Avalon University School of Medicine

Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial–mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.

BACKGROUND AND AIMS:Atrial functional mitral regurgitation (AFMR) commonly affects elderly and frail individuals. The prognostic impact of transcatheter edge-to-edge repair (TEER) for AFMR has not been investigated. METHODS:Patients with AFMR who underwent TEER were selected from the OCEAN-Mitral registry, and medically managed controls were selected from the REVEAL-AFMR registry, using an identical AFMR definition. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization. The secondary endpoint was all-cause mortality. RESULTS:A total of 1081 patients (mean age 80.1 ± 8.2 years, 60.5% female) with moderate or severe AFMR were included, of whom 441 underwent TEER and 640 remained on medical treatment. Overlap weighting based on the propensity score yielded well-balanced characteristics (n = 441 vs 640; all standardized mean differences <0.01), where TEER was associated with a lower incidence of the primary (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.43-0.99, P = .044) and secondary endpoints (HR 0.58, 95% CI 0.35-0.99, P = .044). In an exploratory subgroup analysis, favourable outcomes might be pronounced in patients with ≤mild residual AFMR after TEER, while event rates in those with ≥ moderate residual AFMR were comparable with the medication group. As sensitivity analyses, inverse probability of treatment weighting (n = 158 vs 173), propensity score matching (n = 104 vs 104), and multivariable Cox regression (n = 441 vs. 640) all confirmed favourable associations of TEER with both endpoints. CONCLUSIONS:In real-world data, TEER for patients with moderate or severe AFMR were associated with a lower incidence of adverse events compared with medical treatment.

The number of patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), continues to increase in many countries and regions. With recent rapid advances in medical therapies targeting intestinal inflammation, the number of patients with long-term disease duration is also increasing. It is well-recognized that longstanding IBD carries an increased risk of developing gastrointestinal (GI) neoplasia, particularly colorectal cancer. However, compared to sporadic GI tumors, IBD-associated GI tumors are relatively rare, and even among specialists in GI diseases, opportunities to encounter such cases remain limited. In light of this situation, the Japanese Society for Cancer of the Colon and Rectum (JSCCR), in collaboration with the Japanese Inflammatory Bowel Disease Research Group (funded by the Japan Sciences Research Grant for Research on Intractable Diseases affiliated with the Ministry of Health, Labour, and Welfare) launched the Guideline Development Committee for IBD-associated Gastrointestinal Tumors in 2021, with the aim of establishing clinical practice guidelines to support the diagnosis and management of these tumors. The committee-comprising experts in gastroenterology, surgery, pathology, guideline development, and literature review-conducted extensive discussions and successfully published the first Japanese edition of the guidelines in July 2024. We believe that the current edition provides the best possible guidance based on presently available knowledge. Furthermore, the guideline development process highlighted several key issues to be addressed in future research and clinical practice. We are pleased to present here the English version of the JSCCR Guidelines 2024 for the Clinical Practice of IBD-associated Intestinal Neoplasia.

Introduction:Menstrual disorders-including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea-are highly prevalent among women of reproductive age and are associated with impaired academic performance, psychological distress, and reduced social functioning. Nursing students are particularly vulnerable due to the combined demands of intensive academic schedules and clinical training, yet prevalence estimates and institutional responses remain inconsistent. Methods:A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD420251109363). PubMed, Scopus, Web of Science, CINAHL Ultimate, and APA PsycINFO were searched for studies published between 2016 and 2025. Eligible studies reported prevalence or impact of PMS, PMDD, or dysmenorrhea exclusively in nursing students. The Joanna Briggs Institute checklist for prevalence studies was used for quality appraisal. Random-effects meta-analysis was applied to calculate pooled prevalence estimates, and thematic synthesis was used to evaluate academic, social, and psychosocial impacts, coping strategies, and interventions. Results:Twenty studies involving 5,131 nursing students were included. The pooled prevalence was 62% for PMS, 21% for PMDD (including severe PMS), and 72% for dysmenorrhea, with substantial heterogeneity (I 2 > 80%). Reported impacts included absenteeism, reduced concentration, diminished clinical performance, and impaired quality of life. Coping strategies were largely self-directed, including analgesics, rest, and dietary modifications, while few students accessed formal healthcare or institutional support. Only a limited number of studies evaluated structured interventions such as exercise, yoga, or nutritional supplementation. Conclusion:Menstrual disorders are highly prevalent among nursing students and carry significant academic, social, and psychological consequences. Nursing education programs should integrate routine screening, structured wellness initiatives, and evidence-based interventions to improve student wellbeing, reduce academic disruption, and strengthen workforce preparedness. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/view/CRD420251109363, PROSPERO CRD420251109363.

Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.