Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.

Molecular inhibitors added to the corrosive medium attacking metallic materials are a well-established way of combating corrosion. The inhibitive action proceeds via adsorption of the inhibitor on the surface to be protected. Aromatic building blocks in the inhibitor play a major role in their protective action, further details like substituents, heteroatoms and molecular geometry contribute. An overview is provided focused on aromatic inhibitors aiming at the identification of particularly promising inhibitors and their mode of action. Directions of further research and development are pointed out in conclusion.

This paper examines the quantitative structure–inhibitory activity relationship of 15-lipoxygenase (15-LOX) in sets of 100 homo- and heterocyclic compounds using GUSAR2019 software. Statistically significant valid models were built to predict the IC50 parameter. A combination of MNA- and QNA-descriptors with three whole molecular descriptors (topological length, topological volume, and lipophilicity) was used to develop 18 statistically significant valid consensus QSAR models. These compounds had varying degrees of inhibition of the catalytic activity of 15-LOХ: the range of variation in the pIC50 value was 3.873. The satisfactory coincidence between the theoretically calculated and experimentally determined pIC50 values for compounds TS1, TS2 and 1–8 suggests the potential use of models M1–M18 for virtual screening of virtual libraries and databases to find new potentially efficient inhibitors of 15-LOX.

Feline infectious peritonitis (FIP) is a severe and invariably fatal disease affecting both domestic and wild felines with limited effective therapeutic options available. By considering the significant immunomodulatory effects of vitamin E observed in both animal and human models under physiological and pathological conditions, we have provided a full in-silico investigation of vitamin E and related compounds and their effect on the crystal structure of feline infectious peritonitis virus 3C-like protease (FIPV-3CLpro). This work revealed the β-tocotrienol and δ-tocotrienol analogues as inhibitor candidates for this protein, suggesting their potential as possible drug compounds against FIP or their supplementary use with current medicines against this disease.

The management of erectile dysfunction (ED) shows several grey zones, especially in terms of patient satisfaction and adherence to the treatment. The main and first-line treatment for ED is drug therapy, mainly phosphodiesterase-5 inhibitors (PDE-5is) but the adherence to the therapy is not optimal due to the low patient satisfaction reported in several cases. To address this issue, different administration routes and PDE-5is pharmacological formulations have been introduced in the pharmacological market. The pharmaceutical market has recently seen the introduction of a novel sildenafil oral suspension. This device offers access to all therapeutic regimens in one device, releasing 0.5 mL of suspension containing 12.5 mg of sildenafil with each pulse. This formulation enables tailored dosing based on clinical requirements and the demands of ED patients. Here, we aim to give a brief narrative review of the management of this new oral suspension in order to provide the readers with some suggestions to use in everyday clinical practice, on the basis of the recent evidence, by using an easy and rapid-to-consult questions and answers form. Also included are the conclusions of a board meeting of experienced andrologists regarding the most recent developments in this area.

The concept of intelligence has many applications, such as coatings and cyber security. Smart coatings have the ability to sense and/or response to external stimuli and generally interact with their environment. Self-healing coatings represent a significant advance in improving material durability and performance using microcapsules and nanocontainers loaded with self-healing agents, catalysts, corrosion inhibitors, and water-repellents. These smart coatings can repair damage on their own and restore mechanical properties without external intervention and are inspired by biological systems. Properties that are affected by either momentary or continuous external stimuli in smart coatings can be related to corrosion, fouling, fungal, self-healing, pie-zoelectric, microbiological, etc. These coating properties can be obtained via combinations of either organic or inorganic polymer phases, additives and pigments. In this article, a review on the advancements of micro/nanocapsules for self-healing coatings is reported from the aspect of ex-trinsic self-healing ability. The concept of extrinsic self-healing coatings is based on the use of capsules or multichannel vascular systems loaded with healing agents/inhibitors. The outcome is that self-healing coatings exhibit improved properties compared to traditional coatings. It is mentioned that self-healing anticorrosive coating not only has enhanced passive barrier function, but also realizes active defense. As a result, there is a significant improvement of the service life and overall performance of the coating. Future research should be devoted to refining self-healing mechanisms and developing cost-effective solutions for a wide range of industrial applications.

The chemical investigation of the anti-yeast methanol extract from the stem bark of Terminalia mantaly led to the isolation of seven compounds: 3-O-methyl-4-O-α-rhamnopyranoside ellagic acid (1), 3-O-mehylellagic acid (2), arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid (3), arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside (4), 2α,3α,24-trihydroxyolean-11,13(18)-dien-28-oïc acid (5), stigmasterol (6), stigmasterol 3-O-β-D-glucopyranoside (7). Their structures were established by means of spectroscopic analysis and comparison with published data. Compounds 1-5 were tested in vitro for activity against three pathogenic yeast isolates, Candida albicans, Candida parapsilosis and Candida krusei. The activity of compounds 1, 2 and 4 were comparable to that of the reference compound fluconazole (MIC values below 32 µg/ml) against the three tested yeast isolates. They were also tested for inhibitory properties against four enzymes of metabolic significance: Glucose-6-Phosphate Deshydrogenase (G6PD), human erythrocyte Carbonic anhydrase I and II (hCA I and hCA II), Glutathione S-transferase (GST). Compound 4 showed highly potent inhibitory property against the four tested enzymes with overall IC₅₀ values below 4 µM and inhibitory constant (Ki) <3 µM.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Coronaviruses (CoVs) have recently emerged as significant causes of respiratory disease outbreaks. The novel coronavirus pneumonia of 2019, known as COVID-19, are highly infectious and triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding virus-host interactions and molecular targets in host cell death signalling is crucial for treatment development. Small natural compounds like celastrol and curcumin, acting as proteasome inhibitors, can potentially modify NF-κB signalling for treating SARS-CoV-2 infections. Various natural constituents, including alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones, inhibit viral infection, progression, and amplification of coronaviruses. Derived from medicinal herbs, these compounds possess anti-inflammatory and antiviral properties, impacting the viral life cycle, including entry, replication, assembly, and release of COVID-19 virions. This review focuses on the development of small molecules of non-covalent inhibitors targeting the Main Protease (Mpro, also called 3CLpro) enzyme of SARS-CoV-2. It highlights the design using molecular dynamics (MD) studies and computational methods for further improvements in Mpro inhibitor design. The in-silico approach, which is pivotal in this process, provides an accelerated virtual avenue for exploring and developing potential inhibitors, representing the latest advancements in drug design.

Malignant melanoma and urological cancers originate from different tissues and organs, yet several studies highlight connections between these malignancies, including common risk factors, genetic predispositions, and immunological pathways. Research indicates that individuals with a history of melanoma have an elevated risk of developing renal cell carcinoma (RCC), while those with RCC are more likely to develop melanoma. Shared factors such as a personal or family history of cancer, UV radiation exposure, smoking, and obesity have all been linked to an increased incidence of various cancer types. A major link between malignant melanoma and urological cancers is the presence of shared genetic mutations and familial cancer syndromes. Key mutations, including germline mutations in BRCA1, MITF, CDKN2A, TP53, and alterations in the PI3K/AKT pathway, significantly contribute to the risk of both types of malignancies. Personalized medicine, which tailors prevention and treatment strategies to an individual’s genetic, environmental, and lifestyle factors, has significantly improved cancer care. The primary aim is to select the most effective treatment for each patient, maximizing therapeutic outcomes, reducing side effects, and minimizing the risk of drug resistance. Advances in genomics and immunology are driving the development of personalized therapies that target specific molecular pathways and immune responses common to both melanoma and urological cancers. Angiogenesis inhibitors and checkpoint inhibitors have demonstrated notable success in treating these cancers, with tumor mutational burden serving as a valuable biomarker for predicting the efficacy of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

The aim of the present study was to predict the response of non-small cell lung cancer (NSCLC) patients to immune checkpoint inhibitors (ICIs) by leveraging computed tomography (CT) images using deep learning techniques. Retrospectively, 624 sequential CT images were gathered from 156 patients at Jiangsu Province Hospital, along with their clinical data. The dataset was subsequently partitioned into three groups: training (n=547), validation (n=64), and test (n=64). Moreover, an external validation cohort included 37 CT images from patients at Nanjing Pukou Peoples' Hospital, accompanied by comprehensive clinical data. An advanced Video Vision Transformer (ViViT) model incorporating global self-attention was utilized to analyse patients treated with ICIs and predict their response. The ViViT model's efficacy was evaluated using a confusion matrix and a receiver operating characteristic curve (ROC). Notably, the ViViT model demonstrated predictive prowess for ICIs response, yielding respective areas under the receiver operating characteristic curve (AUC) of 0.74 (95% CI: 0.69-0.78), 0.74 (95% CI: 0.61-0.86), 0.76 (95% CI: 0.62-0.88), and 0.69 (95% CI: 0.5-0.87) in the training, validation, test, and external validation cohorts. The present study illustrates how a deep learning model can provide a non-invasive means to predict clinical outcomes in NSCLC patients undergoing ICIs, potentially transforming personalized treatment approaches for individuals with NSCLC.

Skin cancer is a prevalent and heterogenous disease with several subtypes, such as melanoma, basal cell carcinoma, and squamous cell carcinoma. Among them, melanoma is the most aggressive subtype, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes, and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitors resistance in melanoma.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

With around one billion of the world's population affected, the era of Metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which, to date there is almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it affects also extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for Metabolic dysfunction associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Despite that a pharmaceutical industry is still lagging behind to develop an ap-proved pharmacologic therapy for MAFLD, research has been recently intensified and many molecules which are underway in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was ap-proved via accelerated procedure for treatment of MAFLD, i.e. of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

Tight regulation of gene transcription is essential for normal development, tissue homeostasis and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation. Interestingly, a number of approved therapeutic agents such as cyclosporine, steroid hormones, and thiazolidinediones actually function by affecting enhancer landscapes by directly targeting very specific transcription factor programs. More recently, a broader approach to targeting deregulated enhancer programs has been achieved via Bromodomain and Extraterminal (BET) inhibition or perturbation of transcription-related cyclin-dependent kinases (CDK). One challenge to enhancer-targeted therapy is proper patient stratification. We suggest that monitoring of enhancer RNA (eRNA) expression may serve as a unique biomarker of enhancer activity that can help to predict and monitor responsiveness to enhancer-targeted therapies. A more thorough investigation of cancer-specific enhancers and the underlying mechanisms of deregulation will pave the road for an effective utilization of enhancer modulators in a precision oncology approach to cancer treatment.

Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population [1]. Current treatment strategies, the combination of BRAF and MEK inhibitors (BRAF/MEKi) in BRAFV600 mutant melanoma, and immune checkpoint inhibitors (ICI), have changed the clinical evolution of this disease [2]. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphoid populations, could contribute to the identification of ICI responders. The aim of this review is to thoroughly examine significant published data on this topic in melanoma patients and to evaluate the potential role of lymphoid subsets as prognostic and predictive response biomarkers.

Vitiligo is a chronic autoimmune disease characterized by progressive depigmentation of the skin caused by the selective destruction of melanocytes. Although its etiopathogenesis remains unclear, multiple factors are believed to be involved, including genetic and metabolic factors linked to cellular oxidative stress, melanocyte adhesion defects, innate and adaptive immunity. The aim of this review is to provide an overview of the current state of knowledge regarding the role of different cellular mechanisms, including cytokines and chemokines interactions in the pathogenesis of vitiligo. Although there is no definitive cure for vitiligo, excessive progress has been made and several treatments have shown favourable results. A thorough understanding of the basis of the disease, uncover promising drug targets for future research, providing clinical researchers with valuable insights for developing improved treatment options.

Skin cancers, including melanoma, and non-melanoma- cutaneous basal cell carcinoma and cutaneous squamous cell carcinoma, are a diverse group of malignancies characterized by variations in their molecular and cellular features. Melanoma is a highly heterogenous tumor characterized by the dysregulation of a myriad of cell-cycle associated signaling pathways. In the non-melanoma skin cancers, such as cutaneous basal and cutaneous squamous cell carcinoma, the role of cyclin-dependent kinases and cyclins remains poorly understood with relatively limited investigation. Although revolutionary therapies against diverse molecular targets have been introduced over the last decade leading to significant prognostic benefit, advanced stages of melanoma remain exceptionally difficult to treat. The three cancers are united by evidence of stem-like, cancer initiating cell populations which dictate highly dynamic microenvironments and rely on disrupted cell cycle signaling to support treatment resistance and cancer progression. Potential of cell cycle targeting in skin cancer in underexplored in terms of identification of specific mechanisms supporting the maintenance of skin cancer stem cell pools and could offer potential targets to advance the therapy in these malignancies. In this review, we comprise the existing data on major cell of cell cycle regulators in skin cancer, the regulation of cancer stem cells and most recent developments and limitations surrounding cell cycle-targeted therapies, with a focus on the application of CDK inhibitors.

A number of agents, including immune checkpoint inhibitors, have become available for the treatment of hepatocellular carcinoma (HCC). However, the objective response rate of these drugs is currently only 30% to 40%, with a high incidence of side effects. There are also no prac-tical biomarkers to predict their therapeutic effects. Most of the systemic therapies for HCC are performed in general hospitals without research facilities. Such hospitals can perform imaging tests, like CT and MRI, as well as pathological diagnosis using tumor tissue sampling and im-munohistochemical staining. However, analyzing tumor genomic or transcriptomic profiles is difficult because of limitations in facilities, personnel, and cost. Therefore, in this review, we provide an overview of the wide range of research that has been conducted on HCC biomarkers from blood, tissue, or imaging information that can be used practically in general hospitals for predicting the therapeutic effect of systemic therapies before treatment begins. For general hos-pitals that treat HCC patients, we recommend conducting treatment after assessing the state within the tumor tissue as much as possible by collecting blood and tissue samples and per-forming pre- treatment MRI image evaluations.

Background: In the aftermath of the ORAL Surveillance trial, real-world studies are needed to elucidate the effectiveness and safety of Janus kinase inhibitors (JAKis) in routine clinical practice. Methods: We performed a multicenter, retrospective cohort study investigating the real-life effectiveness and safety of filgotinib, a novel JAK1 inhibitor, in adult patients with rheumatoid arthritis (RA). Demographic information, disease characteristics, prior treatment history, and comorbid conditions, were retrieved from clinical records at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment. Results: A total of 82 patients (63 women) agreed to participate in the study, of which 39 (47.6%) were older than 65 years. Average RA duration was 13 ± 9 years; 19 patients (23.1%) were current or former smokers and 4 patients (4.9%) had a past history of cardiovascular events. Most patients had previously received at least one biologic disease-modifying antirheumatic drug (range: 1–6+); in addition, 11 patients (13.4%) had been already exposed to another JAKi. During the follow-up, 7 patients discontinued treatment due to primary failure (n = 3) or adverse events (n = 4). Significant reductions in pain and number of tender and swollen joints were observed at T3 and T6. A relevant proportion of patients achieved DAS28-CRP remission at T3 and T6 (46.3% and 66.2%, respectively). Conclusion: Our data provide additional insight into the effectiveness and safety of filgotinib in a real-world setting, even among patients with difficult-to-treat RA and a high prevalence of cardiovascular risk factors.

Despite the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitor-urinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a high sensibility to immune checkpoint inhibitors, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitors receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with photon irradiation or chemotherapeutic drugs in the management of breast cancer. Studies on combination of HDACi and particle type of radiation remain limited. CUDC-101 is a multitarget inhibitor of Histone deacetylases (HDACs), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2(HER-2). In this paper, the effectiveness of CUDC-101 in enhancing radiation response to protons irradiation was studied in MCF-7, MDA-MB-231 and MCF-10A cell lines, using X-rays as reference radiation. γ-H2AX foci assays showed increased sensitivity to CUDC-101 in MDA-MB-231 cell line compared to the MCF-7 cell line. In both cell lines, induction of apoptosis was enhanced in CUDC-101 pre-treated cells compared to radiation (protons or X-rays) alone. Increased apoptosis was also noted in CUDC-101 pre-treated cells in the MCF-10A cell line. Cell cycle analysis showed increased G2/M arrest by CUDC-101 mono-treatment as well as combination of CUDC-101 and X-irradiation in the MDA-MB-231 cell line. Collectively, the findings indicate that CUDC-101 effectively enhances response to both X-radiation and proton irradiation, in the triple negative MDA-MB-231 cell line. The study highlights that CUDC-101 holds potential in the management of triple negative breast cancer as monotherapy or in combination with X-irradiation.

Recently, neglected and underutilized species (NUS) have deservedly come to the forefront of scientific interest because they can contribute to the human nutrition, due to the content of bio-active substances such as antioxidants. Despite the great diversity and rich tradition in use of Philippine NUS, the nutritional properties of many edible plants remain unexplored. The main objective of this study was to evaluate various parts of eleven NUS fruits and vegetables traditionally consumed in the Philippines, namely Allaeanthus luzonicus, Canarium ovatum, Dillenia philippinensis, Ficus pseudopalma, Flacourtia indica, Flacourtia inermis, Garcinia intermedia, Heliotropium arboreum, Posoqueria latifolia, Stelechocarpus burahol and Sterculia quadrifida for their total phenolic content (TPC) and in vitro antioxidant activity (DPPH and ORAC assays). The strongest antioxidant activity obtained in both assays were inflorescence of A. luzonicus (DPPH IC50 = 91.0 μg/mL, ORAC IC50 = 37.9 μg/mL) and fruit of S. burahol (DPPH IC50 = 253.7 μg/mL, ORAC IC50 = 32.2 μg/mL). These two species also had the highest TPC (202.1 and 133.0 µg GAE/mg extract, respectively). For all samples tested, the strong correlation was found between TPC and antioxidant activity. Based on our results, A. luzonicus and S. burahol have a promising potential as novel antioxidant rich food.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to PPI at double dosage. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies − the only accurate method of assessing PPI response − efforts have been made to identify PPI responder patients. Clinical or endoscopic features and biomarkers evaluated so far however, have not proved good enough in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we give an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all researches evaluating the effect of GAS use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95% CI) for overall survival (OS) and progression-free survival (PFS) were calculated with fixed-effects or random-effects model. The study population included n=16 retrospective studies and 372,418 patients. Series concerned gastrointestinal tract tumors (n=5 studies), renal cell carcinomas (RCC, n=3 studies), non-small cell lung cancers (NSCLC, n=5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n=3 studies. The pooled HRs for OS and PFS were 1.31 (95% CI: 1.20–1.43; P<01) and 1.3 (95%CI 1.07-1.57; P<0.01) for GAS and no GAS users, respectively. Only studies of EGFR mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

(1) Background: BRCA mutation and homologous recombination deficiency (HRD) are used to administrate PARP inhibitors (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy.; (2) Methods: Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org.; (3) Results: Thirty-nine patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97), and the specificity 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the AUC was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%; (4) Conclusions: KELIM score seems to be a new, cheaper and faster tool to identify patients that can benefit from PARPi maintenance therapy.

Histone deacetylases inhibitors (HDACi) have shown promising therapeutic outcomes in haematological malignancies such as leu-kaemia, multiple myeloma and lymphoma, with dis-appointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACi can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACi has been reported as early as 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols on the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted.

Objective: Aims to investigate the effects of empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, on renal fibrosis in male diabetic Sprague-Dawley (SD) rat model. Methods: Streptozotocin(STZ) were injected to establish diabetes model, EMPA (10 mg/kg·d) or normal saline (NS) were administered for four weeks. The changes in renal fibrosis-related biomarkers, include vimentin (VIM), collagen types I(Col-I), collagen types III(Col-III), fibroblast-specific protein 1(FSP-1), connective tissue growth factor (CTGF), fibronectin (FN) were evaluated. Renal pathology, serum glucose levels and urinary protein excretion were also assessed. Results: Biomarkers of renal fibrosis were significantly reduced in the EMPA group compared to those in the NS group after 4-week treatment, including VIM (519.84±83.37 vs. 663.27±91.84 ng/ml, P<0.05), Col-I (21.27±1.46 vs. 25.71±2.82 ng/ml , P<0.05) and Col-III (7.06±1.12 vs. 9.43±1.36 ng/ml, P<0.05), FSP-1 (4.38±0.81 vs. 5.70±0.78 ng/ml, P<0.05), and CTGF (1147±217 vs. 1556±235 pg/ml, P<0.05),respectively. Nevertheless, compared to normal control (NC) group, the levels of renal fibrosis-related biomarkers in the EMPA group showed no significant differences except for VIM, which was VIM (336.66±28.87 vs. 519.84±83.37 ng/mL, P<0.001). NS group rats showed notable renal tubular dilation and casts, EMPA group exhibited only mild tubular dilation. Conclusion: These findings suggest that empagliflozin reverse renal fibrosis potentially through inhibiting CTGF-mediated epithelial-mesenchymal transition.

APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemo-resistance through the control of gene expression by a redox-based mechanism. APE1 is overex-pressed and serum-secreted in different cancers, representing a prognostic and predictive factor, and a promising non-invasive biomarker. Strategies directly targeting APE1 funtions led to the identification of inhibitors showing a potential therapeutic value, which some of them are cur-rently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating oncomiRs maturation, and oxidized-RNA decay. Recent data point out a control role of APE1 in the expression and sorting of oncomiRs, within secreted extracellular vesicles (EVs). This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or the DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy coming from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.

Introduction. Psoriatic disease (PsD), encompassing psoriasis, psoriatic arthritis, inflammatory bowel disease, and uveitis, presents a significant burden due to its chronic and diverse inflammatory nature, affecting various clinical domains including skin, joints, and internal organs. Psoriasis, affecting up to 3% of the global population, not only poses physical challenges but also profoundly impacts patients' psychological well-being, ranking among the most debilitating chronic conditions. Furthermore, PsD exhibits a spectrum of manifestations ranging from skin lesions like plaque psoriasis to systemic complications such as cardiovascular comorbidities, necessitating comprehensive assessment and management strategies. The increasing understanding of the aetiopathogenic mechanisms of these immune-mediated diseases and of the proinflammatory intracellular signalling pathways involved in Psoriatic disease (PsD) has facilitated the identification and development of new small molecules capable of inhibiting JAK proteins, emerging as effective treatment options for rheumatic and dermatological manifestations JAK inhibitors act rapidly, within a few days, with a striking beneficial class effect on pain. The oral formulation they share makes them a well-tolerated class of drugs, with a clear advantage over FAME in terms of convenience of administration, improving therapeutic compliance. Material and method. This observational, retrospective study conducted in a single-centre dermatology-rheumatology consultation of a second-level hospital in Granada, Spain, focused on patients diagnosed with Psoriatic Arthritis (PsA) over the last two years, who initiated treatment with Tofacitinib or Upadacitinib due to DMARD failure, excluding those with major contraindications to JAK inhibitors. Results: This study analyzed data from 32 patients diagnosed with Psoriatic Arthritis (PsA), focusing on their demographics, disease characteristics, and treatment history. The majority of patients (75%) initiated treatment with Tofacitinib, while the remainder started with Upadacitinib. The mean age of the patients differed between the two treatment groups. All patients met the CASPAR criteria for PsA diagnosis, with predominantly peripheral joint involvement. The average time from PsA diagnosis to initiation of JAKinhib treatment was 6.5 years, slightly longer for Upadacitinib users. Most patients presented with cutaneous psoriasis, and a minority exhibited radiographic erosions. Before JAKinhib therapy, all patients had previously received DMARDs. A subset of patients received concomitant DMARD therapy, predominantly methotrexate. Additionally, a proportion of patients were on low-dose corticosteroids. Baseline CRP and ESR levels were indicative of systemic inflammation. Disease activity measures at baseline indicated moderate disease activity, with a substantial proportion of patients having mild psoriasis involvement. Upadacitinib recipients with psoriasis primarily exhibited mild involvement. This study provides valuable insights into the characteristics and treatment patterns of PsA patients initiating JAKinhib therapy. Discusion. In this study, the efficacy, safety, and real-world outcomes of Janus kinase inhibitors (JAKinhibs) in the treatment of Psoriatic Arthritis (PsA) were assessed and compared with findings from pivotal randomized controlled trials (RCTs). Both Tofacitinib and Upadacitinib demonstrated significant efficacy in PsA patients refractory to DMARDs and TNF inhibitors, with rapid improvement in joint and skin activity indices. Although patients in this cohort exhibited younger age, higher female prevalence, and shorter disease duration compared to those in RCTs, treatment responses were comparable or even superior. Notably, despite fewer concurrent DMARDs and a higher proportion of patients receiving monotherapy, JAKinhibs maintained a favorable safety profile, with a low frequency of mild adverse events leading to treatment discontinuation. These findings emphasize the robust efficacy and tolerability of JAKinhibs in real-world clinical settings, supporting their role as effective therapeutic options for PsA patients.

The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one tar-get-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy- 2,3-dihydro-1H-inden-1-one (1a), which in the E diastereomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound the thermal stable E diastereoisomer, along with the E/Z mixture as produced by UV-B light irradia-tion in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-diastereoisomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, re-spectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z diastereoselectivity of 1h toward the two target enzymes.

The signaling complex around voltage-gated sodium (Nav) channels includes accessory proteins and kinases crucial for regulating neuronal firing. Previous studies showed that one such kinase, WEE1—critical to the cell cycle—selectively modulates Nav1.2 channel activity through the accessory protein fibroblast growth factor 14 (FGF14). Here, we tested whether WEE1 exhibits crosstalk with the AKT/GSK3 pathway for coordinated regulation of FGF14/Nav1.2 channel complex assembly and function. Using the in-cell split luciferase complementation assay (LCA), we found that the WEE1 inhibitor II and GSK3 inhibitor XIII reduce FGF14/Nav1.2 complex formation, while the AKT inhibitor triciribine increases it. However, combining WEE1 inhibitor II with either one of the other two inhibitors abolished its effect on FGF14/Nav1.2 complex formation. Whole-cell voltage-clamp recordings of sodium currents (INa) in HEK293 cells co-expressing Nav1.2 channels and FGF14-GFP showed that WEE1 inhibitor II significantly suppresses peak INa density, both alone and in the presence of triciribine or GSK3 inhibitor XIII, despite the latter inhibitors’ opposite effects on INa. Additionally, WEE1 inhibitor II slowed the tau of fast inactivation, and caused depolarizing shifts in the voltage dependence of activation and inactivation. These phenotypes either prevailed or were additive when combined with triciribine but were outcompeted when both WEE1 inhibitor II and GSK3 inhibitor XIII were present. Concerted regulation by WEE1 inhibitor II, triciribine and GSK3 inhibitor XIII were also observed on long-term inactivation and use-dependence of Nav1.2 currents. Overall, these findings suggest a complex role for WEE1 kinase—in concert with the AKT/GSK3 pathway—in regulating the Nav1.2 channelosome.

Melanin content significantly influences the skin-lightening effects of active ingredients, with inhibition of melanin synthesis contributing to skin-lightening effects. This study evaluates the effects of novel cyclopeptide CHP-9 as a safe and potent human tyrosinase inhibitor. CHP-9 showed a significant inhibition rate of approximately 28.57% at 1% concentration. The melanin formation assay, upon exposure to CHP-9 alone, resulted in a reduction of cellular melanin content from 30.90±1.13 μg/mL to 23.51±1.14 μg/mL. Additionally, in silico molecular docking experiments were conducted to verify the tyrosinase inhibitory activity of the cyclopeptide CHP-9 on tyrosinase and it was observed that hydrogen bonding is pivotal in the binding affinity of CHP-9 with the target enzyme in docking. These results suggest that the cyclopeptide CHP-9 may serve as a valuable bioactive compound for skin-lightening agents in cosmetics applications, specifically in reducing melanin production.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on development of oral therapies with improved efficacy and safety compared to available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways, such as AhR, PDE-4 and Jak-STAT. Topical tapinarof, an AhR modulator, and roflumilast, a PDE-4 inhibitor, have exhibited favorable efficacy and safety outcomes have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis and specially on those that are currently under evaluation and development for the treatment of psoriasis.

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, tumor distant recurrence remains a concern, prompting exploration of Total Neoadjuvant Therapy (TNT) as a comprehensive treatment strat-egy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Non-operative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving clinical complete response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for treatment response assessment. This review synthesizes current evidence on TNT, ICIs, NOM and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Although transplantation procedures have been developed for patients with end-stagec hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces depression and headache; methotrexate affects the central nervous system; mouse monoclonal immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms have greatly reduced neurotoxic events. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, using drugs to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize the recent topics on the mechanisms of neurotoxicity of immunosuppressive drugs. In addition, some information about neuroprotective effects of several immunosuppressants are also discussed.

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

Lumpy skin disease (LSD), caused by a virus within the Poxviridae family and Capripoxvirus genus, induces nodular skin lesions in cattle, spreading through direct contact and insect vectors, significantly affecting global cattle farming. Despite available vaccines, their effectiveness is limited by poor bioavailability and adverse effects. Our study aimed to identify potential inhibitors targeting LSD-associated DNA polymerase protein, selecting LSDV039 for further investigation through comprehensive analysis and computational methods. Virtual screening revealed rhein and taxifolin as potent binders among 380 phytocompounds, with respective affinities of -8.965 and -7.195 kcal/mol. Canagliflozin and tepotinib exhibited strong affinities (-9.858 and -8.856 kcal/mol) among 718 FDA-approved antiviral drugs. Molecular dynamics simulations of canagliflozin, tepotinib, rhein, and taxifolin highlighted taxifolin's superior stability and binding energy. Rhein displayed compactness in RMSD and RMSF but fluctuations in Rg and SASA, while canagliflozin demonstrated stability compared to tepotinib. The study highlights the promising potential of repurposed drugs and phytocompounds as LSD therapeutics. However, extensive validation through in-vitro, in-vivo, and clinical trials is crucial for their practical application.

