAp (SHAp) material was synthesised from Achatina achatina snail shells and phosphate-containing solutions. The SHAp material was characterised using X-ray diffractometry (XRD), Fourier transform infrared (FTIR) spectroscopy, and Raman spectroscopy to determine the structural configuration, after which it was blended with a conductive polymer [poly(3,4-ethylenedioxythiophene): poly-4-styrene sulfonate (PEDOT: PSS)] to improve the electrochemical responses. The SHAp/PEDOT: PSS blend was used to modify a screen-printed carbon electrode (SPCE) by drop-casting, followed by seeding of pheochromocytoma (PC 12) and human embryonic kidney (HEK)-293T cells on the modified SPCE to record the EP using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Red blood cells (RBCs) were used as a control.
The CV analysis showed lower peak currents for HEK 293T (50 µA) and PC 12 (120 µA) compared to the RBC (230 µA). Also, the EIS showed impedance values of 0.70 for HEK 293T, 0.62 for PC 12, and 0.52 mΩ for RBC. The findings indicate that SHAp/PEDOT: PSS enables the differentiation of cell proliferation signals through voltammetric and impedimetric measurements.
The unique current and impedance differences among the cells could serve as potential markers for rapid cell detection.
Transthoracic echocardiography (TTE) is the first-line imaging test for patients with chronic coronary syndrome (CCS) and the cornerstone of risk stratification is left ventricular (LV) ejection fraction (EF). Aim of the study was to investigate the value of TTE supplemented with strain echocardiography (STE) and lung ultrasound (LUS) to assess the risk of patients with CCS.
In a prospective, single-center, observational study, from November 2020 to December 2022, 529 consecutive patients with CCS were recruited. All patients were evaluated at rest. A single vendor machine (GE Vivid E95) was used. EF with biplane Simpson’s method (abnormal cut-off < 50%), LV global longitudinal strain (GLS%, abnormal cut-off ≤ 16.2% by receiver-operating characteristics analysis) by STE, and B-line score (abnormal cut-off ≥ 2) by LUS (4-site simplified scan) were assessed. Integrated TTE score ranged from 0 (all 3 parameters normal) to 3 (all parameters abnormal). All patients were followed-up and a composite endpoint was considered, including all-cause death, acute coronary syndrome (ACS), and myocardial revascularization.
During a follow-up of 14.2 months ± 8.3 months, 72 events occurred: 10 deaths, 11 ACSs, and 51 myocardial revascularizations. In multivariable analysis, B lines [hazard ratio (HR) 1.76, 95% confidence Interval (CI) 1.05–2.97; P = 0.03], and GLS ≤ 16.2% (HR 2.0, 95% CI 1.17–3.45; P = 0.01) were independent predictors of events. EF < 50% was a significant predictor in univariate, but not in multivariable analysis. Event rate at 2 years increased from score 0 (8%), to score 1 (21%), 2 (23%), and 3 (40%), P < 0.0001.
TTE with left ventricular ejection fraction (LVEF) can be usefully integrated with STE for GLS, and LUS for B-lines, for better prediction of outcome in CCS. The 3 parameters can be obtained in every echo lab with basic technology, no harm, no risk, and no stress.
Drug-induced liver injury (DILI) is an adverse reaction to drugs and other xenobiotics that can have serious consequences and jeopardise progress in pharmacological therapy. While DILI is predominantly hepatocellular, a non-negligible percentage of patients who present with cholestatic damage. Mixed damage is typically lumped together with cholestatic damage in the literature. Drug-induced cholestasis is often caused by the use of some non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (i.e., amoxicillin-clavulanic acid), statins, and anabolic agents, among others. Drug-associated cholestasis tends to have a more chronic course and mostly affects older population. There is also a genetic predisposition to toxic cholestasis caused by some drugs (amoxicillin-clavulanic acid, statins, etc.). Recently, anatomical alterations of the biliary tract induced by drugs (especially immunotherapy drugs) have been described. Bile duct injury is one of the histopathological findings that have prognostic significance in DILI. A correct differential diagnosis with other causes of cholestasis is mandatory to reach an accurate diagnosis. Ursodexycholic acid, corticosteroids, and replacement therapies have been used as a therapeutic arsenal, although more evidence is needed to establish them as a routine therapeutic management in clinical practice. The breakthrough and validation of biomarkers of cholestasis and bile duct injury is an urgent need for drug development and post-marketing phase.
Malignant tumors of the external auditory canal (EAC) are rare neoplasms that appear in the head and neck area. A common feature of these malignancies is their rarity, as well as their delayed diagnosis due to the appearance of non-specific symptoms that mimic various benign otologic conditions. The reported histological types of cancer of the external ear are: squamous cell carcinoma, basal cell carcinoma, malignant melanoma, Merkel cell carcinoma, angiosarcoma, adnexal carcinoma (including ceruminous adenocarcinoma and adenoid cystic carcinoma), and lymphoma (Lancet Oncol. 2005;6:411–20. doi: 10.1016/S1470-2045(05)70208-4). Several therapeutic interventions have been proposed, primarily orientated towards the cure of the patient, placing the surgical excision of the lesions at the tip of the spear. Subsequently and depending on the clinical stage and the pathological characteristics of the tumor, radiation, chemotherapy, a combination thereof, or some form of palliative treatment for particularly advanced cases, may be recommended. The aim of all the above-mentioned approaches is the complete resection of the mass with negative surgical margins along with lymph node dissection, the elimination of any residual disease or metastasis, and the improvement of survival. The anatomical complexity of the region will always remain a demanding challenge. Nevertheless, advances in the fields of ear microsurgery, imaging, radiation, molecular biology, and genomics have led to remarkable outcomes compared to the past, with a view to the patient’s quality of life. Large, well-organized, and prospective studies with the participation of multiple centers in contrast to existing retrospective studies with a limited number of patients will help to establish universally accepted guidelines. The exploration of the molecular and genetic background of these cancers in conjunction with the search for new biomarkers and target molecules seems promising for providing upgraded and more personalized treatment modalities for the future.
Complex enzyme interactions play a role in the spread of cancer, a process fueled by unregulated cell proliferation. DNA topoisomerases, which are important for fixing DNA topological problems, have drawn a lot of interest as potential targets for anti-cancer medications. Cancer treatment, which includes radiation, surgery, and chemotherapy, tries to control cell survival, demise, and mobility, which are mediated by ion transportation across cell membranes via channels and carriers. The malignant transition is characterised by altered channels and carriers. Chemoresistance, which commonly develops after chemotherapy, denotes decreased therapeutic effectiveness against cancer progression. Chemosensitizers are used in combination with anti-cancer medications to overcome this resistance, particularly against adenosine triphosphate (ATP)-binding cassette (ABC) transporters including P-glycoprotein, multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP). Effective targets for treatment are transcription factors, which play a key role in the development of cancer. With the use of interactions with receptors, enzymes, ion channels, transporters, and TFs, nanotechnology improves the safety of tumour localization, treatment, and diagnostics. As a result of mutations or altered signalling, rat sarcoma (RAS) proteins regulate signalling, which is essential for both healthy growth and the development of cancer. Rational treatments that target RAS pathways have the potential to inhibit the growth and spread of tumours. New treatments are still being developed, and they are showing promise in clinical settings. The roles of receptors on tumour cells, their significance for cancer therapy, and recent advancements in preclinical and clinical research are all included in this overview.
The purpose of this study was to examine the association among body mass, blood pressure (BP), and cognitive functioning for octogenarians and centenarians.
A total of 300 participants (221 centenarians and 79 octogenarians) from the Georgia Centenarian Study were included in this study. Demographic variables included age, gender, and ethnicity. Body mass was measured with the body mass index (BMI), and systolic and diastolic BP, as well as mean arterial pressure (MAP) and the Mini-Mental Status Examination (MMSE) were assessed.
Results showed age differences indicating that centenarians had lower BMI and MMSE scores when compared to octogenarians. Women had lower cognitive functioning scores compared to men. Black Americans had higher BMI and BP as well as lower MMSE scores. Participants with low BMI values (< 18.5 kg/m2) and normal BP had a significantly lower MMSE score when compared to those with elevated BMI values (≥ 25 kg/m2 to < 30 kg/m2) and high BP. Multiple regression analyses determined that age, gender, ethnicity, and BMI were significantly associated with cognitive function in very late life.
The results suggest that extreme values of body mass (low and high) in combination with normal BP (< 130 mmHg) are potential risk factors for compromised cognition.
From the start of the pandemic, several aspects of healthcare policies changed, not least the clinical trials management from recruiting capabilities to the protocol compliance in terms of schedule of procedures, follow-up visits, staff constraints and monitoring. This study aims to assess the impact of the COronaVIrusDisease-2019 (COVID-19) pandemic in the conduction of clinical trials at the site of clinical oncology, Ancona (Italy), to identify the strengths and weaknesses upfront the past emergency, and to select better strategies for future similar situations.
Data from February to July of the years 2019, 2020 and 2021 were collected and three practical parameters of the trial unit were investigated: milestones, performance, and impact.
The trials mean numbers were 18, 24, and 23, in 2019, 2020, and 2021 respectively. The pre-Site Initiation Visit (PRE-SIV) rate grew from 66.6% in 2019 to 95.5% in 2021 with a deflection in 2020. Protocol deviations were 40 in the period February-July 2019, in the same period of 2020 the number of deviations increased due to COVID related ones, then there was a significant total decrease in February-July 2021. In 2020 and 2021, all the investigator meetings were online.
The growing number of remote Site Initiation Visit (SIV) and meetings over the last 3 years suggests the feasibility of the on-line processes. The significant reduction in protocol deviations during 2021 is probably due to an under check of data during a pandemic. But that is also a possible key indicator of the coping strategy made out by clinical oncology to guarantee the continuity of care in clinical trials and to offer new opportunities of cancer care in a bad scenario such as a pandemic one.
Childhood obesity is a global health concern that affects the daily life of children. It has a complex pathogenesis that involves genetic and nutritional factors among others. Moreover, the dysbiosis of gut microbiota has been recently associated with the development and progression of obesity.
A total of 43 faecal samples were collected from Saudi children; among them, 26 were normal and 17 were obese. Whole genomic DNA was extracted from their faecal samples and sequenced using an Illumina Sequencing platform.
The gut microbiota was dominated by Phyla Firmicutes (69.00%) and Bacteroidetes (20.00%), followed by Actinobacteria (8.50%). In children with obesity, the abundance of Firmicutes was decreased, while Bacteroidetes was relatively enriched. Verrucomicrobia and Proteobacteria were not detected in the obese group, but they were found in low abundance in the control group. Phylum Firmicutes was dominated by the families Ruminococcaceae (17.86%) and Lachnospiraceae (41.20%). Less Ruminococcaceae was found in the obese group. Phylum Bacteroidetes was dominated by families Bacteroidaceae (12.98%) and Prevotellaceae (4.10%), which were enriched in the obese group. Genus Blautia (14.29%) was highly abundant, followed by Bacteroides (12.98%), Faecalibacterium (10.08%), Bifidobacterium (7.96%), and Prevotella (5.04%). Ruminococcus_g2 and _g4, Subdoligranulum, Roseburia, Fusicatenibacter, Anaerostipes, and Faecalibacterium were decreased (P > 0.05) in the obese group, while Streptococcus, Agathobacter, Prevotella, Bacteroides, and Bifidobacterium were increased (P > 0.05).
In conclusion, a diverse bacterial community was profiled in Saudi preschool children, and changes in bacterial community composition were observed between obese- and normal-weight children.
Wound healing is a very dynamic and complex process as it involves the patient, wound-level parameters, as well as biological, environmental, and socioeconomic factors. Its process includes hemostasis, inflammation, proliferation, and remodeling. Evaluation of wound components such as angiogenesis, inflammation, restoration of connective tissue matrix, wound contraction, remodeling, and re-epithelization would detail the healing process. Understanding key mechanisms in the healing process is critical to wound research. Elucidating its healing complexity would enable control and optimize the processes for achieving faster healing, preventing wound complications, and undesired outcomes such as infection, periwound dermatitis and edema, hematomas, dehiscence, maceration, or scarring. Wound assessment is an essential step for selecting an appropriate treatment and evaluating the wound healing process. The use of artificial intelligence (AI) as advanced computer-assisted methods is promising for gaining insights into wound assessment and healing. As AI-based approaches have been explored for various applications in wound care and research, this paper provides an overview of recent studies exploring the application of AI and its technical developments and suitability for accurate wound assessment and prediction of wound healing. Several studies have been done across the globe, especially in North America, Europe, Oceania, and Asia. The results of these studies have shown that AI-based approaches are promising for wound assessment and prediction of wound healing. However, there are still some limitations and challenges that need to be addressed. This paper also discusses the challenges and limitations of AI-based approaches for wound assessment and prediction of wound healing. The paper concludes with a discussion of future research directions and recommendations for the use of AI-based approaches for wound assessment and prediction of wound healing.
The current literature findings on autophagy’s beneficial and detrimental roles in diabetes mellitus (DM) and diabetes-related comorbidities were reviewed. The effects of oral hypoglycaemic medicines and autophagy in DM. Autophagy plays an important function in cellular homeostasis by promoting cell survival or initiating cell death in physiological settings was also assessed. Although autophagy protects insulin-target tissues, organelle failure caused by autophagy malfunction influences DM and other metabolic diseases. Endoplasmic reticulum and oxidative stress enhance autophagy levels, making it easier to regulate stress-induced intracellular changes. Evidence suggests that autophagy-caused cell death can occur when autophagy is overstimulated and constitutively activated, which might prevent or develop DM. Even though the precise role of autophagy in DM complications is uncertain, deregulation of the autophagic machinery is strongly linked to beta cell destruction and the aetiology of DM. Thus, improving autophagy dysfunction is a possible therapeutic objective in treating DM and other metabolic disorders.
The development of patient-specific prosthetics, medication administration, the manufacture of tissues and organs, and surgical planning have all benefited significantly from the use of three-dimensional (3D) printing during the past few decades. The enthusiasm for customized healthcare has increased because the United States of America launched its Precision Medicine Initiative in 2015. In a nutshell, the phrase “personalized medicine” refers to medical care that is tailored to the patient. Nevertheless, the biomedical materials utilized in 3D printing are often stable and can’t react or be adaptive and intelligent in the body’s interior environment. Ex-situ fabrication of these substances, which includes printing on a flat substrate before releasing it onto the target surface, may cause a discrepancy between the printed portion and the target areas. The 3D printing is one method that might be used to provide customized treatment. The four-dimensional (4D) printing is developed while employing components that can be tweaked with stimulation. Several researchers have been looking at a new area recently that blends medicines with 3D and 4D printing. The development of 4D printing overcomes a number of these issues and creates a promising future for the biomedical industry. Smart materials that have been pre-programmed can be used in 4D printing to create structures that react interactively to outside stimuli. Despite these benefits, dynamic materials created using 4D technology remain in their development. As a result, several ideas for pharmaceutical products and formulas that may be customized and printed have emerged. Furthermore, Spritam®, the first medicine produced by 3D printing, has indeed reached a medical facility. This paper offers a summary of several 3D and 4D printing technologies and how they are used in the pharmaceutical industry for customized medicine and drug delivery systems.
A number of questions remain unanswered concerning how infected individuals regulate their immune response to Plasmodium falciparum (P. falciparum) parasites at varying levels of exposure. Due to the interactions of inflammatory mediators and cytokines with the P. falciparum parasite complex density, several mediators influence parasitaemia and may give some indications of disease severity and represent effective signs in clinical manifestations of malaria disease.
In this study, various levels of immune response mediators of interleukin 8 (IL-8), tumor necrosis factor-beta (TNF-β, also known as lymphotoxin-α), interferon-gamma (IFN-γ), IL-6, and IL-10 were investigated to the different phases of infection with P. falciparum in hyperendemic states in Sudan (White Nile, Blue Nile). This study vetted the association between certain inflammatory mediators during malaria infection and parasite density. This study was based on a total of 108 cases, in which 86 patients (62.0%) were uncomplicated and (17.6%) were severe, all met the diagnostic criteria and were clinically admitted for malaria infections. Commercial enzyme-linked immunosorbent assay (ELISA) kits were employed to determine the inflammatory mediator’s serum concentration.
The analysis of data indicated that older infected children had substantially raised levels of IFN-γ (P < 0.05), among study groups, levels of IFN-γ, TNF-β, and IL-8 were strongly linked with the severity of malaria, in severe and uncomplicated cases (P < 0.001), IL-6 and IL-10 were significantly associated with severe malaria cases uniquely (P < 0.001). Furthermore, we reported a positive correlation between IL-8 and TNF-β during all infection cases (r = 0.760, P < 0.001). Additionally, in severe malaria cases IL-6 was positively correlated with IL-10 (r = 0.575, P = 0.010).
