Search Results (380)

The wnt gene family encodes a group of highly conserved secreted glycoproteins that play essential roles in vertebrate development, including tissue patterning, cell differentiation, and gonadal regulation. However, the genomic organization, evolutionary dynamics, and functional roles of Wnt signaling components in flatfish remain poorly understood. In this study, we performed a comprehensive genome-wide identification, evolutionary characterization, expression profiling, and functional analysis of wnt genes in Cynoglossus semilaevis, a flatfish species exhibiting ZW/ZZ sex determination and temperature-induced sex reversal. A total of 20 wnt genes were identified and classified into 13 subfamilies, displaying conserved structural organization and phylogenetic relationships consistent with other teleosts. Chromosomal mapping revealed lineage-specific WNT clusters, including a unique wnt3–wnt7b–wnt5b–wnt16 block, as well as syntenic associations with reproduction-related genes (e.g., adipor2, sema3a, nape-pld, erc2, lamb2), suggesting coordinated genomic regulation. Tissue transcriptome analysis demonstrated strong sex- and tissue-biased expression patterns, with wnt5a predominantly expressed in ovaries and wnt5b specifically upregulated in pseudo-male testes. Functional assays revealed that knockdown of wnt5a or wnt5b induced testis-specific genes (sox9b, tesk1) and suppressed ovarian markers (foxl2, cyp19a1a), indicating antagonistic regulatory roles in gonadal fate determination. Promoter analysis identified yy1a as a selective repressor of wnt5b, but not wnt5a, providing a mechanistic basis for paralog divergence. Furthermore, pull-down combined with LC–MS/MS analysis showed that WNT5b interacts with proteins enriched in ribosome biogenesis and ubiquitin-mediated proteolysis, suggesting a role in translational regulation and protein turnover during spermatogenesis. Together, these findings establish WNT5 signaling—particularly wnt5b—as a key driver of testicular development in C. semilaevis and provide new insights into the molecular mechanisms underlying sex differentiation and sex reversal in flatfish. Full article

Background/Objectives: In England, gay, bisexual, and other men who have sex with men (GBMSM) are eligible for vaccination at NHS sexual health services, including human papillomavirus (HPV), hepatitis A virus (HAV), and hepatitis B virus (HBV) vaccines. However, current research shows limited understanding of the factors influencing vaccination uptake among GBMSM. This study aimed to examine the barriers and facilitators affecting the offer and uptake of these vaccination programmes. Methods: A qualitative interview study following the Person-Based Approach (a systematic method for developing and optimising health interventions) involving GBMSM and sexual health service staff from two regions of England. Purposive sampling aimed to include GBMSM with diverse backgrounds and engagement with sexual health services. Patient and public involvement shaped the study design and interview topic guides. The interviews were recorded, transcribed, and thematically analysed to identify barriers and facilitators which were interpreted using the COM-B model of behaviour change. Results: Twenty GBMSM and eleven staff took part. The findings showed that opportunistic delivery of HPV, HAV, and HBV vaccination within sexual health services is mostly acceptable and feasible for GBMSM and staff, while also highlighting areas for optimization. Despite low knowledge of these viruses and their associated risks, willingness to be vaccinated was high, with healthcare provider recommendations and the convenience of vaccine delivery during routine clinic visits acting as important facilitators. However, the reach of opportunistic models was limited, particularly for individuals underserved by sexual health services or disengaged from GBMSM social networks. System-level barriers such as complex vaccine schedules (particularly when multiple schedules are combined), inconsistent access to vaccination histories, and limited system-level follow-up processes (e.g., automated invites and reminders) were also found to act as obstacles to vaccination uptake and delivery. Conclusions: To improve equitable uptake, sexual health services should explore the feasibility of addressing both individual and structural barriers through additional strategies, including targeted and persuasive communication to increase knowledge, leveraging regular contact with GBMSM to promote uptake, and implementing enhanced approaches to support vaccination completion (e.g., automated prompts or reminders). Full article