Background: Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation &gt; 10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Nest, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Results: Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in a MKN-45 GC cell xenograft model. Furthermore, combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE-33 cells. Conclusions: Therefore, targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on July 20, 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis, obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and July 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) has been approved by the EMA in August 2024. Several other potential biosimilar candidates are under development, including FYB202 (Formycon), BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g. Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review will summarize the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and the third leading cause of cancer-related death worldwide. Liver transplantation (LT) is the best therapy for most patients with non-metastatic HCC. In recent years, the management of patients with HCC has changed considerably, thanks to the improvement of molecular biology knowledge and the introduction of immunotherapy. To date, systemic therapy is authorized in the Western world only in patients with advanced HCC. However, this therapy could lead not only to stabilize the tumour disease or improve survival but could display excellent response and lead to downstaging of the tumor that finally permits liver transplantation. There are increasing reports of patients that have performed liver transplantation after pretreatment with immune checkpoint inhibitors (ICIs). However, due to the intrinsic mechanism of ICIs to stimulate the immune response against tumors, they could also cause graft rejection. This review aims to evaluate the readiness and outcomes of liver transplantation in patients with advanced HCC who have previously undergone treatment with ICIs. It seeks to identify the challenges, risks, and benefits associated with this conversion therapy. The integration of ICIs into the treatment paradigm for advanced HCC necessitates a nuanced approach to liver transplantation. While early evidence supports the feasibility of LT following ICI therapy, there is an urgent need for standardized guidelines and more extensive longitudinal studies to optimize patient selection, timing, and post-transplant management.

Background: The implementation of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has brought a significant improvement in the prognosis for CML patients and a decrease in the number of patients requiring allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, the impact of TKIs on allo-HCT outcomes have not been thoroughly explored. Objectives: The main endpoint of our research was to assess the impact of prior TKI treatment on acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD). Methods: In our retrospective analysis we included 240 patients treated between 1993 and 2013, and divided them into 3 groups according to the therapy administered prior to matched related or matched unrelated donor allo-HCT (imatinib group n=41, dasatinib/nilotinib group n=28, TKI naïve group n=171). Results: Both the cumulative incidence of aGvHD (p=0.044) and cGvHD (p&lt;0.001) in individuals receiving second generation TKIs (2G-TKIs) prior to allo-HCT compared to patients receiving no TKIs or imatinib (IMA) (40.7% vs 61.4% vs 70.7%, p=0.044; 25.0% vs 76.4% vs 51.2%, p&lt;0.001, respectively). In case of the 2G-TKI cohort, the number of low-grade aGvHD and cGvHD was significantly lower compared to the IMA and TKI-naïve groups (p=0.018, p=0.004; p&lt;0.001 versus TKI-naïve, respectively). In terms of 3-year overall survival (OS) there were no important variations between TKI-naïve, IMA and 2G-TKI (55% vs 49.9% vs 69.6%, p=0.740). Conclusions: The results of our study suggest that TKI treatment prior to allo-HCT may have protective impact on immune-mediated outcomes.

B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

Influenza viruses cause acute respiratory infections responsible for significant mortality and morbidity around the world. Various factors, such as antigenic drift, allow influenza strains to avoid being fully suppressed by seasonal vaccines. This has led to the increased scrutiny of antivirals as treatment and prophylaxis options for seasonal outbreaks and potential pandemics. Unfortunately, many influenza antivirals suffer from a lack of adequate clinical trials, as well as a lack of toxicity data. This is especially true of umifenovir (arbidol), a drug popularly used for the prevention and treatment of influenza strains in China and Russia. Neuraminidase inhibitors, though widely prescribed, display a potential for future resistance. Adamantanes, while proven to be effective in treating influenza A, are already encountering rapid and widespread cross-resistance and are effectively obsolete. Baloxavir marboxil, a newer antiviral, shows promise in treating acute uncomplicated influenza and may avoid the development of resistance when co-administered with other antiviral drugs. Indeed, the low genetic barrier to resistance associated with influenza antivirals could potentially be overcome by co-administration with other antivirals. This review explores the most widely prescribed antivirals for influenza treatment, their mechanisms of action, and the data currently available about their susceptibility to resistance and efficacy.

BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) encode for tumor suppressor proteins which are critical regulators of the homologous recombination (HR) pathway, the most precise and important DNA damage response mechanism. Dysfunctional HR proteins cannot repair double-stranded DNA breaks in mammalian cells, a situation called HR deficiency. Since their identification, pathogenic variants and other alterations of BRCA1 and BRCA2 genes have been associated with an increased risk of developing mainly breast and ovarian cancer. Interestingly, HR deficiency is also detected in tumors not carrying BRCA1/2 mutations, a condition termed “BRCAness”. One of the main mechanisms causing the BRCAness phenotype is the methylation of the BRCA1/2 promoters and this epigenetic modification is associated with carcinogenesis and poor prognosis mainly among patients with breast and ovarian cancer. BRCA1 promoter methylation has been suggested as an emerging biomarker of great predictive significance, especially concerning Poly (ADP-ribose) Polymerase inhibitors (PARP inhibitor-PARPi) responsiveness, along with or beyond BRCA1/2 mutations. However, as its clinical exploitation is still insufficient, the impact of BRCA1/2 promoter methylation status needs to be further evaluated. The current review aims to gather the latest findings about the mechanisms that underline BRCA1/2 function as well as the molecular characteristics of tumors associated with BRCA1/2 defects, by focusing on DNA methylation. Furthermore, we critically analyze their translational meaning and the validity of BRCA methylation biomarkers in predicting treatment response and we suggest a diagnostic pipeline that could be implemented in liquid biopsy to aid precision pharmacotherapy in BRCA-associated tumors.

Background. Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. Case presentation. We identified across different Cancer Centers six cases of both BRCA wild-type and BRCA-mutated EOC spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as by clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Conclusion. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for optimal disease control of this unfortunate patient’s subset. Albeit not being directly investigated in BM patients, the PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

Objective Hypertension is one of the most common chronic diseases, affecting more than 20 % of the population. The side effects experienced due to antihypertensive medications such as tired-ness, muscle pain, and insomnia are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSR) and following differentiation of messages found in more than one patient. Methods We conducted a retrospective analysis of the reported adverse drug reactions (ADR) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) - inhibitors, and sartans for the period 2017-2021. Each ICSR form was observed and data for suspected medicine and type of adverse reaction was analyzed. Results The total number of processed notifications for adverse drug reactions (ADR) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29.) Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusion Cardiovascular medicines from the groups of ACE inhibitors, sartans and statins are with high share of reported ADRs in the BDA system. Some of them are severe and need further investigation.

This mini-review explores the comparative efficacy, safety, and clinical outcomes of high-dose proton pump inhibitor (PPI) intravenous infusion versus oral acid pump inhibitor therapy following endoscopic treatment for bleeding peptic ulcers. Recent evidence suggests that intravenous PPIs can significantly reduce the rebleeding rates within the critical first 72 hours post-intervention, with a noted rebleeding rate of 6% compared to 14% in patients receiving oral Vonoprazan (VPZ) therapy. Additionally, the rapid onset of action associated with intravenous administration leads to faster stabilization of vital signs and a reduced need for subsequent blood transfusions. Safety profiles for both intravenous and oral VPZ were favourable, with minimal adverse effects, the most common being transient headaches.However, the findings from our single-centre study with a moderate sample size prompt consideration of more extensive, multicentre trials to enhance the generalizability of the results. Current limitations include potential biases, short-term focus, missing data issues, and a need for long-term outcome data, necessitating further research. Future studies should also explore the cost-effectiveness of intravenous versus oral VPZ and the impact on patient quality of life and long-term mortality rates.This review underscores the importance of tailored PPI therapy in managing bleeding peptic ulcers post-endoscopy. It suggests a potentially pivotal role for intravenous PPIs in high-risk patient groups, advocating for a shift towards more aggressive and immediate care protocols in specific clinical settings.

Retinoblastoma (Rb) is a rare cancer that nonetheless represents the most common ocular malignancy in children. Rb exists as familiar and sporadic cancer and the increasing incidence of the sporadic one and its pathogenesis is mostly unknown. To date the management of retinoblastoma requires intensive chemotherapy and sometimes invasive surgery in order to preserve vision and quality of life in Rb patients. The discovery of the epigenetic nature of non-hereditable/sporadic Rb led to the development of high-throughput precision investigation strategies for the study of its epigenetic landscape. Here we investigated the effect of the demethylating 5-Aza-2’- deoxycytidine (Decitabine; DAC) agent on preclinical models to assess its possible use as anti-cancer drug in the treatment of Rb patients. We found that DAC treatment induced cell cycle arrest and apoptosis in Weri-Rb-1 cells. We investigated the variation of differential gene expression profile in Rb cells in relation to time of exposure to DAC with respect to controls. Network map analysis evidences 15 hub/driver genes, which share pathways of regulation of TNF-, FAS-, p53-dependent apoptotic signaling and NF-kB pro-survival pathways. Furthermore, a computing expression profile analysis of publicly available datasets of patients’ primary tumors and normal retina cell-derived organoids vs WeriWeri-Rb-1 DEGs depicted the relevancy of these 15 hub genes on retinoblastoma genesis. The antiproliferative effect of DAC treatment on Rb was confirmed in vivo, both in subcutaneous xenograft and orthotopic models also showing the changes the gene methylation status in treated Weri-Rb-1, shedding a new light on the reprogramming antiproliferative dynamics induced by the epigenetic therapy and on the role of this therapeutic approach to spare children sight and life.

Antimicrobial resistance (AMR) is a growing global threat, affecting the effectiveness of antimicrobials and posing significant challenges in the treatment of bacterial and viral infections. The emergence of the coronavirus in 2019 and the ongoing menace of infectious diseases such as HIV/AIDS, tuberculosis, and hepatitis remind us of the impact infections have on economic stability and global health, and therefore, the need for a more holistic and long-term solution as opposed to antibiotics - measures that were previously relied on. This review explores recent advances in immunotherapeutic strategies, particularly cytokine-based therapies, adoptive cell therapy, monoclonal antibodies, and immune checkpoint inhibitors, in the control of AMR. It focuses on pathogens with high clinical relevance, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Mycobacterium tuberculosis, and viral threats such as HIV and SARS-CoV-2. New inventive approaches such as CAR T cell therapy and MAIT cells were discussed in the context of bacterial and viral infections, highlighting promising results from clinical trials and addressing the challenges of toxicity, immune evasion, and therapy resistance inherent in these diseases. Future priorities include optimizing combination therapies and exploring new immunomodulatory targets to improve these interventions' effectiveness in treating AMR and other infectious diseases.

