Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancers and correlates with poor patient survival. In prostate cancer, PRMT5 cooperates with its cofactor pICln to promote tumour growth by epigenetically activating androgen receptor (AR) expression. Using a near-atomic cryo-EM structure of PRMT5/MEP50/pICln complex, we identified a previously undefined, pICln-specific protein-protein interaction (PPI) interface on PRMT5, termed P4I. Structure-based virtual screening identified the FDA-approved compound etravirine as a binder to this site. BiFC, Co-IP, and PLA assays confirmed that etravirine disrupts PRMT5/pICln interaction. A cryo-EM structure of PRMT5/MEP50/etravirine further validated on-target binding at P4I. Functionally, etravirine reduced prostate cancer cell proliferation, inhibited tumour growth, and downregulated AR and AR-V7 expression in cells and in mouse models. These results demonstrate that the unique P4I interface is a promising therapeutic target and that etravirine serves as a proof-of-concept lead compound for exploring the potential of P4I-targeted strategies in prostate cancer.

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive histological subtype of kidney cancer. Previous studies have implicated ribosomal protein L28 (RPL28) in the progression of various cancers; however, its role in ccRCC remains unclear.

This study aimed to investigate the expression, prognostic significance, and potential biological role of RPL28 in ccRCC.

RPL28 expression data and corresponding clinicopathological information were obtained from the UCSC Xena platform, and pan-cancer expression patterns were assessed using TIMER2.0. RPL28 expression was further validated in clinical ccRCC tissue samples. Prognostic, immune-infiltration, and drug-sensitivity analyses were performed, and the biological effects of RPL28 were evaluated using lentivirus-mediated knockdown in ccRCC cells. RPL28 was significantly upregulated in ccRCC tissues and was associated with unfavorable overall survival (OS) and disease-specific survival (DSS), as well as adverse clinicopathological features, including higher histological grade, advanced T stage, distant metastasis, and advanced TNM stage. Immune analyses revealed associations between RPL28 expression and selected features of the ccRCC immune microenvironment, while pharmacogenomic analyses suggested potential associations between RPL28 expression and predicted sensitivity to selected targeted agents. In vitro, RPL28 knockdown significantly inhibited ccRCC cell proliferation and migration. Gene set enrichment analysis (GSEA), together with experimental findings, further suggested that RPL28 may be involved in epithelial-mesenchymal transition (EMT)-related processes in ccRCC.

RPL28 is overexpressed in ccRCC and is associated with poor survival outcomes, malignant cellular phenotypes, EMT-related signaling, selected immune-microenvironmental features, and predicted therapeutic-response phenotypes. These findings suggest that RPL28 may serve as a prognostic biomarker and potential therapeutic target in ccRCC, although further mechanistic and clinical validation is required.

Electrochemotherapy (ECT) is a well-established local cancer treatment that combines the administration of chemotherapeutic drugs with the application of short electric pulses to enhance intracellular drug uptake. Over the past 3 decades, ECT has become an accepted therapeutic modality in both human and veterinary oncology for the treatment of a wide range of superficial and deep-seated tumors. Although favorable response rates have been reported across many tumor types, treatment outcomes remain variable among patients and neoplasms. Currently, patient selection is based primarily on clinical and pathological factors, while validated predictive biomarkers are lacking. This review summarizes the evidence regarding factors influencing ECT response in veterinary oncology, including tumor histotype, size, local invasiveness, clinical stage, previous treatments, immunohistochemical and molecular markers, and tumor blood perfusion. Available data indicate that smaller tumors, lower disease burden, and earlier intervention are associated with improved outcomes, whereas recurrent and advanced-stage tumors show reduced responsiveness. Future research integrating molecular profiling, immune characterization, functional imaging, and liquid biopsy approaches may facilitate the development of predictive biomarkers and support a more personalized application of ECT in veterinary cancer patients.

A 23-year-old man with metastatic extraskeletal Ewing sarcoma, who was unable to tolerate standard-dose chemotherapy, received 1 cycle of 177Lu-FAP-2286, followed by 2 cycles of reduced-dose ifosfamide/epirubicin/mesna chemotherapy. Follow-up 68Ga-FAP-2286 PET/CT at 2 months showed a marked metabolic response with reduced tumor size and tracer uptake. No adverse events were observed. The patient remained symptom-free at 2 months. This case suggests that 177Lu-FAP-2286 combined with chemotherapy may have clinical utility in advanced Ewing sarcoma.

A man in his late 40s presented with progressive chest pain, cough and dyspnoea. Imaging revealed left lung collapse with pleural involvement. Thoracoscopic pleural biopsy confirmed pulmonary adenocarcinoma by immunohistochemistry. Staging fluorodeoxyglucose positron emission tomography-CT demonstrated nodal disease and unexpectedly diffuse marrow uptake with widespread lytic lesions involving the axial and appendicular skeleton, raising concern for a haematological malignancy. Serum protein electrophoresis revealed no monoclonal band, arguing against plasma cell dyscrasia. CT of the brain demonstrated multiple lytic calvarial lesions without parenchymal involvement, an unusual pattern in lung adenocarcinoma. The patient was diagnosed with stage IV lung adenocarcinoma with extensive skeletal metastases. Owing to poor performance status and advanced disease, the patient was managed with the best supportive care and died 5 months after diagnosis. This case highlights that lung adenocarcinoma may rarely present with diffuse marrow involvement and highlights the importance of histopathological correlation when imaging mimics haematological disease.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10^-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10^-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Lung ultrasound (LUS) is accurate for diagnosing pneumonia in the emergency department (ED), but standard training is time-intensive, limiting its widespread implementation. We evaluated LUS proficiency for pneumonia diagnosis and perceived adoption barriers after a short training programme.