In the digital tourism marketplace, online reviews have become a decisive source of information for travelers who cannot directly assess the quality of hospitality services before purchase. However, it remains unclear how service-related and sustainability-related cues interact to shape guest perceptions in sustainable hotel contexts. This study investigates how intrinsic and extrinsic cues are reflected in online user reviews of sustainable hotels. Drawing on Cue Utilization Theory, a longitudinal content analysis was conducted on a worldwide online travel platform’s (OTP) reviews of hotels certified for their sustainability practices (2004–2024) by user selection. A coding framework was developed deductively based on prior studies on hotel service quality and sustainability practices, and data were analyzed using MAXQDA, Leximancer, and VADER sentiment analysis. Findings indicated that reviews primarily emphasize service quality attributes—particularly staff efficiency, food quality, and accommodation facilities—while sustainability themes appear less frequently, often in nature-related contexts. Sentiment analysis revealed a predominantly positive emotional tone shaped by service quality experiences. Overall, intrinsic cues play a central role in forming guest perceptions, highlighting the need for emotionally engaging sustainability communication strategies. Full article

Background/Objectives: Real-world data on the therapeutic use of FLT3 inhibitors in Turkey remain limited. Therefore, we retrospectively evaluated outcomes from 13 academic centers nationwide, focusing on the multikinase inhibitor midostaurin in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). Methods: We collected comprehensive information regarding treatment efficacy, safety, and tolerability. Results: The overall response rate to intensive chemotherapy (3 + 7) plus midostaurin was 87.7%, with a complete remission rate of 84.2%, consistent with previously reported clinical trial results. Treatment discontinuation due to intolerance or toxicity was low (3.5%). One patient discontinued therapy because of septic shock during induction, and another due to a drug–drug interaction during consolidation. Median overall survival was 21.4 months. Allogeneic stem cell transplantation was performed in first remission in 52.6% of patients. Five patients (8.8%) were refractory to induction therapy, and relapse occurred in 21.1% (12 patients). Conclusions: These findings support the effectiveness and acceptable tolerability of midostaurin in routine clinical practice for FLT3-mutated AML. Full article

Cervical cancer remains a significant global health burden, with chemoradioresistance representing a major obstacle to successful treatment. To elucidate the mechanisms underlying this resistance, we established a unique pair of isogenic primary cervical cancer cell lines, AdMer35 and AdMer43, obtained from a patient with squamous cell carcinoma of the cervix before and after radiation therapy. The aim of our study was to characterize the transcriptomic and cellular heterogeneity of these cells. We conducted an in-depth comparative analysis using single-cell RNA sequencing. Analysis of this paired, patient-derived isogenic model suggests that chemoradioresistance can arise through coordinated multilevel cellular adaptations. Resistant AdMer43 cells demonstrated transcriptional reprogramming, with the upregulation of embryonic stemness factors (HOX, POU5F1, SOX2), a shift in extracellular matrix from fibrillar to non-fibrillar collagens, and activation of inflammatory pathways. We identified and characterized critical cell-state dynamics: resistant cells exhibited a remodeled ecosystem with a metabolically reprogrammed senescent-like cell population showing an enhanced pro-tumorigenic communication via EREG, SEMA3C, BMP, and WNT pathways. Furthermore, we identified a progenitor-like cell population with a minimal CNV burden, potentially serving as a reservoir for tumor persistence. These findings offer novel insights for developing targeted strategies to eliminate resistant cell pools and improve cervical cancer outcomes. Full article