Background. The type-2 sodium-glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single center, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Methods. We evaluated the consecutive patients affected by chronic heart failure (CHF) since January 2022. At baseline clinical visit the therapy taken by the patients as well as that prescribed were accurately collected. During a 6-12 month follow-up the the changes in concomitant therapy were analyzed. Results. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i, 13 with HFrEF, 2 with CHF with mild reduced (HFmrEF) and 2 with preserved ejection fraction (HFpEF). After baseline evaluation, SGLT2i were prescribed to 220 (63%) of all the patients enrolled, among whom 178 (84%) of HFrEF patients, 25 (42%) of HFmrEF and 17 (22%) of HFpEF. After follow-up, SGLT2i therapy was highly tolerated and it was associated with a significant increased prescription of sacubitril/valsartan and a reduced use of diuretics. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. Conclusions. In this single center “real world” study, SGLT2i were prescribed in HFrEF patients most of all already in therapy with the other classes of drugs currently recommended for their treatment. Moreover, a further optimization in prescribed ther-apy was observed during a short term follow-up. These data further support the use of this thera-peutic approach in routine clinical practice.

Sirtuins are nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylases and have been linked to the pathogenesis of numerous diseases such as HIV, metabolic disorders, neurodegeneration and cancer. Docking of the virtual pan-African natural products library (p-ANAPL), followed by in vitro testing, resulted in the identification of two inhibitors of sirtuin 1, 2 and 3 (sirt1-3). Two bichalcones; rhuschalcone IV (8) and rhuschalcone I (9), previously isolated from the medicinal plant Rhus pyroides, were shown to be active in the in vitro assay, with rhuschalcone I showing the best activity against sirt1, having an IC₅₀ = 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided.

This study presents a transversal investigation, that we performed at Fundeni hospital, into the therapeutic benefits and efficacy of Emicizumab, a non-factor therapy, in the context of hemophilia A. Ten patients diagnosed with hemophilia A were closely monitored, using clinical and laboratory resources, during the course of Emicizumab treatment, with an average of 12.8 months. Among these patients, six exhibited anti-factor VIII inhibitors, changing the medical approach and adding complexity to their clinical profiles. A comprehensive approach was adopted to assess the coagulation status of patients under Emicizumab therapy. The study employed several key coagulation monitoring tools, of which including thrombin generation time (TGT) and thrombelastography (TEG). These methodologies proved highly valuable results in evaluating the patients' coagulation profiles during the treatment regimen. Additionally, traditionally coagulation assays were utilized to gain a comprehensive understanding of the overall coagulation dynamics. Noteworthy, impressive outcomes emerged from the study. During prophylaxis with Emicizumab all patients had experienced a reduced number of bleeding events. Moreover, a subset of these patients underwent major surgical procedures (orthopedic joint replacements) with successful outcomes. These findings underscore the potential of Emicizumab therapy as an effective option for hemophilia A patients, including those that presented a prompt production of anti-factor VIII inhibitors. As for the outcomes, this transversal study sheds some light on the positive impact of Emicizumab therapy in addressing the coagulation challenges posed by hemophilia A. The utilization of global coagulation assays, such as thrombin generation time, thrombelastography and combined with traditional coagulation assays, used as monitoring tools highlights their significance once more in evaluating the therapeutic response. This research contributes by providing physicians with valuable insights to the field, offering a potential avenue for improved patients’ care and treatment strategies that translate in enhanced quality of life for hemophilia A patients undergoing Emicizumab therapy.

Background: Tumor mutational burden (TMB) is increasingly recognized as a vital biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. Despite its growing importance, the effectiveness of TMB as a predictive marker are well established in lung cancer and melanoma but remain ambiguous for breast and prostate cancers. Objective: This study aims to evaluate the role of TMB in predicting response to ICIs across four major cancer types—lung, melanoma, breast, and prostate—and to address the variability in TMB's predictive value in different cancers. Methods: A comprehensive review of the current literature was performed, analysing studies that investigated TMB and its association with ICI therapy outcomes in the specified cancer types. Results: The analysis reveals a strong consensus on the predictive value of TMB in lung cancer and melanoma, where high TMB levels are associated with improved clinical outcomes and better responses to ICIs. In contrast, the evidence for breast and prostate cancers is less conclusive, with variability in results highlighting the need for further research. Specifically, high TMB in these cancers does not consistently predict better responses to ICIs, suggesting that additional biomarkers or refined criteria might be necessary. Conclusion: TMB is a promising biomarker for predicting responses to ICI therapy, particularly in lung cancer and melanoma. However, its predictive value in breast and prostate cancers remains uncertain, underscoring the need for more extensive studies. Future research should focus on standardizing TMB evaluation methods and exploring additional biomarkers to improve treatment personalization and outcomes in these cancer types.

Dengue is the most prevalent arthropod-borne disease globally and affects approximately 2.5 billion people living in over 100 countries. The increasing geographic expansion of Aedes aegypti mosquitoes which transmit the virus has made dengue fever a global health concern. There are currently no approved antivirals available to treat dengue, and the only approved vaccine used in some countries is limited to seropositive patients. Treatment of dengue therefore remains largely supportive to date; hence research efforts are being intensified for the development of antivirals against dengue. The NS3 and NS5 nonstructural proteins have been the major targets for dengue antiviral development due to their indispensable enzymatic and biological functions in the viral replication process. NS5 is the largest and most conserved nonstructural protein encoded by flaviviruses including dengue. Its multifunctionality makes it an attractive target for antiviral development against dengue, but research efforts are hindered due to its limited structural characterization compared to the NS5 of other flaviviruses like the Zika virus. Increase in structural insights into the dengue NS5 protein will accelerate drug discovery efforts focused on NS5 as an antiviral target. In this review, we will give an overview of the current state of therapeutic development against dengue.

Histone deacetylase 6 (HDAC6) regulates many physiological processes that are involved in cancer development and progression such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, by deacetylation of multiple substrates and association with interacting proteins. Due to its the ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cells survival. HDAC6 is often overexpressed in tumors, including colorectal cancer (CRC) and is correlated with poor disease prognosis. However, it has been shown in animal models that HDAC6 is not essential for normal mammalian development. Therefore, it represents a good target for the development of novel cancer therapeutics. Selective inhibition of HDAC6 impairs growth and progression of many tumors without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown potential to reduce tumor progression and to enhance the therapeutic effect of other drugs. As HDAC6 is involved in regulation of immune responses, HDAC6 inhibitors have shown potential to improve antitumor immunity by increasing immunogenicity of tumor cells, augmenting immune cell activity and alleviating immunosuppression in tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect and to overcome resistance to immunotherapy.

PTK6, a Non-Receptor–Tyrosine-Kinase, modulates the pathogenesis of breast and prostate cancers, and is recognized as a biomarker of breast cancer prognosis. There are over 30 known substrates of PTK6, including signal transducers, transcription factors and RNA binding proteins. Many of these substrates are known drivers of other cancer types such as colorectal cancer. Colon and rectal tumours also express higher levels of PTK6 than the normal intestine suggesting a potential role in tumorigenesis. However, the importance of PTK6 in colorectal cancer remains unclear. PTK6 inhibitors such as XMU-MP-2 and Tilfrinib have demonstrated potency and selectivity in breast cancer cells when used in combination with chemotherapy, indicating the potential for PTK6 targeted therapy in cancer. However, most of these inhibitors are yet to be tested in other cancer types. Here, we discuss the current understanding of the function of PTK6 in normal intestinal cells compared with colorectal cancer cells. We review existing PTK6 targeting therapeutics and explore the possibility of PTK6 inhibitory therapy for colorectal cancer.

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases like the main proteases of SARS-CoV and MERS-CoV were tested. Then a huge effort has been done by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead, and the second one is a diverse group including chemical compounds which do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.

The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors has been investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks, statistical potentials, energy frustration, and volumetric cavity analyses. The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.

The difficulties faced by the society in its goal of reducing mortality and improving the health status during the period of the COVID-19 pandemic showed that it is necessary to develop new approaches in the therapy of infectious diseases, leading to higher treatment efficiency and few side effects. The subject of the present study is the formation and characterization of the proper-ties of stable liposomes loaded with extracts from Bulgarian medicinal plants and monitoring their antiviral action against the human strain of coronavirus OC43 (HCoV-OC43) in vitro. The hydrodynamic diameter and -potential of the liposomes containing each type of payload were determined with DLS and electrokinetics. The encapsulated amount of extracts was evaluated against quercetin and gallic acid by using colourimetric methods. The BALB 3T3 Neutral Red Uptake (NRU) phototoxicity/cytotoxicity assay was used to estimate the safety of the compounds. For assessment of the antiviral activity against HCoV-OC43 of liposomes (Lip) containing medicinal plant extracts, the cytopathic effect inhibition test was used. Measurements of the virucidal activity and the effect on the virus adsorption stage was carried out using the endpoint dilution method, and ∆lgs were calculated by comparison with untreated controls. The estimated photo irritation factors (PIF) for the Lip containing extracts were < 2 which assigns them to the category of non-phototoxic substances. When the extracts were introduced into the liposomes as their carriers, the antiviral activity of the vesicles against the replication of HCoV-OC43 in vitro in-creased by several times compared to their individual activity described in our previous study. The determination of the effect of structures loaded with extracts on the extracellular virions and the stage of their adsorption to sensitive HCT-8 cells proved that the liposomes do not affect directly the viral surface or cell membrane, but only perform a function of carriers of the active substances and the observed result is due solely to the intracellular action of the extracts.

Type 2 Diabetes mellitus (T2DM) and cancer share common risk factors including obesity, in-flammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and an-ti-apoptosis. The inhibition of PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy, however, the combination of therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.

HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.