Eliminating P. falciparum blood-stage infection needs effective, specific, and tuned immune response strategies, which may present in the mediator’s correlations and depend on the density of the infection. Besides the effective levels contribution of certain cytokines that play protective roles during different stages of an infection.
Abnormal energy metabolism is one of the ten hallmarks of tumors, and tumor cell metabolism provides energy and a suitable microenvironment for tumorigenesis and metastasis. Tumor cells can consume large amounts of glucose and produce large amounts of lactate through glycolysis even in the presence of oxygen, a process called aerobic glycolysis, also known as the Warburg effect. Lactate is the end product of the aerobic glycolysis. Lactate dehydrogenase A (LDHA), which is highly expressed in cancer cells, promotes lactate production and transports lactate to the tumor microenvironment and is taken up by surrounding stromal cells under the action of monocarboxylate transporter 1/4 (MCT1/4), which in turn influences the immune response and enhances the invasion and metastasis of cancer cells. Therapeutic strategies targeting lactate metabolism have been intensively investigated, focusing on its metastasis-promoting properties and various target inhibitors; AZD3965, an MCT1 inhibitor, has entered phase I clinical trials, and the LDHA inhibitor N-hydroxyindole (NHI) has shown cancer therapeutic activity in pre-clinical studies. Interventions targeting lactate metabolism are emerging as a promising option for cancer therapy, with chemotherapy or radiotherapy combined with lactate-metabolism-targeted drugs adding to the effectiveness of cancer treatment. Based on current research, this article outlines the role of lactate metabolism in tumor metastasis and the potential value of inhibitors targeting lactate metabolism in cancer therapy.
The idea that proteins are the main determining factors in the functioning of cells and organisms, and their dysfunctions are the first cause of pathologies, has been predominant in biology and biomedicine until recently. This protein-centered view was too simplistic and failed to explain the physiological and pathological complexity of the cell. About 80% of the human genome is dynamically and pervasively transcribed, mostly as non-protein-coding RNAs (ncRNAs), which competitively interact with each other and with coding RNAs generating a complex RNA network regulating RNA processing, stability, and translation and, accordingly, fine-tuning the gene expression of the cells. Qualitative and quantitative dysregulations of RNA-RNA interaction networks are strongly involved in the onset and progression of many pathologies, including cancers and degenerative diseases. This review will summarize the RNA species involved in the competitive endogenous RNA network, their mechanisms of action, and involvement in pathological phenotypes. Moreover, it will give an overview of the most advanced experimental and computational methods to dissect and rebuild RNA networks.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can result in a range of persistent symptoms impacting everyday functioning for a considerable proportion of patients, a condition termed Long coronavirus disease (COVID) or post COVID-19 syndrome. The severity and set of symptoms vary between patients, and include fatigue, cognitive dysfunction, sleep disturbances, palpitations, tachycardia, pain, depression, and anxiety. The high prevalence of Long COVID combined with the lack of treatment approaches has resulted in considerable unmet clinical needs. There is a growing body of evidence that cannabis-based medicinal products (CBMPs) can be used to treat symptoms including pain, anxiety, depression, fatigue, sleep, headaches, and cognitive dysfunction, which are commonly reported in Long COVID. This article provides an overview of the pathophysiology of Long COVID and discusses preliminary pre-clinical, clinical trials, and real-world evidence (RWE) for CBMPs in the context of Long COVID. This review summarises current clinical trials and studies exploring CBMPs in Long COVID. The current evidence provides a rationale to further explore CBMPs as a treatment for Long COVID symptoms. In addition to further randomised controlled trials (RCTs), the increasing availability of CBMPs globally, coupled with the continued prevalence of Long COVID in the population, also highlights the value of real-world data in the research of CBMPs in Long COVID. Critically, there is an evident need for multidisciplinary approaches of CBMPs and Long COVID in real-world clinical practice settings.
Stroke, a central nervous system (CNS) injury, is responsible for the second leading cause of death in the world, bringing a great burden on the world. Stroke is normally divided into ischemic and hemorrhagic stroke, among which ischemic stroke takes up 87% proportion. Accumulating evidence has denoted a rather pivotal role for autophagy in the pathogenesis of ischemic stroke, which is activated in neuronal cells, glial cells, and endothelial cells. Besides, circular RNAs (circRNAs), a novel type of epigenetic regulation, are highly expressed in the CNS and are involved in the process of CNS diseases, which is regarded as an important molecular mechanism in ischemic stroke. Meanwhile, circRNA and autophagy have a significant correlation. The intracellular signaling pathways regulating autophagy can either restrain or activate autophagy. However, under the circumstances of ischemic stroke, the precise communication between circRNA and stroke is largely unknown. This review aims to provide a summary of the relationship between circRNA, autophagy, and ischemic stroke, as well as the current research advancements in understanding how circRNA regulates autophagy in the context of stroke.
Broncho-alveolar lavage (BAL) represents a safe tool for the differential diagnosis of various pulmonary fibrotic diseases. Idiopathic pulmonary fibrosis (IPF) belongs to a heterogeneous group of diseases, interstitial lung disease (ILD), presenting a progressive impairment of pulmonary functions. IPF is characterized by the excessive accumulation of extracellular matrix (ECM) in the alveolar parenchyma that may lead to irreversible pulmonary remodeling. Although the exact pathogenetic mechanisms leading to IPF development are still unclear it has been demonstrated that fibroblasts differentiating toward myofibroblasts are the major actors involved in this process. The possibility of obtaining and expanding fibroblasts from the BAL of ILD patients for research purposes has been recently explored. This approach is discussed here as a reliable chance, helpful to advance the scientific community knowledge and to devise two- and three-dimensional (2D/3D) pre-clinical in vitro models of these diseases, further overcoming technical and ethical concerns related to the use of fibroblasts derived from tissue biopsy.
DNA damage involves in the carcinogenesis of some cancer and may act as a target for therapeutic intervention of cancers. However, it is unclear whether aflatoxin B1 (AFB1)-DNA adducts (ADAs), an important kind of DNA damage caused by AFB1, affect the efficiency of post-operative adjuvant transarterial chemoembolization (po-TACE) treatment improving hepatocellular carcinoma (HCC) survival.
A hospital-based retrospective study, including 318 patients with Barcelona Clinic Liver Cancer (BCLC)-C stage HCC from high AFB1 exposure areas, to investigate the potential effects of ADAs in the tissues with HCC on po-TACE treatment. The amount of ADAs in the cancerous tissues was tested by competitive enzyme-linked immunosorbent assay (c-ELISA).
Among these patients with HCC, the average amount of ADAs was 3.00 µmol/mol ± 1.51 µmol/mol DNA in their tissues with cancer. For these patients, increasing amount of ADAs was significantly associated with poorer overall survival (OS) and tumor reoccurrence-free survival (RFS), with corresponding death risk (DR) of 3.69 (2.78–4.91) and tumor recurrence risk (TRR) of 2.95 (2.24–3.88). The po-TACE therapy can efficiently improve their prognosis [DR = 0.59 (0.46–0.76), TRR = 0.63 (0.49–0.82)]. Interestingly, this improving role was more noticeable among these patients with high ADAs [DR = 0.36 (0.24–0.53), TRR = 0.40 (0.28–0.59)], but not among those with low ADAs (P > 0.05).
These results suggest that increasing ADAs in the cancerous tissues may be beneficial for po-TACE in ameliorating the survival of patients with HCC.
Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression—most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.
Cancer stem cells (CSCs) are a small subpopulation of cells that drive the formation and progression of tumors. However, during tumor initiation, how CSCs communicate with neighbouring immune cells to overcome the powerful immune surveillance barrier in order to form, spread, and maintain the tumor, remains poorly understood. It is, therefore, absolutely necessary to understand how a small number of tumor-initiating cells (TICs) survive immune attack during (a) the “elimination phase” of “tumor immune-editing”, (b) the establishment of regional or distant tumor after metastasis, and (c) recurrence after therapy. Mounting evidence suggests that CSCs suppress the immune system through a variety of distinct mechanisms that ensure the survival of not only CSCs but also non-stem cancer cells (NSCCs), which eventually form the tumor mass. In this review article, the mechanisms via which CSCs change the immune landscape of the tissue of origin, which contains macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and tumor-infiltrating lymphocytes, in favour of tumorigenesis were discussed. The failure of cancer immunotherapy might also be explained by such interaction between CSCs and immune cells. This review will shed light on the critical role of CSCs in tumor immune evasion and emphasize the importance of CSC-targeted immunotherapy as a cutting-edge technique for battling cancer by restricting communication between immune cells and CSCs.
In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC).
The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context.
High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity (P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs (P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors.
In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations.
Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer.
Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol.
All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase.
Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.
Over the past decade, knowledge of the pathophysiology and immunology of multiple sclerosis (MS) and depression, and the complex links to vitamin D (VitD) balance, has increased rapidly. Both diseases are characterized by an imbalance of proinflammatory and antiinflammatory cytokines, increased serum neurofilament light chains (sNfLs), disruption of the blood-brain barrier (BBB), abolition of the physiological function of the various types of microglia (MG), decreased calcidiol-serum levels, and disorders of the gut microbiome in combination with hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis/microbiome-gut-brain-axis characterized. In depression, stress initiates cellular and molecular changes in the brain via increased cortisol release in the HPA-axis. Microglial activation and neuronal damage as well as dysregulation of neuroplastic and neurotrophic factors complete the spectrum of pathological damage. It is shown that gut dysbiosis leads to increased gut permeability, which favors endotoxemia and ultimately paves the way to systemic inflammation. A VitD supplementation could restore the balance of microorganisms in the intestine and reduce the inflammatory processes at various levels. VitD promotes regulatory T cell (Treg) proliferation, inhibits the expression of T helper 1 (Th1) cells and Th17 immune cells, and inhibits proinflammatory interleukin-17 (IL-17). 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] reduces also the secretion of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Increased calcitriol levels lead to a reduction in MG activation, oxidative stress, and lower BBB permeability. An early, permanent, daily sufficient VitD supplementation as an add-on therapy under control of the serum 25-hydroxyvitamin D [s25(OH)D] levels is an essential therapeutic tool to slow down the disability caused by MS and thereby primarily prevent or reduce the stress and subsequently the manifestation of depression. Through the future continuous measurement of the biomarkers serum neurofilament ligth chains and glial fibrillary acidic proteins as well as the s25(OH)D level in MS and comorbidity depression, future therapy successes or failures can be avoided.
The use of 5-fluorouracil in glaucoma surgery is associated with a high risk of corneal complications, as even minimal doses of the drug at the ocular surface inhibit corneal epithelial cell division and lead to corneal epitheliopathy and erosion. The aim of this study was to evaluate the clinical and functional results of the proposed method of postoperative adjuvant subconjunctival injection of 5-fluorouracil after non-penetrating deep sclerectomy (NPDS) in comparison with the control group.
Patients with primary open-angle glaucoma who underwent NPDS and received at least 1 subconjunctival injection of 5-fluorouracil in the postoperative period were included in a two-group retrospective comparative study. Patients who received a subconjunctival injection of 5-fluorouracil after surgery using the standard technique were included in Group 1; Group 2 included patients who received an injection using the proposed method. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), rate of corneal complications, and number of office visits during the first 4 weeks after surgery were analysed.
The compared groups did not differ in demographic characteristics, preoperative BCVA, and IOP parameters. Fluorescein-stained corneal epithelial defects were statistically significantly more frequent in Group 1 compared to Group 2, P < 0.001. Four weeks post NPDS IOP reduction was greater in Group 2, P = 0.042. Mean BCVA loss was 1.9 lines in Group 1 and 1.3 lines in Group 2, P < 0.001. The number of follow-up visits during the first month after surgery was lower in Group 2 than in Group 1, P = 0.002.
The proposed method was simple and effective in reducing the risk of corneal epithelial defects after subconjunctival injection of 5-fluorouracil, significantly improving clinical and functional outcomes of NPDS and reducing the need for outpatient visits.
Hyperuricemia is known to be a necessary and causal condition for gout, but much more prevalent than gout. Medicine has standardized treatments for gout, but has no such determination for asymptomatic hyperuricemia. Nevertheless, people with hyperuricemia, gouty or not, too often continue to be at risk for shortened lifespans from life-threatening comorbidities, all of which are known to be consequences of obstructive sleep apnea (OSA), which is shown herein to cause most hyperuricemia. This review also presents the wide variety of OSA consequences, many of which are irreversible and life-threatening, as the rationale for treating all hyperuricemia (gouty and asymptomatic) by diagnostic testing and effective treatment for OSA as soon as hyperuricemia is detected. It advocates frequent ultrasonic screening for aggregated urate crystals. Multiple epidemiological studies have found OSA to be significantly more prevalent in those people with gout diagnosed with OSA than it is in those never diagnosed with it. A clinical study shows an even higher prevalence of OSA in people with gout. The pathophysiology of hypoxia from OSA explains how it would lead to both the overproduction and the underexcretion of uric acid, leading to hyperuricemia and the precipitation of monosodium urate crystals which cause a gout flare. Resolving OSA has been shown to prevent or even reverse life-threatening diseases that are recognized comorbidities of hyperuricemia and gout, and can prevent further gout flares. In order to extend the length and quality of life of people with gout or hyperuricemia, when either first manifests a patient sleep study is recommended, followed by effective OSA treatment as warranted.
Vaccination has made an enormous contribution to global health. Treatment resistance for infectious diseases is growing quickly, and chemotherapeutic toxicity in cancer means that vaccines must be made right away to save humanity. But subunit vaccinations alone don’t give enough strong and long-lasting protection against infections that can kill. Nanoparticle (NP)-based delivery vehicles, such as dendrimers, liposomes, micelles, virosomes, nanogels, and microemulsions, offer interesting ways to get around the problems with traditional vaccine adjuvants. The nanovaccines (50–250 nm in size) are most efficient in terms of tissue targeting, staying in the bloodstream for a long time. Nanovaccines can improve antigen presentation, targeted delivery, stimulation of the body’s innate immune system, and a strong T-cell response without putting people at risk. This can help fight infectious diseases and cancers. Also, nanovaccines can be very helpful for making cancer treatments that use immunotherapy. So, this review highlights the various types of NPs used in the techniques that have worked in the new paradigm in viral vaccinology for infectious diseases. It gives a full rundown of the current NP-based vaccines, their potential as adjuvants, and the ways they can be delivered to cells. In the future, the best nanovaccines will try to be more logically designed, have more antigens in them, be fully functionalized, and be given to the right people.
Changes occurring in the immune system along the ageing process increase the risk of infection, susceptibility to tumor development, and autoimmunity. Interventions such as physical exercise, supplements, and probiotics have been proposed in order to circumvent these conditions. Vitamin D supplementation could contribute to the immune system homeostasis in older adults since a large proportion of this population has low levels of circulating vitamin D. Additionally, observational studies have shown the association between vitamin D status and infections, chronic diseases such as cancer, diabetes, and cardiovascular disease. Recently it was observed that old patients with COVID-19 and vitamin D deficiency had enhanced severity of lung damage, longer stay at the hospital, and increased risk of death, suggesting that vitamin D plays an important role in the patient outcome from COVID-19. A high dose of vitamin D supplementation improved clinical recovery in a case-series report but in another study, no evident link between levels of vitamin D and risk of COVID-19 infection was found. Results also remain debatable for vitamin D supplements and improvement of immune response after vaccination, tuberculosis, pneumonia, and sepsis. It has been hypothesized that vitamin D could modulate the immune system and thus provide both efficacies in the immune response to pathogens/vaccinations and reduction of the inflammatory phenotype. This review will discuss vitamin D and homeostasis of the immune system; the literature-based clinical data on vitamin D and infections; and the possible link between vitamin D and immune response after vaccination.
In this study, Polyphenol and chemical profiles in core, pulp, and peel of 7 apple varieties [Fuji (FS), Qinguan (QG), Qingping (QP), Jinshuai (JS), Gala (GL), Changmiou (CMO), and Huahong (HH)] were comparatively studied to distinguish the different metabolism biomarkers in the three parts of apple fruit.