This study was conducted in the frame of the PLUS-IS-LESS trial (Procalcitonin and Lung UltraSonography-based antibiotherapy in patients with Lower rESpiratory tract infection in Swiss Emergency Departments) (NCT05463406), a pragmatic stepped-wedge cluster-randomised clinical trial evaluating a clinical management algorithm combining LUS and procalcitonin to guide antibiotic use for lower respiratory tract infections (LRTIs) in 10 Swiss EDs.

All medical supervisors (senior registrars and senior physicians) from the participating EDs were invited to go through the PLUS-IS-LESS LUS training programme and all those who completed the training programme were included in this study.

The training programme included an e-learning course, followed by a half-day on-site training session with theory and hands-on practice. For proficiency evaluation, a validated structured assessment of LUS skills (LUS-OSAUS) was adapted into a 32-question online quiz and five bedside LUS examinations. Success was defined as achieving a score ≥80% on both the online quiz and supervised practical assessment. Success rates were compared between physicians according to their characteristics (age, sex, medical experience, previous use of ultrasound or LUS, linguistic region of work and type of hospital) using a χ² test. A 6-month follow-up survey identified factors associated with non-certification and barriers to the clinical use of LUS for managing LRTIs.

Of 122 trained physicians, 83 (68 %) completed both quiz and supervised LUS and 61 (50%) achieved certification. The most challenging items were pleural line assessment (83% success), recognition of consolidations (83%) and decision-making based on LUS findings (72%). Physicians <40 years had a higher success rate (p=0.009). Among those without complete certification, limited access to an ultrasound machine and low perceived added value of LUS were the main identified reasons. Lack of time was the most frequently reported barrier overall to LUS integration into ED workflows (77%).

After receiving short training and focused proficiency testing, only half of physicians achieved certification, underscoring the challenges of broad LUS implementation. Limited time, equipment access and low perceived clinical value were key barriers, and integrating LUS findings into decision-making remained difficult. Ongoing support, supervision and protected time may be needed to enhance LUS adoption in EDs.

NCT05463406.

Child abuse and neglect impacts millions of children each year, and the many detrimental impacts on health, well-being, and the economy persist across the lifespan and intergenerationally. Risk and protective factors make child abuse and neglect more or less likely, but during humanitarian crises like economic downturns and health crises, the context and conditions are ripe for increased risk of perpetration and victimization. Prevention is possible when we take a public health approach, and every sector assures the conditions that bolster families, like concrete and economic supports, access to mental health services, and coordinated, aligned ecosystems.

BackgroundChronic obstructive pulmonary disease (COPD) is a global health concern, characterised by exacerbations, worsening outcomes and increasing costs. Real-world studies are essential for understanding treatment regimens and long-term outcomes.ObjectiveTETRIS focused on the impact of triple therapy in managing COPD.Trial DesignTETRIS was a prospective, observational study that enrolled 1,196 patients with COPD from 134 centres who were on triple therapy for at least 2-48 weeks prior to inclusion.MethodsThe primary objectives were to quantify the proportion of patients continuously receiving triple therapy at 6, 12 and 24 months and assess time to discontinuation using Kaplan-Meier methodology. Clinical outcomes and therapy changes were evaluated overall and in subgroups by dosing regimen (once-daily [OD] vs. twice-daily [BID]) and specific single-inhaler triple therapies.ResultsPersistence with triple therapy was 92.5%, 84.4% and 38.5% at 6, 12 and 24 months, respectively. Only 10% of patients changed therapy over 24 months. At 24 months, the mean change in CAT sum score since baseline was -4.4 among patients on OD triple therapy (FF/UMEC/VI OD). The overall CAT responder rate was 50.1%. Exacerbation and hospitalisation rates remained low throughout the study. The composite endpoint of clinically important deterioration occurred in 53.6% of patients, with lower rates of 45.9% among patients receiving FF/UMEC/VI OD.ConclusionIn this real-world cohort, 38.5% of patients remained on triple therapy at 24 months, and most patients did not require a change in their initial therapy. The steep drop at 24 months was mostly because only few patients remained under observation since the protocol permitted study completion at 18 months, and any patient who dropped out from the study was not censored but counted as patient no longer on continuous triple therapy. These findings support the effectiveness and stability of triple therapy in routine practice and highlight the value of OD single-inhaler regimens in optimising COPD management.Registrationhttps://clinicaltrials.gov/study/NCT04657211.

As the most common type of genetic variants, gene polymorphisms form an important basis for disease susceptibility and individual difference in drug response. They are also a core subject for pharmacogenomic research. To study the role of gene polymorphisms in disease development and drug metabolism can provide new biomarkers and therapeutic targets for diseases and assist clinicians in developing personalized therapeutic regimens, thus promoting precision medicine. Pediatric respiratory diseases are common disorders in children, and traditional medication practices based on age and body weight often result in poor efficacy or adverse drug reactions. Numerous studies have shown that genetic polymorphisms are closely associated to disease susceptibility, drug sensitivity, and clinical efficacy. In this review, we have focused on common pediatric diseases such as pneumonia, bronchiolitis, and bronchial asthma, and discussed the association between polymorphisms of genes such as METTL4, GSDMA, and ADRB2 and disease susceptibility and drug efficacy, with an aim to provide a reference for targeted prevention and rational treatment of pediatric respiratory diseases.