The interplay between the human gut microbiota and the peripheral immune system significantly affects the efficacy of immune checkpoint inhibitors (ICIs) in cancer therapy. Despite this profound connection, the practical implications of microbiota dysbiosis in cancer immunotherapy ICIs & and CAR-T remain intricate and poorly understood in practical terms. This paper offers a comprehensive review of current literature on the role of gut microbiota dysbiosis in tumor development, and emerging microbiota modulation interventions, with a focus on fecal microbiota transplantation (FMT). FMT is a cost-effective therapeutic avenue, particularly in addressing diseases rooted in antibiotic-resistant bacteria, such as Clostridium difficile. Here we provided insights into the applications of FMT and other gut microbiota therapies in the landscape of cancer treatment, emphasizing their influence on the tumor microenvironment and the efficacy of ICIs with suggestions for future research directions and their implications for clinical practice.

The non-structural protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been in consideration in literature, and therefore, we decided to explore this strategy to develop a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25` to Arg-28` at the core of NS4A21`-33` needed to activate the NS3 protease. Some of the synthesized MOC compounds were able to compete with and displace NS4A21`-33` for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21`-33` with a competition IC50 of 1.9 ± 0.12 µM in a fluorescence anisotropy assay, stabilized the denaturation of NS3 by increasing the aggregation temperature by ΔTagg 0.6 ± 0.140 ℃. MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations rationalized the structure-activity relationship (SAR) differences between the active MOC-24 and the inactive MOC-26. Our data shows that MOC compounds are possibly the first examples of NS4A peptidomimetics that demonstrated promising activities against NS3 proteins.

While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and FOXA1, rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.

Background: Cardiovascular comparisons between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Sodium-glucose co-transporter-2 (SGLT-2) inhibitors in type 2 diabetes(T2D) remain an area of interest. Thus, the purpose of this meta-analysis is to compare the impact of these two drug classes on major CV outcomes, such as heart failure hospitalization(HHF), major adverse cardiovascular events (MACE), CV mortality, myocardial infarction, stroke, and all-cause mortality, with an emphasis on heart failure hospitalizations. Methods: PubMed (including MEDLINE), Google Scholar, Cochrane Central Library, PLOSONE, and Science Direct databases were searched for studies that compared GLP-1 RAs and SGLT-2 inhibitors in patients with type 2 diabetes. Six cohort studies were selected for the analysis. Odds ratios (OR) with 95% CI were calculated and a random-effects model was used to estimate the hazard ratios (HR) of the studies. The quality of the studies was evaluated using the Newcastle-Ottawa Scale (NOS), and publication bias was assessed using funnel plots and Egger’s test. Results: Pooled analysis demonstrated a significant reduction in heart failure hospitalizations with SGLT-2 inhibitors compared to GLP-1 RAs (HR: 0.78 [0.62–0.98], I² = 87%, p < 0.01). Cardiovascular mortality was also significantly reduced by SGLT-2 inhibitors (HR: 0.74 [0.31–1.67], I² = 87%, p < 0.01), and a modest reduction was observed for all-cause mortality (HR: 0.85 [0.44–1.64], I² = 17%, p = 0.27). While SGLT-2 inhibitors appeared to slightly reduce the risk of myocardial infarction (HR: 0.83 [0.74–0.92], I² = 0%, p = 0.85), no significant difference was observed for MACE (HR: 0.91 [0.82–1.01], I² = 0%, p = 0.70) or stroke (HR: 0.88 [0.77–1.00], I² = 0%, p = 0.85). Conclusions: Compared to GLP-1 receptor agonists, SGLT-2 inhibitors were more effective in lowering heart failure hospitalizations and cardiovascular mortality in patients with type 2 diabetes. It was also found that all-cause mortality and myocardial infarction were moderately reduced using oral agents. However, the differences were not significant for MACE or stroke. These results imply that SGLT-2 inhibitors may potentially provide better cardiovascular benefits, especially with respect to heart failure and cardiovascular mortality, than GLP-1 RA. Further research should be conducted to determine the effects of the long-term use of these therapies on stroke and other cardiovascular events.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are known for efficacy in managing blood sugar levels in type 2 diabetes and also improving cardiovascular and renal outcomes. However, increased risk of urogenital infections (UGIs) remains a significant concern in their safety profile. This study aimed to investigate the association between SGLT2i therapy and UGIs in a real-world clinical set up of a tertiary care centre in India. The key hypothesis was SGLT2i use is associated with incidence of UGIs while the secondary hypothesis included the relationship of the incidence of risk with the dose. Methods: This was a six-month prospective observational study, that enrolled 309 adults ≥18 years of age, who were newly prescribed SGLT2 inhibitors, particularly Dapagliflozin 5 mg and 10 mg from October 2023. The incidence of UGIs was assessed through patient interviews and medical records during the follow up from 2 weeks of initiation. UGIs were defined as clinical manifestations that resolved on SGLT2i discontinuation or appropriate treatment. Results: Of 309 initiators, 300 patients were followed up. 9 patients didn’t follow up in OPD. From these, 58 (19.3%)patients developed UGIs, comprising of 47 (15.6%) bacterial infections and 11 (3.6%) UGIs of fungal origin. The association was performed on basis of logistic regression analysis which revealed a statistically significant association of UGIs with the prescription of SGLT2i. Higher doses of SGLT2 inhibitors was observed to be associated with significantly increasing the risk of UGIs (p < 0.05). No significant risk factors such as body mass index (BMI), age, sex, HbA1c, or educational status were identified to have significant associations with UGI occurrence. Conclusion: This study highlights a clinically relevant association between SGLT2i use and urogenital infections.

Background/Aims: Conflicting results have been reported regarding the interaction between proton pump inhibitors (PPIs) and clopidogrel. We investigated whether concomitant PPI use influenced the risk of recurrence in patients with stroke and myocardial infarction (MI). Methods: This study used two databases for different designs, the Korean National Health Insurance Service (NHIS) database for a self-controlled case series design, and the national sample cohort of the NHIS database converted to the Observational Medical Outcomes Partnership-Common Data Model version for a cohort study. Results: In the PPI co-prescription group, recurrent hospitalization with stroke occurred in 17.6% of the 8,201 patients with history of stroke, and recurrent MI occurred in 17.1% of the 1,216 patients with history of MI during 1 year. According to the self-controlled case series, the overall relative risk (RR) of recurrent stroke was 2.09 [95% confidence interval (CI); 1.83-2.38], and the RR showed an increasing trend with PPI duration. In the cohort study, there was a higher incidence of recurrent stroke in the PPI co-prescription group [Hazard ratio (HR): 1.34, 95% CI: 1.01-1.76, P=0.04]. The overall RR of recurrent MI was 1.47 (95% CI; 1.02-2.11) in the self-controlled case series; however, there was no statistically significant difference in recurrent MI in the cohort study (HR:1.42, 95% CI:0.79-2.49, P=0.23). The impact of individual PPIs on stroke and MI showed different patterns. Conclusions: PPI co-prescription with clopidogrel was associated with recurrent stroke; however, its association with recurrent MI remains inconclusive. The influence of individual PPIs should be clarified in the future.

Novel drugs profoundly changed the outcomes in CLL patients and traditional prognostic/predictive factors that were delineated in the era of chemo-immunotherapy need to be validated in the contest of these new targeted therapies. Currently, the most important prognostic genetic biomarkers are immunoglobulin heavy chain variable (IGHV) mutational status, genetic aberrations including del(17p)/TP53 abnormalities and the complex karyotype. In this review we discuss the prognostic/predictive role of these genetic markers in relation to novel treatments. Moreover, we present and discuss the new score systems that were elaborated and validated in the era of new drugs. Given the deeper responses obtained with small molecules, new prognostic/predictive markers, including measurable residual disease, and validated prognostic scores could possibly be incorporated into routine prognostic scores, to better identify “very-high” CLL patients, who will need more effective treatments.

The ErbB/HER family of protein-tyrosine kinases (ErbB) and the phosphatidylinositol 3-kinase (PI3K) represent crucial targets in the treatment of head and neck squamous cell carcinoma (HNSCC). We previously reported that a combination therapy using Afatinib (ErbB inhibitor) and Copanlisib (PI3K inhibitor), both FDA-approved kinase inhibitors, suppressed the growth of HPV-positive HNSCC. In our current study, we further evaluated the efficacy and clinical potential of this combination therapy for treating HPV-negative HNSCC in vitro and in animal model. We found that the combination treatment of Afatinib and Copanlisib dramatically enhanced inhibition of cell proliferation and reduced cell survival when compared to treatment with either inhibitor in two HPV negative HNSCC cell lines. Notably, this combination led to significant inhibition of xenograft tumor growth in mice, without any apparent effects on body weight. Copanlisib alone effectively blocked PI3K/Akt signaling, but caused up-regulation of HER2 and HER3 phosphorylation as previously reported in other types of cancer. However, the combination treatment with Copanlisib and Afatinib completely blocked phosphorylation of the ErbB family (including HER3) and Akt, while also remarkedly increasing apoptosis. These results suggest that co-targeting the ErbB family and PI3K kinases by a combination treatment of Afatinib and Copanlisib can have clinical potential for patients.

Background: Newer personalized medicine including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have shown to improve survival of breast and gynaecological cancer patients. However, efficacy outcomes may be hampered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies suggest that add-on mistletoe (Viscum album L., VA) improves quality of life and ameliorates cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy in breast and gynecological cancer patients. Methods: The present study is a real-world data study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted with or without Helixor® VA therapy as well as safety - associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stage breast or gynecological cancer patients (n = 242) were on average 54.5±14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation uses blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte Antigen 4 and anti-programmed Death-1 antibodies has shown promise by enhancing T cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T cell receptors could further augment the anti-tumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

Gap junctions (GJs) made of connexin-43 (Cx43) are important for the conduction of electrical impulses in the heart. Modulation of Cx43 activity may be useful in the treatment of cardiac arrhythmias and other dysfunctions. Search of novel GJ modulating agents using molecular docking approach allows to predict the binding affinities that often significantly differ from experimentally estimated their potencies. The objective of this study was to demonstrate that Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using the QSAR model and molecular docking, we evaluated the known Cx43 GJ inhibitors, suggested a new one, and tested it experimentally. Our QSAR model predicted the concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds and estimated the correlation between predicted and experimental IC50ies (pIC50 and eIC50). This led to suggestion of monocyclic monoterpene d-limonene as putative Cx43 inhibitor with pIC50 = 1.07. In turn, dual whole-cell patch-clamp measurements provided eIC50=1.41. The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR model well correlated with their eIC50ies (R = 0.88) in contrast to pIC50s obtained from molecular docking (R = 0.42). However, the molecular docking suggested that inhibitor potency may depend on their docking sites on Cx43.