This study investigated the distribution of 15 polyphenolic compounds using a combination of multivariate analysis and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS).
chlorogenic acid, catechin, epicatechin, phloretin were the most abundant components. While phloretin was the dominant component in core, chlorogenic acid was the main phenolic compound in pulp, and quercetin was mainly found in apple peel. The multivariate analysis showed that the chemical profile of peel was significantly distinct from that of apple pulp and core, whereas apple pulp and core overlapped with each other. The difference attributed to the compounds that were predicted from ultra-high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), which were remarkably different (P < 0.05) and belong to polyphenol.
It indicates that the potential superior biomarker of polyphenols is to differentiate the products from apple core, pulp, and peel respectively. This research provided an insight on the polyphenolic profile of core, pulp, and peel of apple fruits.
The on-site, rapid, and intelligence detection methods are the wave in food safety. Recently, intelligent point-of-care test (iPOCT) methods serve as a promising alternative for advanced monitoring in food safety. By integrating smartphones with various detection methods, iPOCT methods demonstrate unique merits. Compared with lab-dependent instruments, iPOCT strategies have a short turnaround time (several minutes), high accuracy (μm level or less), and portability (smartphones). This work discussed principles of optical and electrical iPOCT methods, including absorbing light, fluorescence, chemiluminescence, potentiometry, voltammetry, impedance spectroscopy, and amperometry. The review emphasizes the practical applications for testing chemical and biological hazards in complex food matrices. The commercialization, challenges, and future trends of iPOCT are discussed as well.
AT-rich interaction domain 1A (ARID1A) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients.
Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A+.
Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A+ population was higher compared to ARID1A– population (6 vs. 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), catenin beta 1 (CTNNB1), and lysine methyltransferase 2D (MLL2) mutations were enriched in ARID1A+ population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A2+) were all gynecological cancers (83% endometrioid endometrial cancers).
This analysis provides clinical and molecular details about the phenotypes of ARID1A+ cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor.
Interferon (IFN)-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (UBL) protein family that can modify specific proteins via a catalytic process called ISGylation. This posttranslational modification can modulate the stability of the ISGylated proteins and protein-protein interactions. Some proteins modified by ISG15 have been identified in malignant neoplasms, suggesting the functional relevance of ISGylation in cancer. This review discusses the ISGylated proteins reported in malignant neoplasms that suggest the potential of ISG15 as a biomarker and therapeutic target in cancer.
Interest in the mechanisms of aging of the immune system has not faded over the past 100 years, and it is caused by the immune-mediated development of age-related pathology, including autoimmune organ damage, reduced vaccination efficiency, atherosclerosis, the development of cardiovascular pathology, etc. In contrast to many other organs and systems, the immune system aging begins at an early age and has more pronounced changes that lead to the development of secondary pathology, which significantly affects life expectancy. But an effective strategy to restore immune function has not been developed yet. During this time, the mechanisms of age-related dysfunction of organs and cells of both the adaptive and innate immune systems were studied in detail—thymus involution, a decrease in the potential of hematopoietic stem cells, impaired differentiation and functions of immunocompetent cells, as well as the ways of their interaction. Numerous potential therapeutic targets have been identified and various approaches have been used to implement such therapeutic interventions. The review is devoted to replacement therapy using transplantation of hematopoietic stem cells (HSCs) and young lymphoid cells and tissues, cellular and systemic factor exchange in heterochronic parabiosis, and some other widely used life extension approaches. It has been proven that cell therapy using young cells to rejuvenate the old immune system, unfortunately, often turns out to be ineffective because it does not eliminate the root cause of age-related changes. The phenomenon of inflamm-aging that develops with age can significantly affect both the aging of the organism in general and the functioning of immunocompetent cells in particular. Therefore, the most promising direction in the restoration of immune functions during aging is systemic approaches that have a complex effect on the organism as a whole and can slow down the aging process.
Several bare metals, self-expanding stents have been approved by the Food and Drug Administration (FDA) to treat carotid stenosis, but no covered stents have been particularly examined or approved for carotid or cerebrovascular applications. Nonetheless, there are a number of potentially useful applications for covered stents in the brachiocephalic, carotid, and even intracranial arteries. As with currently accepted applications for bare metal carotid stents, the use of covered stents in carotid arteries has been reserved for patients who are at high risk for complications with open surgical management of their specific problem. The present case report emphasizes the safety and efficacy of covered stent in complex carotid artery reconstruction entailing stenosis and aneurysmal dilatation and through light on its impact on minimizing the risk of ischemic complications associated with endovascular or surgical carotid sacrifice.
Cigarette smoking is an addictive behavior that requires high motivation to change, a phenotype related to the functional activity of the brain. The study aims to examine motivation to change among cigarette smokers and to study the association between functional brain activity and motivation to change smoking behaviors.
Motivation to change smoking behaviors of 107 current smokers receiving services in a university hospital was obtained using the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Brain activities related to motivation to change were also explored in a subgroup using functional magnetic resonance imaging (fMRI).
The results showed that most of the current smokers (n = 68, 63.6%) were low motivated to change despite receiving health-related services. Brain activities in the left of the temporal, frontal gyrus, and superior medial gyrus of smokers with motivation were greater activated than those without. In contrast, the brain activities in the left precentral gyrus and bilateral paracentral lobules of smokers without motivation were greater activated.
These preliminary results show the differences in brain activities between smokers with and without motivation to change and warrant further research to see if motivated smokers can quit smoking using a series of strategies based on their functional activities of the brain.
The gut microbiota and dysbiosis have been implicated in various metabolic diseases and gastrointestinal disorders. Recently, there has been growing evidence suggesting the influence of gut microbiota on neurological disorders, including autism. Although the number of children diagnosed with autism is increasing, the exact cause of the disease remains unknown. Numerous factors, such as genetics, environment, and diet, appear to contribute to its onset. Nevertheless, a degree of general consensus exists regarding the notion that the disease’s progression likely demands the participation of multiple factors. Among the potential causes, the role of the microbiota is particularly intriguing. The gut and brain have extensive connections, with a significant number of neuronal cells in the gut, and autism is often associated with gastrointestinal issues. In this review, the most recent information available on autism and microbiota has been analyzed. Findings of this study indicate that: (1) the microbiota is clearly altered in individuals with autism spectrum disorder (ASD); (2) microbiota transplantation appears to be effective in reducing the severity of autism symptoms; (3) while the microbiota is not solely responsible for the onset of autism, it likely plays a significant role. Considering all the available information, it is suggested that modifying the gut microbiota may have a positive impact on individuals with autism. This opens up possibilities for the use of pre- or probiotics in the treatment of children with ASD, as well as the potential use of fecal microbiota transfer.
Thrombocytopenia is one of the most frequent implications of liver cirrhosis. This condition, when present in the severe form [platelet count (PLT) less than 50 × 109/L] correlates, with an increased risk of bleeding during the main diagnostic-therapeutic procedures which cirrhotic patients usually undergone. In these cases, generally, an infusion of platelets is performed, albeit in recent years has been replaced by a cycle of second generation thrombopoietin receptor (TpoR) agonists. This article reports two different cases concerning respectively an 83-year-old female patient suffering from arterial hypertension, aneurysm of the sub-renal aorta, hepatitis C virus (HCV)-positive liver cirrhosis responsive to treatment with antiviral drugs, and a 2.0 cm diameter hepatocellular carcinoma (HCC) nodule localized in the hepatic segment III and a 53-year-old female patient with HCV-positive liver cirrhosis complicated by portal hypertension with splenomegaly, thrombocytopenia, and F3 esophageal varices at high risk of bleeding. Both of them, eligible for invasive procedures such as HCC transarterial chemoembolization (TACE) and for esophageal variceal band ligation, were prescribed prophylaxis with TpoR agonists due to their severe and persistent thrombocytopenia. These two cases show how a short course of lusutrombopag allows to safely perform one or more invasive procedures and how the administration of the drug can be repeated without losing efficacy. Furthermore, this drug shows an excellent safety profile and avoids the risks of platelet transfusion. In conclusion, second generation TpoR agonists can be considered the prophylactic treatment of choice to reduce the risk of bleeding in patients with liver cirrhosis and severe thrombocytopenia.
Nonalcoholic fatty liver disease (NAFLD) is an umbrella definition that describes the ectopic deposition of fat within the liver that occurs in the absence of inciting factors other than the metabolic syndrome and its individual features. NAFLD has a multi-factorial pathogenesis which determines heterogeneous clinical phenotypes and variable natural course spanning from liver-related (steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma) to extrahepatic outcomes (cardio-metabolic and cancer). This narrative review article leverages the key aspects of disease natural history as the background information to discuss studies that may inform strategies to risk-stratify NAFLD patients. Evaluation of hepatic fibrosis with non-invasive tools, including blood-based biomarkers and imaging-based elastometry techniques, seemingly retains the core information useful to predict the heterogeneous outcomes listed above. Additionally, genetic testing and metabolomic profiles may also be utilized to this end. In conclusion, a comprehensive understanding of the variable hepatic, cardio-metabolic and cancer outcomes of NAFLD may enable physicians and researchers to risk-stratify and accurately identify the multilayered prognosis of NAFLD individuals while also defining homogeneous patient subsets to enroll in clinical trials.
Modifications in long non-coding RNA (lncRNA) expression are associated with inflammation and fibrosis in chronic liver diseases. It has been recently demonstrated that human liver stem cells (HLSCs) and their extracellular vesicles (EVs) can effectively reduce inflammation and fibrosis in a murine model of non-alcoholic steatohepatitis (NASH). Now it has been evaluated whether EVs can modify the expression of inflammation-related lncRNAs in NASH liver.
To induce NASH, severe combined immunodeficient mice were fed with a methionine-choline-deficient diet for 4 weeks. After 2 weeks of diet, 2.5 × 109 EVs were intravenously injected twice a week. An array of 84 inflammation-related lncRNAs was performed on the RNA isolated from NASH livers, and the expression of 14 selected lncRNAs was then validated by real-time polymerase chain reaction (PCR) analysis. Expression levels of maternally expressed gene 3 (Meg3) were further evaluated in vitro, in an activated human hepatic immortalized stellate cell line (LX-2) stimulated with EVs.
The screening showed an altered lncRNA expression profile in the liver of NASH mice, in respect to control healthy mice. EV treatment modulated several inflammation-related lncRNAs in NASH livers. Real-time PCR validation of array results indicated that EVs restored to normal levels the expression of 10 lncRNAs altered in NASH. In particular, EV stimulation reduced Meg3 expression levels, which were increased in NASH as well as in activated LX-2.
HLSC-EVs regulate the expression of inflammation-related lncRNAs impaired in NASH livers and in an in vitro model of liver fibrosis.
Coronary flow velocity (CFV) can be obtained with transthoracic echocardiography (TTE) in the left anterior descending coronary artery (LAD). The physiologic flow velocity gradient across the different segments of LAD has not been established. This study aims to assess the normal values of resting CFV in proximal, mid, and distal LAD.
In a single center, prospective, observational study design, TTE was attempted on 110 consecutive, asymptomatic middle-aged subjects (age = 55 years, 46% males) with a low likelihood of coronary artery disease (< 5%). Resting CFV in the LAD was assessed with high-end machines, dedicated coronary pre-set, and high-frequency transducers by pulsed-wave Doppler under color-Doppler guidance in the proximal, mid, and distal segments.
The technical success rate for CFV imaging was lowest for the proximal (101/110, 92%), intermediate for mid (106/110, 96%), and highest for the distal segment (108/110, 98%). All 3 segments were interpretable in 101 subjects. CFV was highest in proximal segments (38.6 cm/s ± 3.9 cm/s), intermediate in mid segments (34.3 cm/s ± 6.04 cm/s, P < 0.01 vs. proximal), and lowest in distal segments (28.1 cm/s ± 1.7 cm/s, P < 0.01 vs. proximal and vs. mid).
A resting evaluation of CFV-LAD can be obtained by TTE in the large majority of consecutive subjects referred to the echocardiography laboratory. Feasibility is highest for distal and lowest for proximal-LAD segments. There is a clear physiologic gradient of CFV with decreasing values, of about 10% for each step, going from proximal to mid and distal segments of LAD. When resting CFV is considered, the site of the sampling is important to obtain comparable and physiologically meaningful data.
This study aims to assess outcomes of gout patients from the treat to target (T2T) perspective at 6 months and 12 months while using urate lowering therapy (ULT): allopurinol, febuxostat, and/or benzbromarone.
All gout patients visiting the Rheumatology department between 2015 to 2021 were identified from the digital hospital system. The diagnosis of gout was based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2015 classification criteria. Patient outcomes were predefined intention to treat (ITT) categories: category 1: patients with serum uric acid (sUA) ≤ 0.360 mmol/L (ACR target for gout); category 2: patients with sUA ≤ 0.300 mmol/L (ACR/EULAR target for severe gout); category 3: patients with sUA > 0.360 (failure to meet ACR target).
Gout diagnoses were present in 1,186 patients: 986 (83.1%) males and 200 (16.9%) females. A follow-visit at 6 months was present in 76.9% (n = 856) out of 1,113 patients reaching sUA < 0.36 mmol/L, but 257 (23%) failed to reach the 0.36 mmol/L target. At 12 months, a follow-up visit was available in 792 (71.1%) patients, and from these, 710 (90%) had reached sUA < 0.36 mmol/L target. The use of benzbromarone was a strong predictor of reaching the sUA < 0.30 mmol/L target: odds ratio (OR) 3.2, 95% confidence interval (CI) (1.735, 6.017) at 6 months. Diabetic patients had the highest proportion of not reaching the target: 18%. Male patients needed higher dosages of allopurinol to reach the sUA target at 6 months compared to female patients.
This is a large study on a T2T approach based in a real-life clinical setting. Only 42% reached the sUA target at 6 months with allopurinol 300 mg quaque die (QD) monotherapy. About 77% of gout patients reach the predefined sUA target of 0.36 mmol/L at 6 months with the availability of three ULTs. There is still a significant unmet need in gout as many patients failed to achieve predefined sUA targets.
Alcohol drinks, especially wine, have been described since 6,000 B.C. For many years in modern medicine, wine in moderation has been considered healthy for cardiovascular prevention, i.e., recommended by nutrition committees. Some regional guidelines still recommend one to two standard drinks per day. By the very recent (January 2023), World Health Organization and Canadian Guidance on alcohol emphasize that any alcoholic drink is hazardous to the health and the safe amount is zero. The risk starts with every single drop. It was also nicely summarized in the manuscript “Alcohol-dose question and the weakest link in a chemical interplay” (Explor Cardiol. 2023;1:15–25. doi: 10.37349/ec.2023.00003) especially from the standpoint of a researcher in the cardiovascular arena. The newest recommendations are based on observational studies and their meta-analysis, therefore establishing associations, pointing out that alcohol may somewhat prevent cardiovascular diseases and diabetes type 2, but with a significant increase in non-cardiovascular morbidity and mortality, especially cancers. Previous recommendations, therefore, may be obsolete as they were based on studies where abstainers from alcoholic beverages had inherent higher risks. The current controversy with conflicting guidelines for alcoholic beverage consumption in the era of precision medicine may stimulate more fundamental investigations up to genetic ones and find the cause-effect relations. In the era of precision medicine, it may come closer to discovering the causes of cancers and many other diseases, enabling predictions of reactions to alcoholic beverages by each person, not just in the population.
One of the major causes of death on the globe is cancer. The fourth most frequent malignancy in women worldwide is cervical cancer. Several cancer patients are remaining incurable due to the emergence of medication resistance, despite notable advances in cancer research over the previous few decades. The importance of natural sources as possible therapeutic candidates may be significant. Anthraquinones are one of the many chemical families of natural products, and they stand out for their wide range of structural variations, notable biological activity, and low toxicity. A natural substance called emodin, an anthraquinone derivative, is present in the roots and rhizomes of several plants. This substance has demonstrated antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative properties. It is also capable of preventing cancer spread and can reverse cancer cells’ multidrug resistance. Emodin, a broad-spectrum inhibitor of cancer cells, have anticancer properties in many different types of biological pathways. These molecular mechanisms in cancer cells include the suppression of cell growth and proliferation, deterioration of the cell cycle arrest, the start of apoptosis, antimetastasis, and antiangiogenic impact. Therefore, the aim of the present review summarised the antiproliferative and anticarcinogenic qualities of cervical cancer of emodin.
The aim of this study was to compare initial and final exercise tolerance and to evaluate the determinants of exercise capacity improvement—after three weeks of inpatient cardiac rehabilitation.
A cohort of 494 patients after acute coronary syndrome (ACS), treated with primary coronary angioplasty (age 60 years ± 10 years, 27.5% women) was studied retrospectively. Possible correlations between improvement and age, gender, body mass index (BMI), left ventricular ejection fraction (LVEF) and the initial exercise capacity (EXT1) were assessed.
