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Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel critical for maintaining intracellular Ca2+ homeostasis and is essential in regulating immune responses, metabolic processes, and signal transduction. Recent studies have shown that TRPV4 activation enhances influenza A virus infection, promoting viral replication and transmission. However, there has been limited exploration of antiviral drugs targeting the TRPV4 channel. In this study, we developed the first machine learning model specifically designed to predict TRPV4 inhibitory small molecules, providing a novel approach for rapidly identifying repurposed drugs with potential antiviral effects. Our approach integrated machine learning, virtual screening, data analysis, and experimental validation to efficiently screen and evaluate candidate molecules. For high-throughput virtual screening, we employed computational methods to screen open-source molecular databases targeting the TRPV4 receptor protein. The virtual screening results were ranked based on predicted scores from our optimized model and binding energy, allowing us to prioritize potential inhibitors. Fifteen small-molecule drugs were selected for further in vitro and in vivo antiviral testing against influenza. Notably, glecaprevir and everolimus demonstrated significant inhibitory effects on the influenza virus, markedly improving survival rates in influenza-infected mice (protection rates of 80% and 100%, respectively). We also validated the mechanisms by which these drugs interact with the TRPV4 channel. In summary, our study presents the first predictive model for identifying TRPV4 inhibitors, underscoring TRPV4 inhibition as a promising strategy for antiviral drug development against influenza. This pioneering approach lays the groundwork for future clinical research targeting the TRPV4 channel in antiviral therapies. [ABSTRACT FROM AUTHOR]

Background: Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), is actually used to prevent organ transplant rejection and treat metastatic breast, renal, and neuroendocrine cancers. Despite significant pharmacokinetic variability among patients, routine therapeutic drug monitoring (TDM) is not commonly used in oncology. Methods: The aim of this multicenter, prospective observational cohort study is to assess the prevalence of everolimus minimum concentration at a steady state (Cminss) falling outside the therapeutic range (10–26.3 ng/mL) during a routine TDM programme. Sixty patients with metastatic breast, neuroendocrine, or renal cancers, either starting or continuing everolimus treatment according to hospital protocols, are to be included between 1st of January 2024 and 31st of December 2025 (patients undergoing clinical trials are excluded). We hypothesize that 30–50% of our patients and their blood samples will not achieve the target optimal plasma concentrations. Blood samples are collected every 4–6 weeks to monitor drug levels. The secondary goal is to explore correlation between out-of-range everolimus levels and factors such as demographic and anthropometric data, treatment specifics, lab results, genetic polymorphisms, and the presence of toxicity. Conclusions: This study could offer valuable insights into optimizing dosing strategies and may contribute to future research on personalizing everolimus and other anticancer treatments. This personalized approach seeks to tailor therapy not only to the tumour's molecular profile but also to the individual characteristics of each patient, improving both drug selection and dosing precision. [ABSTRACT FROM AUTHOR]

Background and Objective: Evidence on health economic outcomes for percutaneous coronary intervention (PCI) comparing different contemporary drug-eluting stents (DES) with each other is scarce, as most previous randomised DES trials did not assess such aspects. This prespecified health economic evaluation of the Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population (BIO-RESORT) trial aimed to compare at 3-year follow-up both health effects and costs of PCI with one of three new-generation drug-eluting stents (DES) in patients with obstructive coronary artery disease. Methods: The randomised BIO-RESORT trial assessed in 3514 patients the ultrathin-strut biodegradable polymer Orsiro sirolimus-eluting stent (SES) and very-thin-strut Synergy everolimus-eluting (EES) stent versus the thin-strut durable polymer Resolute Integrity zotarolimus-eluting stent (ZES). In the current analysis, we used the perspective of a health insurer in the Netherlands. The main endpoints were quality-adjusted life years (QALYs), and costs for each treatment strategy. Bootstrapping with 5000 resamples was performed to capture the uncertainty of results. Results: Mean QALYs for each stent group were 2.566 for the SES, 2.551 for the EES, and 2.550 for the ZES. Mean costs per strategy were €14,670 for the SES, €14,946 for the EES, and €15,069 for the ZES. The SES had the highest probability of being cost-effective for every willingness-to-pay threshold up to €100,000 per QALY. Furthermore, in 79% of modelling scenarios, the SES was more effective and cheaper than ZES. Conclusion: At 3-year follow-up, PCI with the SES had the highest probability of being cost-effective due to greater effectiveness and lower costs compared with the ZES and EES. These findings suggest that, due to the overall high volume of coronary stenting in clinical practice, use of this SES could result in substantial cost savings, complemented by slight additional health benefits. [ABSTRACT FROM AUTHOR]