Scale inhibitors are deployed as preventive and rejuvenation operation in oil and gas industry when production operations are under threat or menace of scale blockage. The application of scale inhibitors is carried out through a method known as squeezing. In general, the squeeze process is governed by inhibitor-rock interaction which is described by adsorption/desorption isotherm. Most reservoirs produce loose sand grains or fine sand which float and flow within the pore spaces along with the squeezed scale inhibitors. Hypothetical reports have shown that not all scale inhibitors pumped into the formation adsorb onto the formation rock. A number of factors (irreversible adsorption, pH changes, competing ions, concentration and temperature) have been considered to affect the adsorption and return profile of these scale inhibitors. This review work examines the performances of most common scale inhibitors used in the oil and gas production activities, theoretical application in reservoirs and how loose fine sand grains affect the adsorption and desorption characteristics of squeezed scale inhibitors. Additionally, presented were overviews of previous reports on fine sand production and migration of fine sands through formation pores in reservoirs.

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics (GLP-1ra and SGLT2-in). Despite new guidelines, clinical inertia, that can be caused by physicians, patients or healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons of clinical inertia and poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiative in diabetes aims to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Biofilm formation in unicellular eukaryotes, such as Candida albicans and Saccharomyces cerevisiae, represents a significant challenge in various sectors, including healthcare, agriculture, and industry. These biofilms are resistant to conventional antimicrobial treatments due to their protective extracellular matrix and complex regulatory mechanisms, such as quorum sensing (QS) and cyclic AMP (cAMP) signaling. Recent advances in the understanding of biofilm formation pathways have led to the identification of novel compounds that target these regulatory mechanisms. This review highlights breakthroughs from 2024 research, focusing on the inhibition of quorum sensing, disruption of extracellular matrix synthesis, and transcriptional/post-transcriptional regulation of biofilm-related genes. The application of these discoveries in Vietnam is particularly promising, given the country's challenges with biofilm-related infections in healthcare and productivity losses in agriculture and aquaculture. Natural product-based approaches, especially those derived from Vietnam's marine biodiversity, offer environmentally sustainable solutions for biofilm control. However, translating these laboratory findings into scalable, cost-effective applications faces challenges such as resistance development, environmental sustainability, and regulatory constraints. This review provides a comprehensive overview of compounds targeting biofilm regulatory mechanisms, evaluates their potential applications in Vietnam, and discusses future research directions, emphasizing the need for interdisciplinary collaboration to address the complexities of biofilm control.

The possibility of treating more patients for a longer time, has exploded the concept of anticipation in the systemic treatment of metastatic prostate cancer (mPC). The genetic analysis of Damage DNA Repair (DDR) mutations in pathogenetic variants (PV) and the development of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors led to the first valid precision medicine option tailored for mPC. PARP inhibitors are repeating the same evolutionary path experienced for androgen receptor signaling inhibitors (ARSI), starting from the late stage of second line mCRPC in a limited population and time frame. Inevitably also PARP inhibitors will be absorbed by the concept of anticipation and intensification of care. The anticipation of PARP inhibitors in the first line mCRPC therapy is already underway and further one in mHSPC will soon be verified. According to the crosstalk between androgen receptors (AR) and DNA repair, the new message that is emerging is that the combination of PARP inhibitors with ARSI, disconnects PARP from the genetic analysis. Most of the recent trials analyzing PARP inhibitors plus abiraterone or enzalutamide, enrolled first line mCRPC irrespectively to gene PV. The conclusion of the PROPEL trial was that the advantage was independent to PV status, however the highest advantage was reported in BRCA1/2 mutated subgroup. The conclusion of the MAGNITUDE trial was different, with a significant advantage only in the DDR mutated subgroup and the DDR non-mutated was closed for further enrollment. The combination of PARP inhibitors with ARSI represents a significant strategy in the concept of anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR.

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1), has changed the landscape of cancer treatment. To date, many Immune Checkpoint Inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as well as locally recurrent advanced cancer. However, immune-related adverse events (irAEs) of ICIs highlight the need for biomarker analysis with strong predictive value. Liquid biopsy is an important tool for clinical oncologists to monitor cancer patients and administer or change appropriate therapy. CTCs frequently express PD-L1 and this constitutes a clinically useful and non-invasive method to assess PD-L1 status in real time. This review summarizes all the latest findings about the clinical significance of CTC for the management of cancer patients during administration of immunotherapy and mainly focuses on the assessment of PD-L1 expression in CTCs.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied methotrexate and tumor necrosis factor inhibitor (TNFi) effects on neutralization responses post-COVID vaccination, in immune-mediated inflammatory disease(IMID). Methods: Prospective data and sera on adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA) and systemic lupus (SLE) were collected at 6 academic centres in Alberta, Manitoba, Ontario, and Quebec between 2022-2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between 5 laboratories, and each lab’s results analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for methotrexate and TNFi effects were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID vaccinations (number/type), and infections in the 6 months prior to sample. Adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for ancestral, and Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) RA, and the remainder PsA, SpA and SLE. Mean age was 57 (62.2 % female). For both individual labs and the meta-analyses, adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval, CI 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Myxomatous mitral valve disease (MMVD) is a leading cause of cardiac morbidity and mortality in dogs, requiring targeted intervention at various stages of disease progression. MMVD is characterized by thickening of the mitral valve leaflets, leading to mitral regurgitation and cardiac remodeling. This progressive disease impairs valve function, causing volume overload in the left atrium and ventricle, which can eventually lead to congestive heart failure. MMVD involves complex mechanisms, including genetic predisposition, neurohormonal activation, and mechanical stress on the valve. Thickened valve leaflets fail to seal properly during systole, resulting in mitral regurgitation and increased left atrial pressure. This triggers compensatory mechanisms like activation of the renin-angiotensin-aldosterone system (RAAS), contributing to further cardiac remodeling. Chronic RAAS activation results in fluid retention, vasoconstriction, and fibrosis, all of which can worsen heart failure. This mini-review provides an overview of current therapeutic strategies for the management of MMVD and discusses preliminary findings from our consortium regarding the preclinical and clinical efficacy of the sodium-glucose co-transporter type-2 (SGLT-2) inhibitor, dapagliflozin, in dogs.

An analysis of the relationship between plasma cytokines and the effectiveness of treatment with TNFαinhibitors was performed in 81 patients with moderate-to-severe psoriasis. Treatment efficacy was assessed by PASI score, and patients were classified into a positive effect (PASI≥75) and no effect group (PASI≤50). A positive effect was reached in 11 (41%) patients for etanercept, 14 (52%) for adalimumab, and 26 (96%) for infliximab. Data analysis did not show  differences in baseline TNFα levels and subsequent treatment effectiveness. The CART algorithm showed that at the baseline level of VEGF ≥ 32 pg/ml and IL17F &lt; 26 pg/ml, there was an 83% probability of a positive effect. Random forest analysis showed the importance of VEGF, ICAM1, sCD40L, IL17F and IL31 baseline levels in the prediction of treatment effectiveness.   Significant differences between the groups before/after the treatment were found only for TNFα: the median values were more than 50 times higher in no effect compared with positive effect group. There were differences before/after therapy in the levels of IL20, ICAM1, IL22, IL23 in the no effect group. The treatment affected the cytokine profile in most cases regardless of the effectiveness of therapy.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest into the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed the CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials that evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are undergoing. In this review, we summarize the current status of knowledge regarding the changes of CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biologic mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Kinases play an important role in regulating various intracellular signaling pathways that control cell proliferation, differentiation, survival and other cellular processes and their deregulation causes more than 400 diseases. Consequently, macrocyclization can be considered a noteworthy approach to develop new therapeutic agents for human diseases. Macrocyclization has emerged as an effective drug discovery strategy over the past decade to improve target selectivity and potency of small molecules. Small compounds with linear structures upon macrocyclization can lead to changes in their physicochemical and biological properties by firmly reducing conformational flexibility. A number of distinct protein kinases exhibit similar binding sites. Comparison of protein binding site provides crucial insights for the drug discovery and development. Binding site similarities are helpful to understand polypharmacology, identifying potential off-targets and repurposing of known drugs. In this review, we focused on comparing binding sites of those kinases for which macrocyclic inhibitors are available/studied so far. Furthermore, we calculated the volume of binding site pocket for each targeted kinase and then compared it with the binding site pocket of the kinase for which only acyclic inhibitors were designed till date. Our review and analysis of several explored kinases might be useful to target new protein kinases for macrocyclic drug discovery.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. Current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities – immune checkpoint inhibitors, cancer vaccines, oncolytic viruses, chimeric antigen receptor T cells and NK cells have shown promise. Clinical trials incorporating combination therapies of the above have overcome the microenvironment resistance and yielded survival and prognostic benefit. Rolling these new therapies out in the real-world scenario in a low cost, high throughput manner is the unmet need of the hour. These will bring practice changing implications to the glioma treatment landscape. In this review article, we focus on describing the hallmarks of the glioma microenvironment and its interplay with the different emerging modalities of immunotherapy.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme and one of the causes of tumor resistance to topoisomerase 1 inhibitors such as topotecan. Inhibitors of this Tdp1 in combination with topotecan may improve the effectiveness of therapy. In this work, we synthesized usnic acid derivatives, which are hybrids of its known derivatives - tumor sensitizers to topotecan. New compounds inhibit Tdp1 in the micromolar and submicromolar concentration range; some of them enhance the effect of topotecan on the metabolic activity of cells of various lines according to the MTT test. One of the new compounds (compound 7) not only sensitizes Krebs-2 and Lewis carcinomas of mice to the action of topotecan, but also normalizes the state of the peripheral blood of mice, which is disturbed in the presence of a tumor. Thus, the synthesized substances may be the prototype of a new class of additional therapy for cancer.