The highest percentage of patients with improvement (43.6%) was in the medium tercile of LVEF (> 42% but ≤ 50%) and was more likely in the medium tercile of initial exercise tolerance [> 5.7 but ≤ 8.4 metabolic equivalent of tasks (METs)]. Receiver-operator characteristic (ROC) curves were developed and the following cut-off values were found: for LVEF > 43% (this value had 69.6% sensitivity in predicting improvement; the chance of improvement was 2.67 higher than in patients with LVEF ≤ 43%); for EXT1 ≤ 8.4 METs (this value had 70.8% sensitivity, the chance of improvement was 1.86 higher than in the other subgroup). No significant relationship between improvement and gender, age or BMI was found.
The combination of LVEF > 43% and EXT1 ≤ 8.4 METs relates to the highest probability of exercise tolerance improvement after cardiac rehabilitation.
Precision oncology is a rapidly evolving field that uses advanced technologies to deliver personalized cancer care based on a patient’s unique genetic and clinical profile. The use of artificial intelligence (AI) in precision oncology has shown great potential to improve diagnosis, treatment planning, and treatment outcomes. However, the integration of AI in precision oncology also raises important ethical considerations related to patient privacy, autonomy, and protection from bias. In this opinion paper, an overview is provided of previous studies that have explored the use of AI in precision oncology and the ethical considerations associated with this technology. The conclusions of these studies are compared, and the importance of approaching the use of AI in precision oncology with caution is emphasized. It is stressed that patient privacy, autonomy, and protection from bias should be made central to the development and use of AI in precision oncology. Clear guidelines and regulations must be established to ensure that AI is used ethically and for the benefit of patients. The use of AI in precision oncology has the potential to revolutionize cancer care, but it should be ensured that it striked a balance between advancements in technology and ethical considerations. In conclusion, the use of AI in precision oncology is a promising development that has the potential to improve cancer outcomes. However, ethical considerations related to patient privacy, autonomy, and protection from bias must be central to the development and use of AI in precision oncology.
As far as is known, the pharmaceutical effects of neem on human B-lymphoblastoid (TK6) cells have not been studied until now. Hence, the present study aimed to obtain neem phenolic extracts for inhibits the proliferation of TK6 cells and explore some possible underlying mechanisms involved in these effects.
Hexane extract (HE) was obtained in the first step. After that, the residual hexane was removed from the neem. The dried neem sample was used in a new extraction for obtaining the ethyl acetate extract (EAE). Total phenolic compounds (TPC) and total flavonoid contents (TFC) were determined by spectrophotometric methods. Lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to evaluate the cytotoxicity in TK6 cells. The stop at G0/G1 cell cycle and inducing apoptosis in the TK6 cells were analyzed by flow cytometry. For deoxyribonucleic acid (DNA) damage evaluation, the alkaline comet test was used.
The higher TFC (65.50 mg/g of extract ± 1.17 mg/g of extract) and TPC (52.08 mg of extract ± 0.88 mg of extract) were obtained in EAE compared to HE that was obtained TFC of 14.61 mg/g of extract ± 0.60 mg/g of extract and TPC of 3.20 mg/g of extract ± 1.20 mg/g of extract. EAE was more significantly cytotoxic to TK6 cells than HE. The apoptosis induction was higher after exposure to 15.0 µg/mL of EAE (11.29%) in comparison to 15.0 µg/mL of HE (2.52%). The G0/G1 phase increased from 72% negative control (NC) to 83% after treatment with neem extracts (15 µg/mL). Neem extracts were also able to cause DNA strand breaks in TK6 cells.
The extraction residue from neem leaf after hexane extraction is a source important of cytotoxic and genotoxic molecules against TK6 cells, the results also can suggest that the toxic effects in TK6 cells can be provided most likely due to the presence of high content of TPC from neem extracts.
Accurate lupus anticoagulant (LA) detection is crucial to antiphospholipid syndrome (APS) diagnosis. Detection is based on LA functional behavior in coagulation assays irrespective of epitope specificity. LA screening tests employ dilute phospholipids to accentuate in vitro inhibition by LAs, although they are not LA-specific and can be elevated by other coagulation abnormalities. Elevated screening tests are reflexed to mixing tests to distinguish between factor deficiency and inhibition. Confirmatory tests with high phospholipid concentration swamp LA to generate shorter clotting times than screening tests, whilst prolongation persists with non-phospholipid-dependent inhibitors. LA heterogeneity means that no single screening test detects every LA and the screen/mix/confirm medley must be applied to at least two assay types, usually dilute Russell’s viper venom time (dRVVT) and an LA-sensitive activated partial thromboplastin time (aPTT). Most laboratories restrict LA testing to these two assays, yet others, such as dilute prothrombin time (dPT), can perform with equal diagnostic efficacy, and additionally detect LA unreactive with dRVVT and aPTT. Converting clotting times to normalized ratios improves assay performance, and practitioners must choose between normal pooled plasma (NPP) clotting time denominators to reflect on-the-day assay performance, or reference interval (RI) mean clotting times to negate the effects of NPP variation. Cut-offs can be generated parametrically from normally distributed data, or different percentiles applied depending on the preferred balance between sensitivity and specificity. Sourcing sufficient donors for accurate cut-off estimations is problematic and transference exercises can be undertaken on low donor numbers. Analytical limitations of mixing tests have led to the adoption of alternative algorithms to the screen/mix/confirm test order, whilst some continue to rigidly apply the latter despite those limitations. Strategies to reduce or eliminate the effects of therapeutic anticoagulation have limitations, whilst the Taipan snake venom time (TSVT) screening test with an ecarin time (ET) confirmatory test is insensitive to vitamin K antagonist (VKA) and direct activated factor X anticoagulation.
Flavonoids present a large group of natural polyphenols with numerous important health benefits for preventing and treating a diverse variety of pathological conditions. However, the actual therapeutic use of these phytochemicals is impeded by their low oral bioavailability. In this commentary article, an interesting paradox is presented: while the ingested flavonoid glycosides can be absorbed by means of sodium-dependent glucose transporters (SGLTs; SGLT1) located in the brush border membrane facing the lumen of the small intestine, certain flavonoid aglycones are able to inhibit these shuttle proteins. It is expected that avoiding the co-intake of such SGLT1 inhibitors concomitantly with flavonoid-rich foods might provide a new option for enhancing the oral bioavailability of flavonoids, thereby preventing the transport of unabsorbed compounds to the large intestine and conversion into catabolites by the colonic microbiota. Altogether, the administration of flavonoids in appropriate combinations is highlighted for getting the maximal health benefits from consuming these bioactive compounds.
Diffuse idiopathic skeletal hyperostosis (DISH) can lead to dysphagia, airway obstruction, and unstable vertebral fractures. Surgery can be performed to relieve cervical compression or stabilize fractures of the spinal column, with or without decompression of spinal cord injuries. In this review, the peri-operative surgical techniques in cases with DISH are discussed, as well as the pre-operative and post-operative pearls and pitfalls. It is essential for spine surgeons, including orthopedic surgeons and neurosurgeons, to be aware of the considerations, anticipations, and approaches for the management of dysphagia, airway obstruction, and fractures in DISH patients in order to improve patient outcomes for this specific at-risk patient population.
The significance of β-amyloid protein as a key player in neuro-degenerative disorders viz. Alzheimer’s disease (AD), Parkinson’s disease (PD) has been extensively researched and reported. Glaucoma being another prominent form of neuro-degeneration involving the loss of retinal ganglion cells (RGCs) and human trabecular meshwork (HTM) cells, is also found to be similar to AD in many aspects, but its relation with β-amyloid has not been studied too far up to understanding its causation and pathogenesis where β-amyloid is expected to play important role. This study is an attempt to evaluate the chances of β-amyloid’s role in pathogenesis of retinal neurodegenerative disorder called glaucoma, in silico.
The study involved determination of feasibility of interaction between β-amyloid and well known glaucoma related proteins namely, myocilin and optineurin. The computational tool called Hex 8.0.0 has been used in this work.
The docking score for β-amyloid and myocilin was found to be –724.1 kJ mol–1 while that for β-amyloid and wild-type optineurin pair was found to be –296.9 kJ mol–1 and that for β-amyloid and mutated optineurin was –607.1 kJ mol–1.
Interaction of β-amyloid with myocilin and optineurin in both forms (wild-type and mutated) is quite energetically favorable. The binding between β-amyloid and mutated optineurin is higher in comparison to that between β-amyloid and wild-type optineurin. Thus, functional significance of β-amyloid in glaucoma pathogenesis is fairly possible which should be studied and proved through in vitro and in vivo studies.
In Europe, allergen products from different manufacturers can be labeled using the same unit with yet different definitions of that unit, which may cause confusion, as is the case for the index of reactivity (IR). In this context, house dust mite (HDM) Staloral 300 IR/mL, from Stallergenes Greer, and HDM Osiris 300 IR/mL, from ALK-Abelló, were characterized in vitro. Qualitatively, namely in terms of protein and allergen profiles, the two products were similar. Quantitatively, and despite the same 300 IR/mL labeling, the two products were shown to have different biological potencies, with HDM Staloral 300 IR/mL displaying a 2.4 times higher total allergenic activity (TAA) than HDM Osiris 300 IR/mL. This higher biological potency of HDM Staloral 300 IR/mL was paralleled by higher allergen and protein contents, namely 1.5 times more Der p 1 and Der f 1, 3.0 times more group 2 allergens, 2.7 times more Der p 23, and 1.8 times more protein. In contrast, HDM Staloral 300 IR/mL was shown to contain far fewer culture medium-derived proteins than HDM Osiris 300 IR/mL.
This study aimed to isolate, characterize, and encapsulate a lupeol-rich fraction obtained from the hexanic extract of Coccoloba uvifera L. leaves to evaluate its potential use in nutraceutical or pharmaceutical applications.
The C. uvifera leaf extract was fractionated by column chromatography and the presence of lupeol was assessed by thin layer chromatography, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, nuclear magnetic resonance (NMR), and liquid chromatography-mass spectrometry (LC-MS). Additionally, the lupeol-rich fraction was characterized according to its antioxidant capacity and cytotoxicity. Finally, this fraction was encapsulated into electrospun nanofibers made of high degree of polymerization agave fructans (HDPAF) combined with polyethylene oxide (PEO). The obtained nanofibers were characterized in terms of morphology, chemical composition, and in vitro permeability using the Caco-2 cell line.
Fraction 6 showed a 77% of lupeol, quantified by chromatography, and presented a 7.3% inhibition of 2,2-diphenyl-1-picrylhydrazyl (DPPH). 100 µg/mL of fraction 6 showed a decrease in Caco-2 cell viability. Finally, fraction 6 was encapsulated into electrospun nanofibers, which showed an increase in the apparent permeability of the lupeol present in fraction 6 in Caco-2 cells in comparison to neat fraction 6.
It was possible to isolate and encapsulate a lupeol-rich fraction from C. uvifera into electrospun nanofibers, which allows the increasing the apparent permeability of lupeol, and consequently, they could be used for nutraceutical or pharmaceutical applications.
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a rare chronic autoimmune cholestatic liver disease, affecting mostly females. With PBС develops chronic cholangiopathy, this is accompanied by the development of gradually progressive liver fibrosis, which leads to intrahepatic cholestasis. Defects in autoimmune tolerance are critical factors in the emergence of the disease. Biochemical signs in PBС appear already in the asymptomatic stage of the disease and they are associated with a disturbance of the secretion of bile acids. Understanding the pathophysiological mechanisms of these signs is essential to both the early diagnosis and treatment of PBC. Early diagnosis of the disease contributes to its more effective treatment. There are many scientifically based modern data on the pathophysiology of clinical and laboratory signs developing in PBС. The purpose of this review is to summarize the data available in the literature and those obtained by the authors on the mechanisms for the development of biochemical criteria for PBC and their diagnostic significance. The opportunity to present the pathophysiological mechanisms of the development of biochemical signs in patients with PBC is associated with the success in the development of modern research methods in biochemistry, molecular biology, and genetics.
Early diagnosis of paediatric brain tumors significantly improves the outcome. The aim is to study magnetic resonance imaging (MRI) features of paediatric brain tumors and to develop an automated segmentation (AS) tool which could segment and classify tumors using deep learning methods and compare with radiologist assessment.
This study included 94 cases, of which 75 were diagnosed cases of ependymoma, medulloblastoma, brainstem glioma, and pilocytic astrocytoma and 19 were normal MRI brain cases. The data was randomized into training data, 64 cases; test data, 21 cases and validation data, 9 cases to devise a deep learning algorithm to segment the paediatric brain tumor. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the deep learning model were compared with radiologist’s findings. Performance evaluation of AS was done based on Dice score and Hausdorff95 distance.
Analysis of MRI semantic features was done with necrosis and haemorrhage as predicting features for ependymoma, diffusion restriction and cystic changes were predictors for medulloblastoma. The accuracy of detecting abnormalities was 90%, with a specificity of 100%. Further segmentation of the tumor into enhancing and non-enhancing components was done. The segmentation results for whole tumor (WT), enhancing tumor (ET), and non-enhancing tumor (NET) have been analyzed by Dice score and Hausdorff95 distance. The accuracy of prediction of all MRI features was compared with experienced radiologist’s findings. Substantial agreement observed between the classification by model and the radiologist’s given classification [K-0.695 (K is Cohen’s kappa score for interrater reliability)].
The deep learning model had very high accuracy and specificity for predicting the magnetic resonance (MR) characteristics and close to 80% accuracy in predicting tumor type. This model can serve as a potential tool to make a timely and accurate diagnosis for radiologists not trained in neuroradiology.
In patients with autoimmune coagulation factor deficiency (AiCFD), the production of autoantibodies that inhibit coagulation factors in the blood reduces the activity of those relevant coagulation factors, resulting in severe bleeding symptoms. Recently, reports of patients with AiCFD have noted the concomitant detection of lupus anticoagulant (LA), a risk factor for thrombosis. LA-positive patients may show bleeding symptoms due to decreased activity of coagulation factor II (FII) caused by autoantibodies against FII, in addition to thrombotic symptoms, a condition termed LA-hypoprothrombinemia syndrome (LAHPS). Anti-FII antibodies in LAHPS cases are frequently cleared antibodies that can be detected using immunological techniques, such as enzyme-linked immunosorbent assay (ELISA). Recently, several cases of coagulation FV inhibitors, known as autoimmune FV deficiency, have been reported. Some of these cases may be complicated by LA, which can cause thrombosis. False-positive results for anticoagulant inhibitors are known to occur in LA cases; therefore, immunological confirmation of antibodies against coagulation factors is recommended. Additionally, acquired hemophilia A (AHA), caused by autoantibodies against FVIII, is a typical acquired hemorrhagic diathesis, although affected patients may present with thrombosis associated with LA. Thus, it is important to remember that hemorrhagic diathesis due to autoantibodies against clotting factors can also result in thrombosis, as demonstrated by the co-detection of LA. When clotting factor inhibitors are detected in LA-positive individuals, it is important to confirm the presence of autoantibodies against coagulation factors using immunological methods, such as ELISA, to avoid false-positive results.
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.
The emergence and re-emergence of pathogens is a public-health concern, which has become more evident after the coronavirus disease 2019 (COVID-19) pandemic and the monkeypox outbreaks in early 2022. Given that vaccines are the more effective and affordable tools to control infectious diseases, the authors reviewed two heterologous effects of vaccines: the trained immunity and the cross-reactivity. Trained immunity, provided by attenuated vaccines, was exemplified in this article by the decreased the burden of COVID-19 in populations with high Bacille Calmette-Guerin (BCG) coverage. Cross-reactive responses were exemplified here by the studies which suggested that vaccinia could help controlling the monkeypox outbreak, because of common epitopes shared by orthopoxviruses. Although modern vaccination is likely to use subunit vaccines, the authors discussed how adjuvants might be the key to induce trained immunity and improve cross-reactive responses, ensuring that heterologous effects would improve the vaccine’s response.
The aim of this study was to investigate the feasibility of developing a deep learning (DL) algorithm for classifying brain metastases from non-small cell lung cancer (NSCLC) into epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement groups and to compare the accuracy with classification based on semantic features on imaging.