Background/Objectives: Obesity is a significant risk factor for obstructive sleep apnea (OSA); however, conventional anthropometric measures, such as body mass index (BMI), may not fully reflect the physiological burden associated with adiposity. The triponderal mass index (TMI) has been proposed as an alternative anthropometric indicator, while inflammation-related biomarkers have emerged as potential complementary tools for characterizing OSA severity. This study aimed to evaluate the relationships between BMI, TMI, hypoxemia, and systemic inflammation, and to assess whether combining anthropometric indices with inflammatory biomarkers improves the identification of severe OSA. Methods: In this retrospective cross-sectional study, 238 adults undergoing full-night polysomnography were classified into four groups: non-OSA, mild OSA, moderate OSA, and severe OSA, based on the apnea–hypopnea index (AHI). Anthropometric indices, polysomnographic parameters, and a comprehensive panel of laboratory biomarkers—including C-reactive protein (CRP), neutrophil- and platelet-derived inflammatory indices, prognostic nutritional index (PNI), CRP-to-albumin ratio (CAR), and CRP-to-lymphocyte ratio (CLR)—were analyzed. Associations were evaluated using Spearman correlation analyses, and diagnostic performance for severe OSA (AHI ≥ 30 events/h) was assessed using receiver operating characteristic (ROC) analyses, DeLong tests, and multivariable models. Results: Both BMI and TMI increased progressively with OSA severity (both p < 0.001) and showed comparable correlations with AHI and nocturnal oxygenation parameters. ROC analyses demonstrated similar discriminative performance for severe OSA (BMI AUC = 0.834; TMI AUC = 0.823; p = 0.229). Among inflammatory biomarkers, CRP, multi-inflammatory index (MII), CAR, and CLR showed moderate diagnostic accuracy. Among the evaluated markers, serum albumin (AUC = 0.836) and PNI demonstrated the highest diagnostic accuracy (AUC = 0.994). A combined model integrating BMI or TMI with PNI achieved near-perfect discrimination for severe OSA (BMI-based AUC = 0.9956; TMI-based AUC = 0.9969), while the addition of CRP-based inflammatory markers did not yield meaningful incremental benefit. Conclusions: BMI and TMI exhibit comparable performance in relation to OSA severity, hypoxemia, and systemic inflammation, with no clear superiority of TMI over BMI in adult patients. Inflammation-related biomarkers—particularly PNI—provide additional discriminatory value beyond anthropometric measures alone. Integrating simple biochemical markers with anthropometric and polysomnographic parameters may enhance risk stratification and identification of severe OSA phenotypes. Full article

Background: Gastrointestinal (GI) mucosal injury is a frequent complication of long-term nonsteroidal anti-inflammatory drug (NSAID) use. Effective mucosal healing requires coordinated epithelial migration, proliferation, and angiogenesis, which may be influenced by focal adhesion kinase (FAK). This study aimed to determine whether our newly developed FAK activators promote intestinal mucosal healing by enhancing angiogenesis and whether FAK activation increases resistance to reinjury. Methods: Ischemic jejunal ulcers were induced in C57BL/6 mice. After 24 h, mice received intraperitoneal injections of the FAK activator ZINC40099027 (ZN27, 900 µg/kg every 6 h) or vehicle for 2, 4, or 14 days. Ulcer areas were quantified, and liver and kidney function were assessed. Ulcer and adjacent tissues were analyzed by immunofluorescence staining for angiogenesis and proliferation markers. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with ZN27 to evaluate proliferation, migration, angiogenesis, and intracellular signaling. In a reinjury model, male C57BL/6J mice received continuous infusion of the FAK activator M64HCl (25 mg/kg/day) or vehicle for 7 days, with a single subcutaneous injection of indomethacin (10 mg/kg) on day 1 to induce GI injury. Fourteen days after the first dose of indomethacin, the mice received a second indomethacin challenge, and one day later, total ulcer areas in the pyloric opening and small intestine were quantified. Results: Ulcer areas were significantly smaller in ZN27-treated mice compared with vehicle-treated controls at 3 and 5 days, accompanied by increased expression of angiogenesis and proliferation markers. In vitro, ZN27 enhanced HUVEC migration via FAK activation in an ERK1/2-dependent manner and increased the number of angiogenic sprouts. In the reinjury model, treatment with M64HCl during the initial indomethacin-induced injury resulted in significantly smaller ulcer areas in both the pyloric opening and small intestine after the second indomethacin challenge compared with controls. Conclusions: FAK activation accelerates ischemic ulcer healing, in part by enhancing angiogenesis. Moreover, FAK activation during an initial injury reduces susceptibility to recurrent NSAID-induced intestinal injury, perhaps because it promotes initial higher-quality ulcer repair. Full article