Cancer immunobiology is one of the hot topics of discussion amongst researchers today, and immunotherapeutic modalities are among the selected few emerging approaches to cancer treatment that have exhibited a promising outlook. However, immunotherapy is not a new kid on the block; it has been around for centuries. The origin of cancer immunotherapy in modern medicine can be traced back to the initial reports of spontaneous regression of malignant tumors in some patients following an acute febrile infection, at the turn of the twentieth century. This review briefly revisits the historical accounts of immunotherapy, highlighting some of the significant developments in the field of cancer immunobiology, that have been instrumental in bringing back the immunotherapeutic approaches to the forefront of cancer research. Some of the topics covered are: Coley's toxin - the first immunotherapeutic; the genesis of the theory of immune surveillance; discovery of T-lymphocytes and dendritic cells and their roles; the role of tumor antigens; relevance of tumor microenvironment; anti-tumor (therapeutic) ability of Bacillus Calmette Guerin; Melacine - the first therapeutic vaccine engineered; theories of immunoediting and immunophenotyping of cancer; and Provenge – the first FDA approved therapeutic vaccine. In this review, head and neck cancer has been taken as the reference tumor, for narrating the progression of cancer immunobiology, particularly, for highlighting the advent of immunotherapuetic agents.

Aim To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods We conducted a retrospective monocentric observational study over a 3 years period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint or tyrosine kinase inhibitors (ICIs or TKIs) as of January-2017. Imaging reports were analysed by two physicians in consensus. Anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results Eighty patients were included and 195 couples of scans analysed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The more frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions Treatment monitoring with 18F-FDG

Aim To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods We conducted a retrospective monocentric observational study over a 3 years period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint or tyrosine kinase inhibitors (ICIs or TKIs) as of January-2017. Imaging reports were analysed by two physicians in consensus. Anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results Eighty patients were included and 195 couples of scans analysed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The more frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions Treatment monitoring with 18F-FDG

Purpose: Data on Eosinophilic esophagitis in Israel is sparse. We appraised the clinical, endoscopic, and histological characteristics of 50 Israeli adults with EoE. Methods: Medical records of 50 adult patients with established diagnoses of EoE who were referred to our center from 2020 until 2023 at Bnai Zion Medical Center, Haifa, Israel, were reviewed. Results: Fifty patients with EoE were included, the mean age at diagnosis was 34±9.5 years. The sex ratio of males to females was approximately 2:1 with 34 males (68%) and 16 females (32%). Twenty-two of the 50 patients had a history of allergic diseases, Symptoms at diagnosis were as follows: Dysphagia was the primary presenting symptom observed (n=25, 50%), followed by food impaction (n=17, 34%) and GERD-like symptoms (n=14, 28%). Less frequent symptoms included vomiting, nausea, and chest pain. The most common endoscopic findings were normal mucosa (n=21, 42%) followed by Trachealization (n=17, 34%), esophagitis (n=7, 14%), and exudates (n=5, 10%). 66% of the subjects were initially treated with proton-pump inhibitors (PPIs). Nine patients (18%) were asymptomatic without any treatment. The remaining eight patients (16%) were given topical steroids. Clinical and histological resolution was detected in 50% of the patients who underwent a second EGD after 6–8 weeks of PPI. Conclusion: Our current study depicts the clinical features of adult patients with EoE in north Israel. This is the first demographic study in Israel that defines the clinical, endoscopic, and histological manifestations of EoE in the adult population.

Menin inhibitors are new and promising agents currently in clinical development that target the HOXA/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemia. The mechanism of action of this new class of agents is based on the disruption of menin-KMT2A complex (constitute of chromatin remodelling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or mutated NPM1. This new class of drugs has been tested alone, or in combination with synergistic drugs, in phase I and II clinical trials (AUGMENT-01 and 02, KOMET-01 and 07, SAVE, COVALENT trial and others), showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this review, we summarise the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data of this emerging and promising class of agents, in particular revumenib and ziftomenib.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care and shown remarkable efficacy clinically. This efficacy is, however, limited to subsets of patients with significant infiltration of lymphocytes into the tumor microenvironment. To extend their efficacy to patients who fail to respond or achieve durable responses, it is now becoming evident that complex combinations of immunomodulatory agents may be required to extend efficacy to patients with immunologically “cold” tumours. Oncolytic viruses (OVs) have the capacity to selectively replicate within and kill tumour cells resulting in the induction of immunogenic cell death and the augmentation of anti-tumour immunity and have emerged as a promising modality for combination therapy to overcome the limitations seen with ICIs. Pre-clinical and clinical data has demonstrated that OVs can increase immune cell infiltration into the tumour and induce anti-tumour immunity, thus changing a “cold” tumour microenvironment that is commonly associated with poor response to ICIs, to a “hot” microenvironment which can render patients more susceptible to ICIs. Here, we review the major viral vector platforms used in OV clinical trials, their success when used as a monotherapy and when combined with adjuvant ICIs, as well as pre-clinical studies looking at the effectiveness of encoding OVs to deliver ICIs locally to the tumour microenvironment through transgene expression.

In this work, the inhibition properties of new bio-based lignine ILs on the corrosion of mild steel in an aqueous solution of 0.01 M NaCl were investigated by Potentiostatic Electrochemical Impedance Spectroscopy (PEIS), Cyclic Potentiodynamic Polarization (CPP). Moreover, the surface was characterized using SEM, EDS, and optical profilometry. The influence of cation and anion on the inhibitor properties and a possible synergistic effect were investigated. The IL choline syringate showed a promising performance, reducing the corrosion current after 24-hour immersion in 0.01 M sodium chloride, from 1.66 µA/cm2 for the control to 0.066 µA/cm2 with 10 mM of the IL present. In addition to the performance as a corrosion inhibitor, both components of this IL also meet or exceed current additional desired properties of such compounds, being readily available, economically efficient, and well tolerated in organisms and the environment.

During blooms, cyanobacteria produce diverse modified peptides. Among these are the microginins, which inhibit zinc-containing metalloproteases. Ten microginins, microginins KR767 (1), KR801(2), KR835 (3), KR785 (4), KR604 (5), KR638 (6), KR781 (7), KR815 (8), FR3 (9), and FR4 (10) were isolated from the extract of a bloom material of Microcystis sp. (IL-405) collected from the Kishon Reservoir, Israel in the fall of 2009. The structures of the pure compounds were elucidated using 1D and 2D NMR techniques and high-resolution mass spectrometry. The absolute configuration of the chiral centers of the amino acids were determined by Marfey’s and advance Marfey’s methods and by comparison of ¹H and ¹³C NMR chemical shifts of the Ahda derivatives with those of known microginins. These microginins differ in sequence and absolute configuration of the chiral centers of the Ahda moieties and by N-methylation of Ahda amine group and extent of chlorination of Ahda terminal methyl group. The compounds were evaluated for inhibition of the zinc metalloprotease aminopeptidase M and exhibited low- to sub-nanomolar IC₅₀ values.

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the road for the emerging nanomedicine as a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 was reported in lung, colon, metastatic breast cancers and bladder squamous carcinoma. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. Sildenafil had been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the expression of Bad and Bax proapoptotic proteins. It was also reported that the use of sildenafil prior to the administration of Doxorubicin (DOX) increased its EPR-related concentration in breast cancer tissues by 2 folds. Further, a substantial reason of anticancer chemotherapeutic failure is due to multidrug resistance (MDR), exacerbated by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCCs. Sildenafil has demonstrated inhibitory effects on the efflux activity of ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing MDR caused by these transporters. In this review, we critically examine the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery pointing up the outcome of the most important related preclinical and clinical studies.

Peptide-based inhibitors represent a promising approach for the treatment of HIV-1, offering a range of potential advantages including specificity, low toxicity, and the ability to target various stages of the viral lifecycle. This review outlines the current state of research on peptide-based anti-HIV therapies, highlighting key advancements and identifying future research directions. Over the past few years, there has been significant progress in developing synthetic peptide-based drugs that target various stages of the viral life cycle, including entry and replication. These approaches aim to create effective anti-HIV therapies. Additionally, peptides have proven valuable in the development of anti-HIV vaccines. In the quest for effective HIV vaccines, discovering potent antigens and designing suitable vaccine strategies are crucial for overcoming challenges such as low immunogenicity, safety concerns, and increased viral load. Innovative strategies for vaccine development through peptide research are, therefore, a key focus area for achieving effective HIV prevention. This review aims to explore the strategies for designing peptides with anti-HIV activity and to highlight their role in advancing both therapeutic and preventive measures against HIV.

Ras homolog enriched in brain (Rheb1 and Rheb2), a small GTPase, regulates neuronal activity and has drawn attention for its implications in cancer development, especially breast cancer. This study explores the multifaceted role of Rheb1 in cancer, elucidating its involvement in crucial cel-lular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses. Despite these acknowledged connections, a comprehensive understanding of the intricate interplay between Rheb1 and cancer remains elusive. This review consolidates cur-rent knowledge on the impact of Rheb1 on cancer hallmarks and examines the potential of Rheb1 as a therapeutic target in cancer treatment. The review underscores the need for a more profound comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes. Furthermore, the review emphasizes the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. This study, by bringing to light the complex associations between Rheb1/Rheb2 and cancer, delivers valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeu-tic strategies for treating cancer.

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

Phytoene is a colourless natural carotenoid that absorbs UV light and provides antioxidant and anti-inflammatory activities as well as protection against photodamage. It is therefore valued for its skin health and aesthetic benefits by the cosmetic industry, as well as by the health food sector. The halotolerant green microalga Dunaliella salina is one of the richest sources of natural carotenoids. We have previously investigated over-production of phytoene in D. salina after cultivation with the well-characterised mitosis inhibitor, chlorpropham. In this study, 15 herbicides with different modes of action were tested for their potential to promote phytoene accumulation. All herbicides showed different levels of capabilities to support phytoene over-production in D. salina. Most significantly, the two mitosis inhibitors tested in this study, propyzamide and chlorpropham, showed similar capacities to support over-production of phytoene by D. salina cultures, as phytoene desaturase inhibitors. The cellular content of phytoene increased by over 10-fold within 48 h after treatment with the mitosis inhibitors compared to untreated cultures. Results indicate a general effect of mitosis inhibitors on phytoene accumulation in D. salina. Furthermore, red light was found to significantly enhance the phytoene yield when used in combination with effective inhibitor treatments. Red light can be applied to maximize the production of phytoene from D. salina.