Data set of 117 patients was analysed from 2014 to 2018 out of which 33 patients were EGFR positive, 43 patients were ALK positive and 41 patients were negative for either mutation. Convolutional neural network (CNN) architecture efficient net was used to study the accuracy of classification using T1 weighted (T1W) magnetic resonance imaging (MRI) sequence, T2 weighted (T2W) MRI sequence, T1W post contrast (T1post) MRI sequence, fluid attenuated inversion recovery (FLAIR) MRI sequences. The dataset was divided into 80% training and 20% testing. The associations between mutation status and semantic features, specifically sex, smoking history, EGFR mutation and ALK rearrangement status, extracranial metastasis, performance status and imaging variables of brain metastasis were analysed using descriptive analysis [chi-square test (χ2)], univariate and multivariate logistic regression analysis assuming 95% confidence interval (CI).
In this study of 117 patients, the analysis by semantic method showed 79.2% of the patients belonged to ALK positive were non-smokers as compared to double negative groups (P = 0.03). There was a 10-fold increase in ALK positivity as compared to EGFR positivity in ring enhancing lesions patients (P = 0.015) and there was also a 6.4-fold increase in ALK positivity as compared to double negative groups in meningeal involvement patients (P = 0.004). Using CNN Efficient Net DL model, the study achieved 76% accuracy in classifying ALK rearrangement and EGFR mutations without manual segmentation of metastatic lesions. Analysis of the manually segmented dataset resulted in improved accuracy of 89% through this model.
Both semantic features and DL model showed comparable accuracy in classifying EGFR mutation and ALK rearrangement. Both methods can be clinically used to predict mutation status while biopsy or genetic testing is undertaken.
The aim of this study is to apply untargeted proton nuclear magnetic resonance (1H NMR) and chemometric analysis to obtain the cacao pod husk (CPH) fingerprint and evaluate the effect of dehydration in the CPH metabolome.
Phosphate buffer extracts (pH 6.5) were obtained and measured using a one-dimension (1D) 1H NMR spectrometry. The 1D 1H NMR spectra were recorded without spinning and using the presaturation (PRESAT) pulse sequence to suppress the residual H2O signal. The 3-(trimethylsilyl) propionic-2,2,3,3-d4 acid sodium salt (TSP) was used as an internal reference. Analysis of processed data, applying an orthogonal projection on latent structure-discriminant analysis (OPLS-DA) model was used to highlight significant differences between the three dehydration treatments. Signal assignment of CPH metabolites was carried out based on the coupling constant, software simulation prediction, published data comparison, and metabolomics databases.
A total of 25 compounds were detected by 1H NMR, methylxanthines, sugars, some amino acids, fatty acids, and organic acids were found among the identified compounds. The fingerprint spectra of the three dehydration methods were clustered separately discriminating the metabolome profile of each of the dehydration treatments, finding that metabolome remarkably differed in theanine, myristic acid, fumaric acid, and aspartic acid composition.
An untargeted metabolomics to obtain the fingerprint of CPH was successfully established. A 1H NMR spectra with a detailed signal assignment aided to identify 25 metabolites present in CPH fresh and dried by different methods. The results complement the information about CPH composition and how it is affected by the temperature used during the dehydration process. The multivariate analysis points out that freeze drying (FD) preserves the metabolites better than microwave drying (MWD) or hot air drying (HAD). FD and MWD are similar in composition maintaining most of the compounds after drying.
Parkinson’s disease (PD) is a prevalent neurodegenerative disease (NDD) affecting millions of individuals. The pathogenesis of PD centers around α-synuclein (α-Syn), a pivotal protein whose aggregation significantly impacts disease progression. Although existing treatments mainly focus on managing motor symptoms by targeting the dopaminergic system, they frequently overlook other non-motor symptoms. The intricate nature of PD pathogenesis contributes to challenges in disease analysis and has hindered the development of effective PD treatments. In recent years, various novel therapies utilizing immunotherapy methods have exhibited promise in preclinical animal models. In NDDs, immunotherapy aims to counteract the detrimental effects of protein accumulation by neutralizing toxic species and aiding their elimination. Numerous active therapy (AI) and passive immunotherapy (PI) strategies have been devised for PD and related synucleinopathies, many of which are currently undergoing clinical trials. Despite demonstrating remarkable success in animal models, immunotherapies encountered substantial setbacks during the late stages of clinical trials, with the exception of lecanemab, which targets amyloid-β (Aβ) in Alzheimer’s disease (AD) and has recently received approval from the Food and Drug Administration (FDA). The lack of translation from experimental investigations to successful clinical outcomes, particularly in terms of cognitive and functional evaluations, highlights the limitations of relying solely on animal studies to comprehend the effects of immunotherapeutic approaches. This comprehensive review focuses on α-Syn-based immunotherapies and delves into their underlying mechanisms of action. Furthermore, Furthermore, the article discusses recent advancements and future prospects concerning the potential of immunotherapeutic strategies for PD. The focus is on highlighting the latest research in this domain to illuminate the challenges and opportunities related to the development of efficacious immunotherapies for individuals with PD.
Amyotrophic lateral sclerosis (ALS) is the most prevalent type of motor neuron disease (MND) and is diagnosed with a delay from the first appearance of symptoms. Surrogate markers that may be used to detect pathological changes before a significant neuronal loss occurs and allow for early intervention with disease-modifying therapy techniques are desperately needed. Using water molecules that diffuse within the tissue and experience displacement on the micron scale, diffusion magnetic resonance imaging (MRI) is a promising technique that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, axonal density, order, and myelination. Diffusion tensor imaging (DTI) is the primary diffusion MRI technique used to evaluate the pathogenesis of ALS. Neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI), and free water elimination DTI (FWE-DTI) are only a few of the approaches that have been developed to overcome the shortcomings of the diffusion tensor technique. This article provides a summary of these methods and their potential as surrogate markers for detecting the onset of ALS at an early stage.
The management of symptomatic chronic subdural hematoma (CSDH) is surgical evacuation and prognosis in most cases is good. Tension pneumocephalus is the presence of air under pressure in the intracranial cavity. A case of tension pneumocephalus developing as a complication of burr hole evacuation of CSDH is illustrated. In this case, tension pneumocephalus was managed by reopening the wound and saline irrigation with a subdural drain placement. Considering this case report and after a careful review of the literature, the physiopathology, diagnosis, and treatment of this complication are highlighted in the article.
A high consumption of ultra-processed food (UPF) is a hallmark of Western diets that has been related to increased risk of non-communicable diseases. As an underlying mechanism, UPF may promote non-alcoholic fatty liver disease (NAFLD) which is a key driver of metabolic impairment with extra-hepatic manifestations like type 2 diabetes, cardiovascular disease, chronic kidney disease, and osteoporosis among others. The present review provides an overview of UPF properties that may promote NAFLD and are thus potential targets for reformulation of UPF. Such approaches should address improvements in the quality of carbohydrates and fat, changes in food texture that lower eating rate as well as ingredients that prevent excess caloric intake or avoid dysbiosis and leaky gut syndrome. Promising strategies are enrichment with fiber, prebiotics, phytochemicals, and protein with a concurrent reduction in glycemic load, energy density, saturated fatty acids (FA; SFA), emulsifiers, fructose, and non-caloric sweeteners. Future studies are needed to examine the interactive and protective effects of such modifications in the composition of UPF on prevention and treatment of NAFLD.
Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by adult-onset asthma, chronic rhinosinusitis with nasal polyps (CRSwNPs), and aspirin/NSAID hypersensitivity, presenting recurrent asthma exacerbation and poor clinical outcomes. Patients with NERD have heterogeneous clinical phenotypes/endotypes, and the management of NERD remains challenging. Dysregulation of arachidonic acid (AA) metabolism and persistent eosinophilic airway inflammation are the major pathogenic mechanisms in the upper and lower airways of NERD. To date, increased levels of urinary leukotriene E4 (uLTE4) [a terminal metabolite of the lipoxygenase (LOX) pathway] have been the most relevant biomarker for NERD. It is demonstrated that mast cells, platelets, and epithelial cells can amplify upper and lower airway inflammation in NERD, and several potential biomarkers based on these complicated and heterogeneous mechanisms have been suggested. This review summarizes potential biomarkers for application in the management of NERD.
Cancer stem-like cells (CSCs) identified by self-renewal ability and tumor-initiating potential are responsible for tumor recurrence and metastasis in many cancers. Conventional chemotherapy fails to eradicate CSCs that hold a state of dormancy and possess multi-drug resistance. Spurred by the progress of nanotechnology for drug delivery and biomedical applications, nanomedicine has been increasingly developed to tackle stemness-associated chemotherapeutic resistance for cancer therapy. This review focuses on advances in nanomedicine-mediated therapeutic strategies to overcome chemoresistance by specifically targeting CSCs, the combination of chemotherapeutics with chemopotentiators, and programmable controlled drug release. Perspectives from materials and formulations at the nano-scales are specifically surveyed. Future opportunities and challenges are also discussed.
Epidermal growth factor receptor (EGFR) is one of the most well-studied oncogenes with roles in proliferation, growth, metastasis, and therapeutic resistance. This intense study has led to the development of a range of targeted therapeutics including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and nanobodies. These drugs are excellent at blocking the activation and kinase function of wild-type EGFR (wtEGFR) and several common EGFR mutants. These drugs have significantly improved outcomes for patients with cancers including head and neck, glioblastoma, colorectal, and non-small cell lung cancer (NSCLC). However, therapeutic resistance is often seen, resulting from acquired mutations or activation of compensatory signaling pathways. Additionally, these therapies are ineffective in tumors where EGFR is found predominantly in the nucleus, as can be found in triple negative breast cancer (TNBC). In TNBC, EGFR is subjected to alternative trafficking which drives the nuclear localization of the receptor. In the nucleus, EGFR interacts with several proteins to activate transcription, DNA repair, migration, and chemoresistance. Nuclear EGFR (nEGFR) correlates with metastatic disease and worse patient prognosis yet targeting its nuclear localization has proved difficult. This review provides an overview of current EGFR-targeted therapies and novel peptide-based therapies that block nEGFR, as well as their clinical applications and potential for use in oncology.
Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins’ anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential “hallmark of cancer” required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation.
Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher’s interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed.
Asthma is a chronic condition characterized by inflammation throughout the entire bronchial airways. Recent findings suggest that ventilation inhomogeneity and small airway dysfunction (SAD) play a particularly significant role in asthma development and clinical manifestations. Obesity is a considerable risk factor for asthma development and morbidity in children and adults. A growing body of evidence suggests that SAD is linked to more severe asthma and poor asthma control in obese patients. However, the knowledge about the relationship between peripheral airway compromise and obesity in asthma is limited, mainly because of the historical lack of access to non-invasive assessment methods for studying SAD. Conventional lung function measurements, like spirometry, cannot accurately assess small airway function. However, in recent years, new specialized tests available in outpatient settings have been found to distinguish SAD from large airway obstruction more accurately compared to spirometry. Therefore, understanding the degree of peripheral airway implication in the underlying pathology is critical for effective asthma control and therapeutic decisions. This review highlights recent findings on the impact of SAD on asthma patients who are obese. Additionally, it explores how new diagnostic methods, such as impulse oscillometry (IOS), may be used in outpatient settings to detect small airway impairment in obese asthma at an early stage, potentially leading to improved asthma treatment.
Cancer is a fatal disease and the second most cause of death worldwide. Treatment of cancer is a complex process and requires a multi-modality-based approach. Cancer detection and treatment starts with screening/diagnosis and continues till the patient is alive. Screening/diagnosis of the disease is the beginning of cancer management and continued with the staging of the disease, planning and delivery of treatment, treatment monitoring, and ongoing monitoring and follow-up. Imaging plays an important role in all stages of cancer management. Conventional oncology practice considers that all patients are similar in a disease type, whereas biomarkers subgroup the patients in a disease type which leads to the development of precision oncology. The utilization of the radiomic process has facilitated the advancement of diverse imaging biomarkers that find application in precision oncology. The role of imaging biomarkers and artificial intelligence (AI) in oncology has been investigated by many researchers in the past. The existing literature is suggestive of the increasing role of imaging biomarkers and AI in oncology. However, the stability of radiomic features has also been questioned. The radiomic community has recognized that the instability of radiomic features poses a danger to the global generalization of radiomic-based prediction models. In order to establish radiomic-based imaging biomarkers in oncology, the robustness of radiomic features needs to be established on a priority basis. This is because radiomic models developed in one institution frequently perform poorly in other institutions, most likely due to radiomic feature instability. To generalize radiomic-based prediction models in oncology, a number of initiatives, including Quantitative Imaging Network (QIN), Quantitative Imaging Biomarkers Alliance (QIBA), and Image Biomarker Standardisation Initiative (IBSI), have been launched to stabilize the radiomic features.
Hepatocellular carcinoma (HCC) constitutes an extremely malignant form of primary liver cancer. Intricate connections linking to the immune system might be associated with the pathogenesis of HCC. Meanwhile, immunotherapy with immune checkpoint inhibitors has been established to be a favorable therapeutic possibility for advanced HCC. Although curative opportunities for advanced HCC are restricted, the immune checkpoint immunotherapy has developed as the main choice for treating HCC. However, patients with metabolic-associated fatty liver disease (MAFLD)-linked HCC might be less likely to benefit from the immunotherapy alone. The limitation of the effect of the immunotherapy might be owing to the impaired T cell activation in MAFLD patients, which could be well explained by a dysfunctional gut-liver axis. Gut microbiota and their metabolites including several bile acids could contribute to modulating the responses of the immune checkpoint immunotherapy. Roles of gut microbiota in the development of cancers have expected great interest in the latest studies. Here, an interplay between the gut and liver has been presented, which might suggest to affect the efficacy of immune checkpoint immunotherapy against HCC.
The deleterious consequences of alcohol consumption are extensively documented across various dimensions of human health, encompassing somatic disorders such as nervous system impairments, digestive system abnormalities, and circulatory dysfunctions, in addition to socio-psychological aspects. Within the domain of cardiology, a substantial portion of the ongoing scientific discourse centers on elucidating the toxic dose of alcohol. Presented herewith are the findings from a comprehensive review of the latest publications pertinent to this crucial issue.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the coronavirus disease 2019 (COVID-19), was declared a pandemic in early 2020. During the past time, several infections control methods have been developed. Nevertheless, all of them have certain limitations: uncertainty in duration, limited efficacy of vaccines, and lack of effective drugs for COVID-19 treatment. So, the issue of creating drugs for symptomatic and etiotropic therapy is still relevant. This review summarizes the current knowledge of using natural compounds as anti-SARS-CoV-2 agents by analysing the results of in vitro studies and completed clinical trials (CTs). Also, this work highlighted the most active molecules and discussed the possibility of using some compounds in clinical practice.
Digital technologies have garnered more attention in this epoch of public health emergencies like coronavirus disease 2019 (COVID-19) and monkeypox (mpox). Digital twin (DT) is the virtual cybernetic equivalent of a physical object (e.g., a device, a human, a community) used to better understand the complexity of the latter and predict, prevent, monitor, and optimize real-world outcomes. The possible use cases of DT systems in public health ranging from mass vaccination planning to understanding disease transmission patterns have been discussed. Despite potential applications in healthcare, several economic, social, and ethical challenges might hinder the universal implementation of DT. Nevertheless, devising appropriate policies, reinforcing good governance, and launching multinational collaborative efforts ascertain early espousal of DT technology.
The coronavirus disease-2019 (COVID-19) pandemic is a significant threat in the modern era. Clinical studies show that the most common symptom of severe COVID-19 is viral pneumonia-induced acute respiratory distress syndrome (ARDS). The underlying mechanisms by which severe respiratory disease syndrome-coronavirus-2 (SARS-CoV-2) results in ARDS and how certain host factors confer an increased risk of developing severe disease remain unknown. Therefore, identifying the distinctive features of this severe and fatal disease and the therapeutic approaches to COVID-19-induced ARDS remains an immediate need to serve as a basis for best practice models of standardized ARDS treatment. This review article aims to comprehensively discuss the immunopathology of ARDS and provides an overview of the precise role of both the innate and adaptive immune system, with emphasis on the current treatment strategies being tested in the COVID-19-induced ARDS patients. This knowledge will supposedly help in revealing further mechanistic insights into understanding COVID-19-induced ARDS.