Background: Sentinel lymph node biopsy (SLNB) is the standard axillary staging procedure in clinically node-negative breast cancer but remains invasive, non-therapeutic and increasingly questioned in contemporary de-escalation algorithms. After neoadjuvant chemotherapy (NACT), however, the safety of omitting SLNB solely on the basis of a negative axillary ultrasound (AUS) is uncertain, particularly across molecular subtypes with heterogeneous chemosensitivity. This study evaluated the diagnostic performance of preoperative AUS after NACT and explored clinicopathological and biological factors associated with SLNB positivity in ultrasound-negative axillae. Methods: In this single-centre retrospective cohort, 135 women with invasive breast cancer who received NACT followed by surgery (2022–2024) were analysed. To avoid spectrum bias, 77 patients with clipped, cytologically or histologically proven node-positive disease at baseline were excluded from the main analysis. All patients underwent preoperative AUS and definitive axillary staging. Ninety-six women with ultrasound-negative axillae who proceeded to SLNB constituted the primary study population. Oestrogen receptor (ER), progesterone receptor (PR), HER2, Ki-67 and immunohistochemistry-based molecular subtype were recorded. Receiver operating characteristic (ROC) analysis and uni/multivariable logistic regression were used as exploratory tools to identify factors associated with SLNB positivity. Results: In the overall cohort, AUS sensitivity, specificity, negative predictive value and false-negative rate for axillary metastasis were 47.8%, 90.9%, 62.5% and 52.2%, respectively. Among ultrasound-negative axillae, SLNB was positive in 37.5%. Compared with SLNB-negative patients, those with SLNB metastases more frequently harboured an intratumoural ductal carcinoma in situ (DCIS) component, showed higher ER/PR expression and lower Ki-67, and were predominantly luminal A or luminal B/HER2−, whereas AUS performance appeared more favourable in HER2-enriched and triple-negative tumours. ROC-derived cut-offs for ER (82.5%), PR (25.0%) and Ki-67 (17.5%) provided only moderate discrimination (area under the curve 0.68–0.70). In multivariable analysis, absence of a DCIS component and low PR expression were independently associated with reduced odds of SLNB positivity, suggesting that DCIS and high PR may act as indicators of residual nodal risk in ultrasound-negative axillae. All estimates are limited by sample size and wide confidence intervals and should be interpreted as hypothesis-generating. Conclusions: Preoperative AUS alone cannot reliably exclude sentinel lymph node metastasis after NACT, particularly in luminal A and luminal B/HER2− tumours with strong hormone receptor expression and a low proliferative index. Until prospective, biology-stratified trials confirm the safety of omission, SLNB should not be withheld solely on the basis of a negative AUS in these subtypes. Axillary management after NACT should systematically integrate both imaging findings and tumour biology when considering further de-escalation of surgery. Full article

Background/Objectives: Takayasu’s arteritis (TAK) is an inflammatory vascular disease, but atherosclerotic mechanisms may also contribute to vascular injury in TAK. This study aimed to evaluate the clinical and imaging characteristics of TAK patients with and without iliofemoral artery involvement on FDG-PET/CT, focusing on the association with classical atherosclerotic risk factors. Methods: Patients fulfilling the 1990 ACR classification criteria for TAK who underwent FDG-PET/CT imaging during follow-up were retrospectively analyzed. Demographic, clinical, and laboratory data were recorded, including traditional cardiovascular risk factors: diabetes, hypertension, hyperlipidemia, smoking, obesity (BMI ≥ 30 kg/m²), and family history of cardiovascular disease. PET vascular activity score (PETVAS) and visual analysis were used to assess vascular inflammation. Results: PET/CT scans of 77 TAK patients (F/M = 63/14) were evaluated. The mean age was 43.0 ± 12.9 years, and the mean disease duration was 120.1 ± 88.8 months. Iliofemoral artery involvement was observed in nine (12%) patients. Compared to those without such involvement, these patients were older (52.5 ± 17.4 vs. 41.3 ± 12.1 years, p = 0.098), more frequently male (44% vs. 6%, p = 0.015), and had higher CRP levels (38.5 mg/L vs. 10.7 mg/L, p = 0.026). Smoking (77% vs. 40%, p = 0.045) and chronic kidney disease (22% vs. 4%, p = 0.046) were also more prevalent. PET activity according to visual analysis was higher among those with iliofemoral involvement (67% vs. 27%, p = 0.015). In multivariate analysis, older age (OR = 1.07, p = 0.044) and male sex (OR = 6.68, p = 0.039) were independently associated with iliofemoral artery involvement. Conclusions: Iliofemoral artery involvement on PET/CT in TAK patients was associated with traditional atherosclerotic risk factors—particularly older age, male sex and smoking. These findings suggest that atherosclerotic mechanisms may coexist with or amplify vascular inflammation in TAK. Aggressive management of cardiovascular risk factors should therefore be emphasized in this subgroup of TAK patients. Full article