Abstract Objective This study aimed to evaluate the effectiveness and safety of everolimus in treating seizures associated with focal cortical dysplasia type 2 (FCD 2). Methods A prospective, crossover, placebo‐controlled clinical trial (ClinicalTrials.gov: NCT03198949) enrolled patients aged 4–40 years with pathologically confirmed FCD 2 and a history of ≥3 seizures per month for two out of the 3 months prior to screening. The trial included a 4‐week baseline phase, two 12‐week core phases, and a 29‐week extension phase. Patients received everolimus or placebo in a blinded manner during core phase I, with crossover to the alternate treatment in core phase II. Everolimus dosage started at 4.5 mg/m2/day, targeting a serum level of 5–15 ng/mL. The primary outcome was the proportion of patients achieving ≥50% seizure reduction from baseline in the last month of each core phase. Safety profiles were compared between groups. Results Between May 11, 2017, and June 19, 2020, 21 patients completed the core phases. There was no significant difference in the primary outcome between everolimus and placebo groups (24% vs. 19%, p = 0.66). The patients showed varied responses. Three patients with a pathogenic variant in the MTOR gene or no genetic abnormalities achieved seizure freedom with everolimus in the last month of the core phase, while none of the patients with variants in other genes did. Adverse events, such as mucositis or skin ulceration, were more common with everolimus (19/21 vs. 7/21, p

Yujing Tan,1,&ast; Hanfang Jiang,2,&ast; Xinzhu Tian,1,&ast; Fei Ma,1 Jiayu Wang,1 Pin Zhang,1 Binghe Xu,1 Ying Fan,1 Weihong Zhao3 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, People’s Republic of China; 3Department of Medical Oncology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Fan; Weihong Zhao, Email fanying@cicams.ac.cn; zhaowh0818@163.comPurpose: This study aims to explore the role of the non-luminal disease score (NOLUS) for everolimus in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).Methods: NOLUS has previously been established as an algorithm: NOLUS (0– 100) = − 0.45 × ER(%) − 0.28 × PR(%) + 0.27 × Ki67(%) + 73. Information of cancer patients was retrospectively collected from three cancer centers in China.Results: Totally, 198 HR+/HER2- ABC patients with complete records in expression rates (%) of ER, PR and Ki67 were enrolled in the study. The expression rates (%) of ER, PR, and Ki67 were 38.8 ± 27.9 versus 80.9 ± 14.2 (p < 0.001), 13.9 ± 14.3 versus 50.2 ± 30.4 (p < 0.001), and 37.8 ± 23.6 versus 28.7 ± 19.9 (p = 0.04), respectively, for NOLUS-positive patients and NOLUS-negative patients. For the overall population, the median PFS was 5.8 months versus 5.1 months in NOLUS-positive and NOLUS-negative patients (p = 0.16, HR = 0.75, 95% CI = 0.50, 1.12). The median 1L-, 2L, and 3L-PFS was 13.9 months versus 11.8 months (p = 0.22, HR = 1.63, 95% CI = 0.74, 3.62), 6.7 months versus 3.6 months (p = 0.08, HR = 0.34, 95% CI = 0.10, 1.18), and 4.6 months versus 4.0 months (p = 0.81, HR = 1.07, 95% CI = 0.63, 1.79) respectively, for NOLUS-positive patients and NOLUS-negative patients.Conclusion: NOLUS-positive patients have a lower percentage of ER and PR, but a higher percentage of Ki67 index. The correlation between the benefits of everolimus and NOLUS failed to develop significance, suggesting that NOLUS may not be applicable in predicting everolimus efficacy in patients with HR+/HER2- ABC. Further research is expected.Keywords: NOLUS, advanced breast cancer, everolimus, HR+/HER2- breast cancer, efficacy

The correction notice in the journal "Frontiers in Oncology" addresses errors in the cropping and placement of images in the article "Anticancer effects of ABTL0812 in glioblastoma models." The authors have rectified these mistakes in Figures 2 and 6 by replacing incorrect images with the correct ones. The corrections do not alter the scientific conclusions of the original article. The study highlights the potential of ABTL0812 in inducing cancer cell death and impairing tumor growth in glioblastoma models. [Extracted from the article]

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that originate from neuroendocrine cells, characterized by their ability to secrete hormones and peptides. Once considered rare, the incidence of NETs has steadily increased due to improved diagnostic modalities. The therapeutic landscape is multifaceted, ranging from surgery for localized disease to pharmacological interventions for advanced cases. However, the absence of robust predictive biomarkers precludes patient stratification and optimization of therapy. Everolimus, an oral mTOR inhibitor, has emerged as a key therapeutic agent due to its dual role in inhibiting cell proliferation and angiogenesis. Nevertheless, challenges such as resistance mechanisms, toxicity and optimal treatment sequencing remain unresolved. This article provides a comprehensive review of the role of everolimus in the management of NETs, focusing in particular on unresolved issues, from the absence of predictive biomarkers to the unavailability of defined guidelines for determining the correct therapeutic sequence.