Nonalcoholic fatty liver disease (NAFLD), its more rapidly progressive steatohepatitic variant [nonalcoholic steatohepatitis, (NASH)], and the recently defined metabolic dysfunction-associated fatty liver disease (MAFLD) may be collectively alluded to as “metabolic fatty liver syndromes” (MFLS). MFLS is a common clinical complaint for which no licensed drug treatment is available and a public health issue posing a heaven burden on healthcare systems. Iron plays a key role in many of the key pathogenic steps concurring in the development and progression of MFLS, notably including genetics, intestinal dysbiosis, adipositis, insulin resistance, metaflammation, oxidative stress and ferroptosis, endoplasmic reticulum stress, and hepatic fibrosis. This notion raises the logical expectation that iron depletion, which can easily be implemented with venesection, might improve several aspects of MFLS. However, few published studies have globally failed to support these expectations. In conclusion, venesection in MFLS exhibits a strong biological rationale and possible metabolic benefits. However, confronted with failures in hepato-histological outcomes, data call for additional studies aimed to reconcile these inconsistencies.
Despite recent advancements in the field of neuro-ophthalmology, the rising rates of neurological and ophthalmological conditions, mismatches between supply and demand of clinicians, and an aging population underscore the urgent need to explore new therapeutic approaches within the field. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), traditionally used in the treatment of type 2 diabetes, are becoming increasingly appreciated for their diverse applications. Recently, GLP-1RAs have been approved for the treatment of obesity and recognized for their cardioprotective effects. Emerging evidence indicates some GLP-1RAs can cross the blood-brain barrier and may have neuroprotective effects. Therefore, this article aims to review the literature on the neurologic and neuro-ophthalmic role of glucagon-like peptide 1 (GLP-1). This article describes GLP-1 peptide characteristics and the mechanisms mediating its known role in increasing insulin, decreasing glucagon, delaying gastric emptying, and promoting satiety. This article identifies the sources and targets of GLP-1 in the brain and review the mechanisms which mediate its neuroprotective effects, as well as implications for Alzheimer’s disease (AD) and Parkinson’s disease (PD). Furthermore, the preclinical works which unravel the effects of GLP-1 in ocular dynamics and the preclinical literature regarding GLP-1RA use in the management of several neuro-ophthalmic conditions, including diabetic retinopathy (DR), glaucoma, and idiopathic intracranial hypertension (IIH) are discussed.
Many small datasets of significant value exist in the medical space that are being underutilized. Due to the heterogeneity of complex disorders found in oncology, systems capable of discovering patient subpopulations while elucidating etiologies are of great value as they can indicate leads for innovative drug discovery and development.
Two small non-small cell lung cancer (NSCLC) datasets (GSE18842 and GSE10245) consisting of 58 samples of adenocarcinoma (ADC) and 45 samples of squamous cell carcinoma (SCC) were used in a machine intelligence framework to identify genetic biomarkers differentiating these two subtypes. Utilizing a set of standard machine learning (ML) methods, subpopulations of ADC and SCC were uncovered while simultaneously extracting which genes, in combination, were significantly involved in defining the subpopulations. A previously described interactive hypothesis-generating method designed to work with ML methods was employed to provide an alternative way of extracting the most important combination of variables to construct a new data set.
Several genes were uncovered that were previously implicated by other methods. This framework accurately discovered known subpopulations, such as genetic drivers associated with differing levels of aggressiveness within the SCC and ADC subtypes. Furthermore, phyosphatidylinositol glycan anchor biosynthesis, class X (PIGX) was a novel gene implicated in this study that warrants further investigation due to its role in breast cancer proliferation.
The ability to learn from small datasets was highlighted and revealed well-established properties of NSCLC. This showcases the utility of ML techniques to reveal potential genes of interest, even from small datasets, shedding light on novel driving factors behind subpopulations of patients.
In the past few years, artificial intelligence (AI) has been increasingly used to create tools that can enhance workflow in medicine. In particular, neuro-oncology has benefited from the use of AI and especially machine learning (ML) and radiogenomics, which are subfields of AI. ML can be used to develop algorithms that dynamically learn from available medical data in order to automatically do specific tasks. On the other hand, radiogenomics can identify relationships between tumor genetics and imaging features, thus possibly giving new insights into the pathophysiology of tumors. Therefore, ML and radiogenomics could help treatment tailoring, which is crucial in personalized neuro-oncology. The aim of this review is to illustrate current and possible future applications of ML and radiomics in neuro-oncology.
Systemic vasculitis is a heterogeneous group of disorders characterized by inflammation and necrosis in the vessel wall. Patients usually present a quite broad spectrum of manifestations which vary in terms of vessels’ size affected, organs involvement, and the extent of inflammatory process as well as an immunological diversity, including autoantibodies profile. Though, the diagnosis is based on clinical features, tissue biopsy, imaging investigations, and serologic tests. The main autoantibodies, important not only in the diagnosis but also in monitoring and prognosis of systemic vasculitides, are anti-neutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane antibodies (anti-GBM), anti-complement component C1q antibodies (anti-C1q), and cryoglobulins. Although other autoantibodies have been analyzed, their clinical utility still needs further investigation. The current work aimed to review the clinical associations of main autoantibodies in systemic vasculitis.
Left ventricular (LV) hypertrophy (LVH) is a common and relevant complication of arterial hypertension (AH) and 12-lead electrocardiogram (ECG) is widely used for its preliminary assessment. The aim of the study was to compare the correlations of four ECG-derived criteria of LVH and left atrial (LA) anteroposterior diameter with LVH assessed by echocardiography and expressed as left ventricular mass (LVM) index (LVMI) in search of the most accurate preliminary indicator of LVH.
The study included 61 subjects with AH [age (year) 69 ± 10, 17 females] and 27 without AH, (age 40 ± 9, 10 females) evaluated with 12-lead ECG and transthoracic echocardiography (TTE). As the ECG-based criteria of LVH Sokolow-Lyon index (SLI), Cornell voltage (CV), Cornell product (CP), and Romhilt-Estes point score (RES) system were evaluated. The ECG indices and LA diameter were correlated with LVMI and correlations coefficients were compared.
Among ECG-LVH indicators SLI showed the closest correlation with LVMI [rank correlation coefficients (rho) = 0.38, P < 0.0001], followed by CV and CP with rho = 0.33, P = 0.002 and rho = 0.32, P = 0.002, respectively, whereas RES did not correlate significantly with LVMI. The strongest correlation with LVMI was found for the LA diameter with rho = 0.73 and P < 0.0001, showing an even stronger correlation in women—rho = 0.8 (P < 0.0001) vs. rho = 0.65 (P < 0.0001) in men. In the multivariate analysis, the LA was the only independent predictor of the increased LVMI with R2 = 0.52, P < 0.0001.
LA diameter outperformed significantly the ECG indices as far as the correlation with LVMI was concerned and emerged as the only independent predictor of mild and moderate LVH in hypertensive patients. Among the ECG criteria, the strongest correlation was shown for SLI, followed by CV and CP indices.
Bochdalek hernia (BH) is a congenital diaphragmatic defect primarily diagnosed in neonates and is usually left-sided. Adult diagnosis, especially of right-sided BH is exceedingly rare and usually presents with symptoms. Till now, only 31 cases have been diagnosed to be right-sided BH along with intrathoracic kidney. This report presents a 26-year-old asymptomatic male who was incidentally diagnosed with a massive right congenital diaphragmatic hernia. Imaging revealed severe abdominal herniation, a right intrathoracic ectopic kidney, and a right liver lobe hypoplasty along with hypertrophied left liver lobe extending down to the pelvic cavity. Several surgeons were consulted, with controversial opinions on whether elective surgery should be performed or withheld. Due to the high risk associated with surgery and the patient’s choice, the surgery was deferred. For almost 18 months, the patient did not report any symptoms or complications. This case highlights the rarity of asymptomatic right-sided BH in adults and the challenges in determining a management approach. Also, it proposes a conservative approach for such patients as a management modality. Most extensive diagrammatic defect reported is estimated to have a neck defect of 10 cm. Most BH cases have been treated surgically and reports on the outcome of a conservative approach are exceedingly rare. In such cases, patient preferences and a thorough risk assessment play vital roles in decision-making regarding conservative versus surgical approaches.
The advent of biological drugs has opened up new therapeutic possibilities in the field of eosinophilic gastro-intestinal diseases (EGIDs). EGIDs are chronic inflammatory diseases of the gastrointestinal tract unrelated to drugs or infections, and eosinophilic esophagitis (EoE) is the most frequent form. EGIDs are complex disorders, which pathogenesis is still partially unknown. The diagnosis of EGIDs relies on the combination of different data, such as clinical manifestations, laboratory tests, endoscopic, and histological data. The gold standard at present is the histological examination obtained from biopsies under endoscopic guidance, but the diagnostic criteria for each disorder are still not fully defined, and few clinical scores are validated, for all these reasons, conducting clinical trials on EGIDs is challenging. The dietary approach remains currently a first-line treatment, despite its efficacy being influenced by patients’ compliance. Exclusion diets, nevertheless, involve potential nutritional deficiencies. Two of the pivotal pharmacological therapies for the treatment of EGIDs are proton pump inhibitors (PPIs), especially for EoE, and systemic or topical steroids. Long-term corticosteroid therapies are, however, associated with even severe side effects, so steroid-sparing therapies are needed to achieve the same results, in the last years monoclonal antibodies have been studied. To date, dupilumab is the only approved biological drug for EoE therapy, but many others are currently being tested in clinical trials also for the other forms of EGIDs. This work presents a complete review of the role of biological drugs in EGIDs to date, systematically structured by pathology.
To identify constitutional morphological features at the knee that associate with knee osteoarthritis (OA, KOA).
This was a case-control study using data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study. Radiographic measurements at the knee were undertaken by a single trained observer. Measurement of 12 characteristics was undertaken in 815 controls with asymptomatic structurally normal knees to examine right-left symmetry and variation with gender and age. Measurements were then compared to “cases” (315 asymptomatic and structurally unaffected knees of people with radiographic and symptomatic OA in the contralateral knee) on the assumption that the morphology of the unaffected knee represented the morphology of the contralateral knee prior to the development of OA. Right-left symmetry of morphological measures in controls was examined using paired t test and minimal detectable change (MDC). Linear regression was used to examine the association between measurements and demographic characteristics. Association of morphological features and unilateral KOA [defined as OA in either patellofemoral (PF) or tibiofemoral (TF) joints], PFOA and TFOA were determined using binary logistic regression and odds ratio (OR) and 95% confidence interval (CI) calculated. Cumulative risk of measurements in determining OA was examined using receiver operating characteristic (ROC) curves.
Narrow sulcus and condylar angles, increasing distal femoral, proximal tibial tilt, and increasing varus alignment associated with KOA. ROC curves including all significant morphological features and age, gender, height, and weight predicted knee, PF joint (PFJ), and TF joint (TFJ) OA with area under the curve (AUC) of 0.91, 0.89, and 0.90 respectively. On the contrary, a model only containing age, gender, height, and weight predicted knee, PFJ, and TFJ OA with AUC of 0.59, 0.67, and 0.59 respectively.
Five morphological features associated independently with KOA were identified. Together they explain a large proportion of risk for OA.
This study aims to develop sensitive and reliable analytical technologies to enable the distinction between wild-caught and farmed fish through appropriate molecular markers to protect consumers from fraudulent fish labelling. Gilthead sea bream, Sparus aurata L. (S. aurata L.), is a very common fish used as foodstuff worldwide and globally produced in aquaculture in the Mediterranean basin. Wild-caught and farmed species are very different in feed and lifestyle and the quality and safety of these products strongly depend on fish growth, processing history, and storage conditions.
Hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray ionization (ESI) and Fourier-transform mass spectrometry (FTMS; HILIC-ESI-FTMS) was employed to discriminate the phospholipidome profiles of fillets extracts of wild-caught from farmed gilthead sea breams.
The untargeted approach led to the annotation of a total of 216 phospholipids (PLs), namely 65 phosphatidylethanolamines (PEs), 27 lyso-PEs (LPEs), 61 phosphatidylcholines (PCs), 34 lyso-PCs (LPCs), and 29 sphingomyelins (SMs). Untargeted lipidomics data were investigated by principal component analysis (PCA) and K-means clustering. Lyso-PLs (LPLs) of PEs and PCs including ether-linked side chains were found as discriminating markers between the two types of fish samples. The PLs that were most responsible for distinguishing between the lipid extracts of farmed and wild S. aurata fillets were successfully characterized by tandem mass spectrometry (MS/MS). The analysis revealed that wild fillet lipid extracts contained some PE exhibiting ether bonds (PE P-), viz. 16:0, 18:0, 18:1, and 18:2 and polyunsaturated fatty acyl chains (i.e., 22:6 and 22:5). In farmed species, the estimated abundance ratios of fatty acyl chains 20:4/18:2 and 22:6/20:5 were 0.9 and 0.05, respectively. However, in wild-caught fish, these ratios were found to be two-fold higher and four-fold higher, respectively.
This work demonstrates that the combination of HILIC-ESI-FTMS and chemometrics can serve as a valuable tool for evaluating fish authenticity and assessing quality concerns by monitoring specific lipid ratios.
This study aims to report an engineered peptide zp39 with favorable bioactivity against enterohemorrhagic Escherichia coli (E. coli, EHEC). Its antibacterial mechanisms and application in a real food system are assessed.
Spatial conformation of synthetic peptide zp39 (GIIAGIIiKIKk-NH2, lowercase letters indicate dextrorotatory amino acids) was predicted by PEPstrMOD and its secondary structure was further determined by circular dichroism (CD) spectroscopy. Then, standard E. coli O157:H7 strain ATCC 43888 was used to evaluate the bioactivity of zp39. A double dilution method was applied to investigate its efficacy in normal broth medium, serum, and highly saline conditions. Its effects on cell membrane permeability and potential were measured by fluorescent assays. Thereafter, morphological changes of E. coli O157:H7 cells were monitored by electron microscopy technologies. Finally, the potential application of zp39 in controlling EHEC in food was tested with spinach juice and the Galleria mellonella larvae model was employed to assess the in vivo efficacy.
Peptide zp39 presented an amphiphilic helical structure. It effectively inhibited the growth of E. coli O157:H7 at a concentration of 4 μmol/L in a bactericidal mode. Mechanistic studies revealed that it affected membrane permeability and potential in a dose-dependent manner. Moreover, zp39 maintained satisfactory bioactivity against E. coli O157:H7 even in the presence of 70% serum or 1,000 μmol/L chloride salts. In spinach juice application, > 90% E. coli O157:H7 cells were killed within 2 h after exposure to 64 μmol/L zp39. In vivo study proved that treatment with 64 μmol/L zp39 could effectively boost the survival ratio of infected larvae by 50%.
This study depicts a synthetic dodecapeptide that shows the potential application in controlling EHEC. This molecule may be developed into a highly effective antimicrobial agent applied to prevent food contamination and associated infections.
The aim of this study is to comprehensively investigate the distribution of amine and phenol compounds in different flavors of Baijiu.
12C-/13C-dansyl chloride labeling was applied for untargeted and quantitative analyses of amine and phenol compounds in Baijiu.
A total of 267 amine/phenol compounds were detected, and 30 of them were confirmed by the standards. 4 of 30 confirmed compounds were newly identified in Baijiu, and 16 ones were related with flavor or biological activity. After statistical analysis, 34 amine/phenol compounds were defined as potential markers for indicating sauce flavor, strong flavor, and light flavor Baijiu. 30 compounds in Baijiu were quantified with high precision, high accuracy, and high sensitivity. Results of the untargeted and quantitative analyses indicated that the number and contents of amine and phenol compounds were generally richest in sauce flavor Baijiu, while lowest in light flavor Baijiu.
The results obtained in the research are beneficial for comprehensively understanding the amine and phenol compounds in Baijiu and further provide the basis for the flavor blending of Baijiu.
Bacterial infections constitute one of the major cases of primary medical incidences worldwide. Historically, the fight against bacterial infections in humans has been an ongoing battle, due to the ability of bacteria to adapt and to survive. Indeed, bacteria have developed various mechanisms of resistance against several therapeutic agents. Consequently, the scientific community is always interested in search of new therapeutic agents, which are able to efficiently kill resistant-bacterial strains. This article covers the most recent antibacterial molecules approved by the Food and Drugs Administration (FDA) and European Medicines Agency (EMA) from 2012 to 2022 and intends to focus on synthetic derivatives to give a pedagogical view, with the goal of highlighting the importance of organic synthesis to obtain greater efficacy. A focus will be made on studies describing the structure and activity of the organic molecules and their interactions with their respective biological targets.
Excessive alcohol intake is still among the leading causes of chronic liver diseases. Epidemiological studies suggest that per capita consumption of alcohol from various alcohol beverages e.g., beer, wine, or spirits, differs markedly between different areas of the world. Studies further suggest that different alcoholic beverages may impact the development of alcohol-related liver diseases (ALD) differentially. Specifically, results of several more recent epidemiological studies suggest that consumption of wine and herein especially of red wine may be less harmful in relation to the development of liver diseases than the intake of hard spirits. Results of studies evaluating the effects of beer on the development of ALD in humans are rather contradictory. Here, results of studies assessing the impact of wine, beer, and spirits on the development of ALD as well as possible underlying mechanisms are summarized and discussed.