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by uncontrolled proliferation of myeloid cells. MicroRNAs (miRNAs), small noncoding RNAs, regulate post-transcriptional gene expression by degrading target mRNAs or repressing translation. Dysregulated miRNA expression has been implicated in various malignancies, including CML, where they can function as oncogenes or tumor suppressors. This study aimed to investigate the relationship between miR-122-5p and cell division cycle 25A (CDC25A) in CML and to elucidate the regulatory mechanisms of miR-122-5p. This study integrates bioinformatics analysis with in vitro RT-qPCR validation in K562 chronic myeloid leukemia cells to explore the potential regulatory relationship between miR-122-5p and CDC25A. mRNA expression profiles were retrieved from the GSE100026 dataset in the Gene Expression Omnibus (GEO), and differentially expressed genes were identified using GEO2R. Quantitative real-time PCR (RT-qPCR) was performed to measure miR-122-5p, CDC25A, and cyclin-dependent kinase 4 (CDK4) expression levels. Bioinformatics analyses (miRNeT, miRDIP, TargetScan, BioGPS, GeneMANIA, STRING) were applied to predict molecular interactions and functional pathways. Public RNA-seq datasets and in silico tools were used to prioritize candidates; RT-qPCR in a single CML cell line (K562) provided in vitro expression validation. In K562 cells, miR-122-5p expression was significantly reduced, while CDC25A and CDK4 were markedly upregulated. Bioinformatics tools confirmed CDC25A as a potential miR-122-5p target. Functional enrichment indicated CDC25A involvement in cell cycle regulation and apoptosis. These findings suggest that miR-122-5p functions as a tumor suppressor in CML by targeting CDC25A. Modulating the miR-122-5p/CDC25A axis may provide potential molecular targets for inhibiting CML progression through regulation of cell cycle pathways. Findings are exploratory and based on bioinformatics with limited in vitro expression confirmation; functional studies are required to establish causality. Full article

Background/Objectives: Radiotherapy (RT) induces oxidative stress and structural damage in solid tissues, including the liver. This study aimed to investigate the histological and immunohistochemical effects of dexmedetomidine (DEX) and amifostine on their potential protective and regenerative properties against liver injury induced by radiation therapy. Methods: This study consisted of five randomized groups: control, RT, RT-D100, RT-D200, and RT-A (Amifostine). A total of 100 µg/kg DEX, 200 µg/kg DEX, and 200 µg/kg amifostine were administered before radiotherapy as per the experimental design. After RT, liver specimens were analyzed for histological alterations, including periportal and perisinusoidal fibrosis, vacuolization, and pyknotic nuclei. Furthermore, immunohistochemistry investigations were conducted to evaluate apoptosis, mitosis, oxidative stress, and neural regeneration in non-neuronal liver tissue following radiotherapy and subsequent treatment. Results: The control group’s liver tissue exhibited standard histological architecture, whereas the RT group displayed severe cellular degeneration, periportal and perisinusoidal fibrosis, cytoplasmic vacuolization, and an increase in pyknotic nuclei. The apoptotic index was markedly reduced in the RT-D100 and RT-D200 groups relative to the RT group. Furthermore, caspase-3 immunoactivity was negligible in the control group, while a significant increase was observed in the RT group. The administration of amifostine significantly increased GAP-43 levels. Conclusions: DEX mitigates RT-induced hepatic injury chiefly through antioxidant and anti-apoptotic pathways, whereas amifostine promotes hepatic regeneration by modulating GAP-43. Full article