Earth’s rotation generates the basic circadian rhythm of day and night to which all living organisms must adapt to survive. In mammals, this happens thanks to a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and to peripheral clock genes at the cellular level. The main environmental cue capable of synchronizing such clocks is light sensed by retinal ganglion cells signaling through a complex nervous pathway to the pineal gland which ultimately regulates melatonin synthesis that occurs during the night, darkness hours in all mammals. The central clock synchronized by melatonin drives the circadian oscillation of the sympathetic nervous system (SNS) adrenergic activity which in turn controls glucocorticoid production in the adrenal glands. These oscillations are integrated with peripheral cellular clocks by still not completely understood mechanisms and drive the homeostatic control of activity-rest (sleep) cycles, cardiovascular activity, body temperature, and immune-hematopoietic functions. The neuronal and hormonal mechanisms governing the circadian oscillation of hematopoiesis and immunity will be addressed in this review focusing on those offering therapeutic perspectives.
A case report of fish allergy is exposed. The responsible allergen was fish collagen, and there was no sensitization to parvalbumin (main fish allergen). The patient acquired collagen sensitization by occupational exposition, not by ingestion.
The treatment of central nervous system (CNS) tumors is complicated by high rates of recurrence and treatment resistance that contribute to high morbidity and mortality (Nat Rev Neurol. 2022;18:221–36. doi: 10.1038/s41582-022-00621-0). One of the challenges of treating these tumors is the limited permeability of the blood brain barrier (BBB). Early pharmacologic treatments worked to overcome the BBB by targeting vulnerabilities in the tumor cell replication process directly through alkylating agents like temozolomide. However, as advancements have been made options have expanded to include immunologic targets through the use of monoclonal antibodies. In the future, treatment will likely continue to focus on the use of immunotherapies, as well as emerging technology like the use of low-intensity focused ultrasound (LIFU). Ultimately, this paper serves as an introductory overview of current therapeutic options for post-resection primary brain tumors, as well as a look towards future work and emerging treatment options.
Hepatocellular carcinoma (HCC) is a complex process that plays an important role in its progression. Abnormal glucose metabolism in HCC cells can meet the nutrients required for the occurrence and development of liver cancer, better adapt to changes in the surrounding microenvironment, and escape the attack of the immune system on the tumor. There is a close relationship between reprogramming of glucose metabolism and immune escape. This article reviews the current status and progress of glucose metabolism reprogramming in promoting immune escape in liver cancer, aiming to provide new strategies for clinical immunotherapy of liver cancer.
Besides trauma, several pathological conditions which directly affect the normal functioning of organs, require new therapeutic strategies to repair damaged or diseased tissues. Tissue regeneration is a complex and spatiotemporal process involving a plethora of cell types, including various immune cells and stem cells in a synchronized relationship. However, individual parameters, namely ageing, obesity, diabetes, and chronic conditions, have been intrinsically correlated with poor regenerative properties of adult tissues. While vast progress has been made regarding stem cell-based therapy to direct self-healing, the immune response is still the Achilles’ heel of such strategies. Whereas the role of effector immune cells has been well defined along the regenerative process, an understanding of the behavior of the main adult stem cells, namely mesenchymal stem cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs), along the different phases of the regenerative process could clarify how these stem cells can be used to positively influence the immune response. In this scope, this review highlights the main interactions between these stem cells and immune cells during tissue repair, exploring the most important regenerative properties of stem cells and correlating them with the modulation of the immune response during tissue regeneration. Furthermore, the utmost strategies used to explore how the behavior and stem cell fate are affected by specific microenvironments and/or stimuli usually found during a regenerative process, are emphasized. This clarification may provide critical insight into the molecular mechanisms by which stem cells modulate the immune response in a positive feedback loop toward tissue repair.
Transmission of a malignancy from a donor’s organ to the recipient of the graft is a rare event, though it is a severe complication that can result in a poor outcome. Usually, immunosuppressive therapy is discontinued and the allograft is removed. However, treatment of patients with the disseminated cancers implies that after the graft removal and cessation of the immunosuppression, radiotherapy, chemotherapy, or immunotherapy with alpha-interferon (INF-α) or interleukin-2 (IL-2) are required. The case report presents a clinical case of a transmitted kidney graft with multiple metastases (MTS) in a 31-year-old woman with the spontaneous regression of the metastatic cancer after transplantectomy and cancellation of the immunosuppressive therapy. Obviously, the determining factor is the recognition of the tumor by the effectors of the antitumor immunity due to the human leukocyte antigen (HLA) mismatch between the donor and the recipient. Therefore, cancellation of the immunosuppressive therapy in cases of transferal of a malignancy with a transplanted organ allows the effectors of the immune system to distinguish the tumor as a foreign tissue and effectively eliminate this neoplasm.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting motor neurons. The complex etiopathogenetic mechanism of ALS can lead to extensive alterations, including cortical changes, neuroinflammation, and changes in muscular structure. These ALS-derived alterations may contribute to fatigue, a symptom severely impacting patients’ quality of life that is commonly associated with muscular exercise. Intriguingly, muscular exercise can be at once a promoter of motor neuron degeneration in predisposed patients as well as an effective non-pharmacological treatment of ALS. To fully disclose its therapeutic potential, muscular exercise must be tailored to patients’ phenotypes, balancing potential benefits and risks that are unique to each ALS case. Biomarkers of muscular fatigue, with their potential for insight into inflammation and oxidation, can be used to ensure that the intensity of physical activity remains below the threshold level beyond which exercise might become harmful. In this review, the authors explore the concept of fatigue in ALS patients, focusing on fatigue generation, definition, detection, quantification, and treatment. The study discusses the most important fatigue biomarkers, putting them in relation to the mechanism of fatigue generation and with monitoring of muscular exercise as a possible treatment of fatigue.
Currently, the predominant targets for the treatment of Alzheimer’s disease (AD) are the main components of the two pathological structures: senile plaques (composed of amyloid beta peptide aggregates) or neurofibrillary tangles (constructed of tau protein polymers). However, the existence of adequate disease modifiers based on such targets is discussed. In this special issue, it has been suggested to search for new possible targets for AD therapy. This contribution tries to analyze non-neuronal tissues (periphery) to identify potential factors (target) involved in the development of AD.
The Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative RNA-splicing which is transcribed from a single gene, while Crk-like (CrkL), which is highly homologous to CrkII, is encoded by a different gene. Thanks to their modular structure, the Crk adaptor proteins can simultaneously interact with activated receptors and a wide range of effector molecules, and orchestrate the assembly of complexes containing enzymes and substrates at the receptor site. They are involved in the regulation of a large number of cellular processes which control cell growth, differentiation, transformation, and apoptosis. Cell activation-dependent tyrosine phosphorylation of CrkII and CrkL serves as a major posttranslational modification mechanism that introduces conformational changes in the proteins by promoting an intramolecular interaction between the phosphotyrosine and the self SH2 domain. The resulting conformational change induces downregulation of CrkII- and CrkL-dependent biological processes. A second type of posttranslational modification mechanism regulates the structure and function of the CrkII adaptor protein by immunophilin-mediated protein isomerization. Two of the most abundant immunophilins in T lymphocytes which function as peptidyl-prolyl cis-trans isomerases (PPIases), namely cyclophilin A (CypA) and FK506-binding proteins (FKBPs), can associate with CrkII and catalyze its reciprocal cis-trans isomerization. This mechanism is of special importance for the regulation of T lymphocyte functions and for T cell-mediated immune responses, since immunophilin inhibitors, such as cyclosporin A (CsA) and FK506, function as immunosuppressive drugs that can prevent allotransplanted graft rejection. The present manuscript focuses on selected functions of Crk adaptor proteins, predominantly in T lymphocytes, and reviews in more detail the current knowledge on the immunophilin-dependent regulation of the structure and function of the CrkII adaptor protein.
Globally, the incidence of Parkinson’s disease (PD) is increasing faster than other neurodegenerative disorders. Neuropathologically, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta due to the accumulation of aggregates of misfolded α-synuclein (α-Syn) in the cytoplasm of these neurons, forming Lewy bodies. Extracellular vesicles (EVs) are associated with the spread of α-Syn to different brain areas. However, at the same time that these EVs contribute to the pathophysiology of PD, they can also be explored as therapeutic, serving as a vehicle to deliver specific molecules, since these vesicles can easily cross the blood-brain barrier. Thus, this review summarizes the recent progress in EVs as a therapeutic strategy for PD, focusing on their delivery to the brain, and discusses the potential challenges and future directions in this field.
Soft tissue sarcomas (STSs) are rare, heterogeneous, and very often asymptomatic diseases. Their diagnosis is fundamental, as is the identification of the degree of malignancy, which may be high, medium, or low. The Italian Medical Oncology Association and European Society of Medical Oncology (ESMO) guidelines recommend magnetic resonance imaging (MRI) because the clinical examination is typically ineffective. The diagnosis of these rare diseases with artificial intelligence (AI) techniques presents reduced datasets and therefore less robust methods. However, the combination of AI techniques with radiomics may be a new angle in diagnosing rare diseases such as STSs. Results obtained are promising within the literature, not only for the performance but also for the explicability of the data. In fact, one can make tumor classification, site localization, and prediction of the risk of developing metastasis. Thanks to the synergy between computer scientists and radiologists, linking numerical features to radiological evidence with excellent performance could be a new step forward for the diagnosis of rare diseases.
This is a Chinese population-based study aimed to determine the causes and clinical features of drug-induced liver injury (DILI) from traditional Chinese medicines (TCMs) and current Western medicines (WMs) and identify the risk factors of drug-induced liver failure (DILF) and chronic DILI for early recognition and better management.
The medical records of patients who were diagnosed with DILI for at least six-month follow-up between January 2018 to December 2020 were reviewed and investigated. The risk factors of DILF and chronic DILI were identified by univariate and multivariate logistic regression analysis.
TCMs (47.5%) including herbal medicine (83.0% in TCM-induced DILI) and some Chinese patent drugs were the leading cause of DILI in the present study. Cholestatic type was more associated with severe and chronic DILI. Pre-existing gallbladder disease, initial total bilirubin (TBIL), initial prothrombin time (PT), initial antinuclear antibodies (ANA), and clinical classification are independent risk factors for DILF. Prolonged T0.5AST and T0.5GGT were independent risk factors for chronic DILI [area under the curve (AUC) = 0.812, 95% confidence interval (CI): 0.748–0.876, P < 0.001] with cut-off values of 8.5 days and 29.5 days, respectively.
TCMs especially herbal medicine were the leading causes of DILI, and the risk of developing severe DILI was associated with pre-existing gallbladder disease, clinical classification, initial TBIL, PT, and ANA. T0.5AST and T0.5GGT might serve as indicators for chronicity.
It is shown that the diminished function of the psoas major is mainly associated with increased lipid content; nonetheless, whether the fat content of the psoas major is associated with intervertebral disc degeneration (IVDD) is still under study. It is hypothesized that IVDD is correlated with the lipid content of the psoas major and that IVDD can be comprehensively investigated using quantitative magnetic resonance imaging (MRI). Consequently, this study aimed to analyse the association between the psoas major extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) content and disc degeneration quantified using MRI T2 mapping in patients with chronic low back pain (CLBP).
In this study, 20 men and 23 women (mean age, 63.1 years ± 2.6 years) underwent magnetic resonance spectroscopy (MRS). The psoas major IMCL and EMCL content of patients was analysed. T2 values of the anterior annulus fibrosus (AF), nucleus pulposus (NP), and posterior AF were evaluated using MRI T2 mapping. Multiple linear regression analysis was used to determine the possible correlations of the psoas major EMCL and IMCL content with the T2 values of the anterior AF, NP, and posterior AF.
The EMCL content and T2 values of the anterior AF were significantly and negatively correlated [standardised partial regression coefficient (β) = −0.60, P < 0.01]. There were no significant correlations between the EMCL content and T2 values of the NP (β = −0.16, P = 0.30) or posterior AF (β = −0.14, P = 0.49) or between the IMCL content and T2 values of the anterior AF (β = −0.04, P = 0.82), NP (β = 0.05, P = 0.73), or posterior AF (β = −0.11, P = 0.58).
The EMCL content and T2 values of the anterior AF were correlated. Conversely, the IMCL content and T2 values were not correlated.
Up to date many successful attempts to identify various types of lesions with machine learning (ML) were made, however, the recognition of Alzheimer’s disease (AD) from brain images and interpretation of the models is still a topic for the research. Here, using AD Imaging Initiative (ADNI) structural magnetic resonance imaging (MRI) brain images, the scope of this work was to find an optimal artificial neural network architecture for multiclass classification in AD, circumventing the dozens of images pre-processing steps and avoiding to increase the computational complexity.
For this analysis, two supervised deep neural network (DNN) models were used, a three-dimensional 16-layer visual geometry-group (3D-VGG-16) standard convolutional network (CNN) and a three-dimensional residual network (ResNet3D) on the T1-weighted, 1.5 T ADNI MRI brain images that were divided into three groups: cognitively normal (CN), mild cognitive impairment (MCI), and AD. The minimal pre-processing procedure of the images was applied before training the two networks.
Results achieved suggest, that the network ResNet3D has a better performance in class prediction, which is higher than 90% in training set accuracy and arrives to 85% in validation set accuracy. ResNet3D also showed requiring less computational power than the 3D-VGG-16 network. The emphasis is also given to the fact that this result was achieved from raw images, applying minimal image preparation for the network.
In this work, it has been shown that ResNet3D might have superiority over the other CNN models in the ability to classify high-complexity images. The prospective stands in doing a step further in creating an expert system based on residual DNNs for better brain image classification performance in AD detection.
Cancer remains the second leading cause of death worldwide despite modern breakthroughs in medicine, and novel treatments are urgently needed. The revolutionary success of immune checkpoint inhibitors in the past decade serves as proof of concept that the immune system can be effectively harnessed to treat cancer. Cytokines are small signalling proteins with critical roles in orchestrating the immune response and have become an attractive target for immunotherapy. Type 1 immune cytokines, including interferon γ (IFNγ), interleukin-12 (IL-12), and tumour necrosis factor α (TNFα), have been shown to have largely tumour suppressive roles in part through orchestrating anti-tumour immune responses mediated by natural killer (NK) cells, CD8+ T cells and T helper 1 (Th1) cells. Conversely, type 2 immunity involving group 2 innate lymphoid cells (ILC2s) and Th2 cells are involved in tissue regeneration and wound repair and are traditionally thought to have pro-tumoural effects. However, it is found that the classical type 2 immune cytokines IL-4, IL-5, IL-9, and IL-13 may have conflicting roles in cancer. Similarly, type 2 immunity-related cytokines IL-25 and IL-33 with recently characterised roles in cancer may either promote or suppress tumorigenesis in a context-dependent manner. Furthermore, type 1 cytokines IFNγ and TNFα have also been found to have pro-tumoural effects under certain circumstances, further complicating the overall picture. Therefore, the dichotomy of type 1 and type 2 cytokines inhibiting and promoting tumours respectively is not concrete, and attempts of utilising these for cancer immunotherapy must take into account all available evidence. This review provides an overview summarising the current understanding of type 1 and type 2 cytokines in tumour immunity and discusses the prospects of harnessing these for immunotherapy in light of previous and ongoing clinical trials.
Immunotherapy strategies targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are revolutionizing oncology. However, its effectiveness is limited in part due to the loss of effector cytotoxic T lymphocytes. Interestingly, supplementation of vitamin D could abolish the repressive effect of programmed cell death-ligand 1 (PD-L1) on CD8+ T cells, which might prevent the lymphocytopenia. In addition, vitamin D signaling could contribute to the differentiation of T-regulatory (Treg) cells associated with the expression of Treg markers such as forkhead box P3 (FOXP3) and CTLA-4. Furthermore, vitamin D may be associated with the stimulation of innate immunity. Peroxisome proliferator-activated receptor (PPAR) and estrogen receptor (ESR) signaling, and even the signaling from phosphoinositide-3 kinase (PI3K)/AKT pathway could have inhibitory roles in carcinogenesis possibly via the modulation of immune checkpoint molecules. In some cases, certain small molecules including vitamin D could be a novel therapeutic modality with a promising potential for the better performance of immune checkpoint blockade cancer therapies.
Human histone deacetylase 8 (KDAC8) is a well-recognized pharmaceutical target in Cornelia de Lange syndrome and different types of cancer, particularly childhood neuroblastoma. Several classes of chemotypes have been identified, which interfere with the enzyme activity of KDAC8. These compounds have been identified under equilibrium or near equilibrium conditions for inhibitor binding to the target enzyme. This study aims for the classification of KDAC8 inhibitors according to the mode of action and identification of most promising lead compounds for drug development.
A continuous enzyme activity assay is used to monitor inhibition kinetics.
A high-throughput continuous KDAC8 activity assay is developed that provides additional mechanistic information about enzyme inhibition enabling the classification of KDAC8 inhibitors according to their mode of action. Fast reversible inhibitors act as a molecular chaperone and are capable to rescue the enzyme activity of misfolded KDAC8, while covalent inactivators and slow dissociating inhibitors do not preserve KDAC8 activity.
The application of continuous KDAC8 activity assay reveals additional information about the mode of interaction with inhibitors, which can be used to classify KDAC8 inhibitors according to their mode of action. The approach is compatible with the high-throughput screening of compound libraries. Fast reversible inhibitors of KDAC8 act as molecular chaperones and recover enzyme activity from misfolded protein conformations. In contrast, slow-binding inhibitors and covalent inactivators of KDAC8 are not capable to recover enzyme activity.
There is a strong comorbidity between methamphetamine (MA) and alcohol use whereby MA use may contribute to increased alcohol consumption. This study aims to determine the associations between alcohol drinking and MA-associated behaviors among MA users in relation to mood disorders, suicidal ideation, and health-related quality of life (HR-QoL).
Substance use characteristics were obtained in 106 participants with MA use at a substance abuse treatment center by using the Severity of Dependence Scale (SDS) and the Thai version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Current alcohol drinking behaviors were estimated using the Substance Outcomes Profile (SOP), which was developed and translated from the Treatment Outcomes Profile, by computing the number of alcohol units x days per month of alcohol use. The Mini-International Neuropsychiatric Interview (M.I.N.I.) was used to estimate lifetime histories of mood disorders and substance abuse and current suicidal ideation.
Current suicidal ideation in MA users is to a large extent predicted by the severity of current alcohol and MA use, female gender, and a lifetime history of mood disorders (major depression, dysthymia, and hypo-mania). Moreover, a lifetime history of mood disorders is positively associated with the severity of MA, but not with alcohol use. Partial least squares (PLS) path modeling shows that lowered HR-QoL in MA users is predicted by the SDS score and alcohol dosing (both inversely) and that lifetime diagnoses of mood disorders and MA use (both inversely) and alcohol dependence (positively) have significant effects on HR-QoL which are completely mediated via the SDS score.
In MA users, the severity of dependence, and MA and/or alcohol use exert adverse effects on current suicidal ideation and HR-QoL. Mechanistic explanations are given which may explain the inverse associations between the severity of MA and alcohol use in MA abusers.
Recently, a tumor cell-platelet interaction was identified in different tumor entities, resulting in a transfer of tumor-derived RNA into platelets, named further “tumor-educated platelets (TEP)”. The present pilot study aims to investigate whether such a tumor-platelet transfer of RNA occurs also in patients suffering from head and neck squamous cell carcinoma (HNSCC).
Sequencing analysis of RNA derived from platelets of tumor patients (TPs) and healthy donors (HDs) were performed. Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for verification of differentially expressed genes in platelets from TPs and HDs in a second cohort of patients and HDs. Data were analyzed by applying bioinformatic tools.
Sequencing of RNA derived from the tumor as well as from platelets of TPs and HDs revealed 426 significantly differentially existing RNA, at which 406 RNA were more and 20 RNA less abundant in platelets from TPs in comparison to that of HDs. In TPs’ platelets, abundantly existing RNA coding for 49 genes were detected, characteristically expressed in epithelial cells and RNA, the products of which are involved in tumor progression. Applying bioinformatic tools and verification on a second TP/HD cohort, collagen type I alpha 1 chain (COL1A1) and zinc finger protein 750 (ZNF750) were identified as the strongest potentially platelet-RNA-sequencing (RNA-seq)-based biomarkers for HNSCC.
These results indicate a transfer of tumor-derived messenger RNA (mRNA) into platelets of HNSCC patients. Therefore, analyses of a patient’s platelet RNA could be an efficient option for liquid biopsy in order to diagnose HNSCC or to monitor tumorigenesis as well as therapeutic responses at any time and in real time.
For more than a decade now, research studies, proof of concept work, and clinical trials have endeavored to understand how mesenchymal stem cells might be used to help protect, repair, and/or regenerate damaged brain tissue following stroke. To date, the majority of studies have not demonstrated significant improvements in either morbidity or medium-long-term outcome, although safety has been relatively well proven. Limitations are likely to be linked to the pathobiological complexity and seriousness of stroke tissue damage, low efficacy of treatment, and short half-life of bio-active proteins released by stem cells. This article will highlight the heterogeneity and limitation of completed studies and the current status of ongoing work. At the same time, the potential of other combinational type treatments, such as drug-loading and targeting, and the use of hydrogels is discussed.
Traumatic brain injury (TBI) is a common neurological condition, which can present with a wide range of neuropsychological symptoms. Treating this broad spectrum of symptoms represents a significant medical challenge. In part because of this, there is growing interest in the use of medical cannabis to treat the sequelae of TBI, as medical cannabis has been used to treat multiple associated conditions, such as pain. However, medical cannabis represents a heterogeneous collection of therapies, and relatively little is known about their effectiveness in treating TBI symptoms. The aim of the present study was therefore to assess medical cannabis use in patients with TBI.
In the present study, a retrospective chart review was conducted of patterns of cannabis use and TBI symptoms in individuals who used medical cannabis to treat TBI-related symptoms. All subjects were recruited from a medical cannabis clinic, where cannabis was authorized by physicians, using licensed cannabis products. A total of 53 subjects provided written consent to have their charts reviewed.
Neuropsychiatric conditions, including depression, pain, and anxiety were frequent in this group. The most common forms of medical cannabis consumption at intake included smoking, vaping, and oral ingestion. Patients used a combination of high tetrahydrocannabinol (THC)/low cannabidiol (CBD) and low THC/high CBD products, typically 1–3 times per day. Medical cannabis appeared to be relatively well-tolerated in subjects, with few serious side effects. At follow-up, subjects self-reported improvements in TBI symptoms, although these were not statistically significant when assessed using validated questionnaires.
Overall findings indicate modest potential benefits of medical cannabis for TBI, but further research will be required to validate these results.
Enhanced recovery after surgery (ERAS) is a recommended surgical strategy at present, the core content is to reduce perioperative stress response and postoperative complications through perioperative multi-mode analgesia and intensive surgery. Electroacupuncture (EA) has been widely used in various clinical applications, and its efficacy and safety have been fully proven. The application of acupuncture in ERAS will have an important impact on rehabilitation research and development. In this review, the molecular mechanism of EA in ERAS are summed up from promoting perioperative efficacy to improving postoperative immune status. The combination of EA and ERAS may better promote the recovery of patients and the development of rehabilitation.
Among treatments for chronic non-cancer pain (CNCP), cannabinoid-based medicines (CBMs) have become extremely popular. Evidence remains modest and limited primarily to delta-9-tetrahydrocannabinol (THC) for neuropathic pain; nevertheless, the use of various CBMs, including cannabidiol (CBD) to treat neuropathic, nociceptive, and mixed pain has increased globally. This observational case-series assessed the impact of CBMs as a complementary treatment by pain mechanism and cannabinoid profile over three months.
An analysis of patients with CNCP and treated with CBMs who consented to an ongoing registry was performed. Outcomes were patient-reported such as the Edmonton Symptom Assessment System-Revised, Brief Pain Inventory-Short Form, and 36-Item Short Form Health Survey. Data from patients with complete outcomes for baseline and 3-month follow-up was extracted. Characteristics of adverse drug reactions (ADRs), including a description of the suspected product were also assessed.
A total of 495 patients were part of this analysis (mean age = 56 years old; 67% women). At 3-month, the proportional use of THC:CBD balanced and THC-dominant products increased. Patients with neuropathic pain had higher pain-severity scores vs. nociceptive pain. In addition to patients with neuropathic pain, patients with nociceptive and mixed pain also reported improvements in pain severity and secondary symptoms such as anxiety, depression, drowsiness, fatigue, sleep disturbances, and overall, health-related quality of life. THC-dominant treatment is more likely to be recommended when pain is severe, whereas CBD-dominant is favored for less severe cases. ADRs were more frequent among cannabis-naive patients and included dizziness, headache, and somnolence among others.
Findings suggest that CBMs can be effective for neuropathic as well as nociceptive and mixed pain. THC is more frequently recommended for neuropathic and severe pain. Future research on CBMs in pain management must include details of CBM composition, and pain mechanism and must consider potential ADRs.
Gastrointestinal (GI) cancer is one of the leading causes of death that affect many patients around the world. The coronavirus disease 2019 (COVID-19) pandemic significantly impacted our healthcare system in large that diagnosis and management of GI cancer have suffered with a reduction in cancer screening. This review will describe the current practices of cancer screening during COVID-19 pandemic and summarize how each GI cancer (esophageal, gastric, colorectal, and hepatocellular cancers) has been affected by COVID-19. World widely there has been a decreasing trend in screening, diagnosis, and management of GI cancers during the COVID-19 pandemic. Many healthcare institutions are now observing the effect of this change and implementing practice variations to adapt to the pandemic.
Pseudoneurological complaints (PNCs) are highly prevalent among the general population. Coronavirus disease 2019 (COVID-19) adversely influences such complaints in individuals who recovered from COVID-19. This study determined the prevalence and identified the predictors of PNCs among individuals who had previously experienced COVID-19 and their healthy counterparts.
This case-control study analyzed the data of 878 Bangladeshi adults (439 patients). Laboratory-confirmed COVID-19 individuals were considered cases, and the controls were those who never tested positive for COVID-19. The controls were matched with cases’ sex and age. The seven-item pseudoneurological sub-scale of the subjective health complaints scale produced by Eriksen et al. evaluated PNCs. The descriptive analysis estimated the prevalence of PNCs among the subgroups, whereas multiple logistic regression models were used to determine the predictors of PNCs.
Overall, the prevalence of PNCs was 40%; however, patients who recovered from COVID-19 reported a PNC rate of 67.4%. The regression analysis identified COVID-19 as a robust independent predictor of PNCs. Furthermore, occupation, monthly household income, current living location, hypertension, and recovery period from acute COVID-19 were independently associated with PNCs.
This study revealed a significant association between COVID-19 and PNCs. The results of this study will be helpful when discussing, planning, and implementing strategies to alleviate the overburden of PNCs among COVID-19 survivors.
Cardiovascular diseases (CVD) are the leading cause of death globally. In the condition of type 2 diabetes mellitus (T2DM), the prevalence of CVD increase parallel with the rise of metabolic complication and higher incidence of coronary artery stenosis. The aim of this study was to compare the level of percent stenosis in coronary arteries in patients with coronary artery disease (CAD) with and without T2DM, and to measure the severity of CVD using Gensini score (GS) through angiographic data.
The current study was conducted in tertiary care specialized hospital in Delhi, India. The level of percent stenosis in coronary arteries was compared in patients with CAD with and without T2DM. The patients were divided into two groups: group I included 100 patients with T2DM, and group II included 100 non-diabetic CAD patients who underwent coronary angiography by Judkin’s technique. The severity of CVD was measured by GS through angiographic data. The serum levels of glycated haemoglobin (HbA1c) ≥ 6.5% were considered diabetic.
Significant difference was observed in serum HbA1c, and random blood sugar levels between group I and group II were also observed (P ≤ 0.001). Serum HbA1c shows a significant positive association with GS (r = 0.36, P = 0.007).
The study shows a significant level of stenosis in coronary arteries of CAD diabetic patients. However, further prospective analysis of a larger population size will be needed to strengthen the findings and the significant association.
Identification of small bioactive regions in proteins and peptides can be useful information in drug design studies. The current study has shown that an inter-cysteine loop of the N-terminal domain of Opisthorchis viverrini granulin-1 (Ov-GRN-1), a granulin protein from the flatworm liver fluke Opisthorchis viverrini which has potent wound healing properties, maintains the bioactivity of the full-length protein.
Peptides corresponding to the three inter-cysteine loops of the N-terminal domain were produced using synthetic chemistry, and their structures and bioactivities were analyzed using nuclear magnetic resonance (NMR) spectroscopy and cell proliferation assays, respectively.
As expected for such small peptides, NMR analysis indicated that the peptides were poorly structured in solution. However, a seven-residue peptide corresponding to loop 2 (GRN-L2) promoted cell proliferation, in contrast to the other fragments.
The results from the current study suggest that GRN-L2 might be responsible, in part, for the bioactivity of Ov-GRN-1, and might be a useful lead molecule for subsequent wound healing studies.
Rectal cancer (RC) is one of the most common tumours worldwide in both males and females, with significant morbidity and mortality rates, and it accounts for approximately one-third of colorectal cancers (CRCs). Magnetic resonance imaging (MRI) has been demonstrated to be accurate in evaluating the tumour location and stage, mucin content, invasion depth, lymph node (LN) metastasis, extramural vascular invasion (EMVI), and involvement of the mesorectal fascia (MRF). However, these features alone remain insufficient to precisely guide treatment decisions. Therefore, new imaging biomarkers are necessary to define tumour characteristics for staging and restaging patients with RC. During the last decades, RC evaluation via MRI-based radiomics and artificial intelligence (AI) tools has been a research hotspot. The aim of this review was to summarise the achievement of MRI-based radiomics and AI for the evaluation of staging, response to therapy, genotyping, prediction of high-risk factors, and prognosis in the field of RC. Moreover, future challenges and limitations of these tools that need to be solved to favour the transition from academic research to the clinical setting will be discussed.
The pathogenesis of drug-induced liver injury (DILI) is still in an early stage of research. However, investigators have shown that both oxidative stress and endoplasmic reticulum (ER) stress play a significant role in the pathological mechanism. However, there is little in-depth literature about these two mechanisms. In order to prevent and improve the clinical symptoms of DILI, it is particularly important to study its pathogenesis. In this review article, the role of ER and oxidative stress in DILI is thoroughly discussed.
The word “Kampo medicine” means the traditional Japanese herbal medicine. Even “natural herb” can cause drug-induced liver injury (DILI). In this review, the characteristics of Kampo medicine-induced liver injury (KMILI) are reported. The main causative herb involved in Kampo medicine is Scutellariae Radix. KMILI is based on certain hypersensitivity reactions. A small amount of Kampo medicine can cause liver injury, and KMILI can develop after a short latency period. The incidence of liver injury related to Scutellariae Radix is about 1%. KMILI is usually mild and not fatal. The latency period usually lasts 4 weeks to 24 weeks. Fatigue and loss of appetite are sometimes observed. Eosinophilia is not frequently observed. All three types of liver injuries are observed in KMILI: cholestatic, hepatocellular, and mixed types. In Japan, lymphocyte transformation test (LTT) has been generally used for the diagnosis of DILI; however, LTT is likely to yield false-positive result for Kampo medicines, and thus often leads to misdiagnosis in many cases. Recently, researchers reported that a specific human leukocyte antigen (HLA) genotype is possibly associated with KMILI. This hypothesis needs to be examined further. Although Kampo medicine is based on rich knowledge and experience that occurred over a period of thousands of years, much is still unknown about KMILI.
177Lu-Dotatate (Lu-177), a form of peptide receptor radionuclide therapy (PRRT), was approved by Food and Drug Administration (FDA) for the treatment of somatostatin-receptor-positive neuroendocrine tumors (NETs) in 2018. Clinical trials prior to the FDA approval of Lu-177 showed favorable outcomes but there is limited published real world outcomes data. This study aims to describe and analyze real world outcomes of patients with NET who received Lu-177.
After obtaining institutional review board approval, retrospective evaluation was performed to analyze the efficacy of Lu-177 for somatostatin receptor-positive gastro-entero-pancreatic NETs (GEP-NETs) patients at the University of Kansas Cancer Center between June 2018 and September 2021. This study aims to determine the response rate to the treatment of the entire cohort and subgroups.
A total of 65 patients received Lu-177 of which 58 completed treatment. The 58 patients had a median age of 61.5 years, 24 females and 34 males, 86% Caucasian and 12% black. The origins of NETs were primarily small bowel (n = 24) and pancr