Search Results (1,284)

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression. Full article

Introduction: Sarcomatoid dedifferentiation may be identified in both clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC). Within the SEER database (2010–2021), we tested the effect of sarcomatoid dedifferentiation in first ccRCC and subsequently in nccRCC on cancer-specific mortality (CSM). Methods: Separate propensity score matching (PSM) and multivariable competing risks regression (CRR) analyses were first applied to ccRCC with vs. without sarcomatoid dedifferentiation and subsequently to nccRCC with vs. without sarcomatoid dedifferentiation. Results: Sarcomatoid dedifferentiation was present in 2496 (3.0%) of 82,146 ccRCC patients and in 501 (1.9%) of 26,584 nccRCC. In ccRCC, after 1:2 PSM, 2496 (100%) patients with sarcomatoid dedifferentiation vs. 4992 (6.2%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 45.7% vs. 33.6% in ccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 1.6-fold higher CSM (HR 1.6, p < 0.001). In nccRCC, after 1:2 PSM 501 (100%) patients with sarcomatoid dedifferentiation vs. 1002 (3.8%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 41.7% vs. 28.1% in nccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 2.0-fold higher CSM (HR 2.0, p < 0.001). Conclusion: Sarcomatoid dedifferentiation is invariably associated with higher CSM in both ccRCC and nccRCC. However, the detrimental effect of sarcomatoid dedifferentiation in CSM is more pronounced in nccRCC than in ccRCC. Full article

In this work, we analyzed the ability to incorporate 8-oxo-dATP by several human DNA polymerases: replicative Pol ε (exo-) from Family B; base excision repair (BER) enzymes Pol β and Pol λ from Family X; and translesion Pol η, Pol ι, and Pol κ from Family Y. We demonstrated that human DNA polymerases differ in their abilities to discriminate against 8-oxo-dATP. Among the tested DNA polymerases, Pol λ exhibited the worst ability to discriminate against 8-oxo-dATP opposite template T on DNA substrates with a protruding single-stranded 5′-end and a double-stranded DNA with a 1 nt gap. Pol β and DNA polymerases of Family Y showed relatively high accuracy. Pol η demonstrated the most effective discrimination against 8-oxo-dATP on templates T and G. Pol ι exclusively incorporated 8-oxo-dATP opposite template G but not T. Unexpectedly, the catalytic subunit of high-fidelity Pol ε (exo-) incorporated 8-oxo-dATP opposite templates T and G with higher efficiency compared with the error-prone polymerases of Family Y and Pol β. While the structures of human polymerases with incoming 8-oxo-dATP are not available, we speculate on a possible mechanism of 8-oxo-dATP discrimination. Full article

Pediatric brain tumor survivors remain at high risk of recurrence, yet current surveillance strategies relying on neuroimaging and cerebrospinal fluid (CSF) cytology have limited sensitivity for early or minimal disease. Tumor-specific peptides (TSPs) derived from individual tumors represent a promising class of highly specific biomarkers for longitudinal disease monitoring through CSF-based proteomic analysis. In this study, tumor tissue and serial CSF samples from six pediatric brain tumor patients (five medulloblastomas and one atypical teratoid/rhabdoid tumor (ATRT)) were analyzed using an integrated proteogenomic workflow combining discovery and targeted mass spectrometry. TSPs were identified from resected tumor tissue and matched against shotgun CSF proteomic datasets to nominate candidate biomarkers. High-confidence peptides were synthesized as isotopically labeled standards and quantified longitudinally using targeted multiple reaction monitoring. Two TSP biomarkers derived from individualized pediatric brain tumors (one medulloblastoma and one ATRT) demonstrated robust detection in serial CSF samples and exhibited temporal concordance with radiographic disease course, declining with treatment response and increasing during disease progression. These findings establish the feasibility of detecting and longitudinally quantifying TSPs in CSF and support further investigation of individualized proteomic biomarkers for treatment response monitoring and disease surveillance in pediatric brain tumors. Full article

Background: Although physical activity (PA) offers substantial physical and psychosocial benefits, engagement remains suboptimal among cancer survivors. A theory-informed understanding of survivors’ perceived barriers, facilitators, and recommendations is needed to inform patient-centered PA about survivorship interventions. Objective: This study aimed to explore perceived barriers, facilitators, and recommendations for PA engagement among adult cancer survivors using the Theoretical Domains Framework (TDF). Methods: A phenomenological qualitative design was used. Eighteen cancer survivors from Nebraska participated in semi-structured interviews via Zoom or telephone. Semi-structured interviews (guided by open-ended questions with flexibility for probing) were transcribed verbatim, imported into MAXQDA 2024, and analyzed using TDF to identify themes and subthemes. Results: Three overarching themes emerged: barriers, facilitators, and recommendations related to PA engagement. Barriers included individual factors (low motivation and self-efficacy, limited awareness of PA guidelines, time constraints, and physical limitations due to treatment and comorbidities), social factors (limited support from family, friends), clinical factors (limited PA guidance from healthcare providers), and environmental factors (restricted access to resources and unfavorable weather). Facilitators included individual factors (PA knowledge, motivation, goals, and health benefits), social factors (support from family, friends), and clinical factors (encouragement from healthcare providers), and environmental factors (favorable weather and available community PA resources). Recommendations emphasized the need for tailored education, supportive counseling, and structured PA programs within survivorship care. Conclusions: Cancer survivors described multilevel determinants of PA engagement across individual, social, and environmental contexts. Findings highlight the importance of theory-informed, patient-centered strategies that enhance PA guideline awareness, strengthen social and clinical support, and improve access to community resources to promote sustained PA during cancer survivorship. Full article

Prophylactic antibiotic use in high-density ornamental aquaculture aims to mitigate infections, yet it is hypothesized to induce severe gut microbiome dysbiosis, contributing to high post-purchase mortality of goldfish purchased from retail stores by end consumers. This study utilized 16S rRNA gene amplicon sequencing, a rapid and high-resolution tool to characterize gut bacterial communities in six goldfish (Carassius auratus) sourced from antibiotic-intensive retail market in Hong Kong SAR, China. Diversity metrics were compared to unexposed reference controls and experimentally antibiotic-exposed cyprinid groups from published datasets. Market-sourced goldfish showed a profound collapse in alpha diversity (mean Shannon index 0.107 ± 0.141), far lower than controls (typically 2.0–4.5) and experimental groups (1.06–4.34). The microbiota exhibited extreme oligodominance by Cetobacterium and Vibrio, with near-total loss of beneficial commensal taxa. Principal coordinates analysis (PCoA) revealed distinct clustering, indicating fundamental and likely irreversible microbial restructuring. These findings show that chronic antibiotic exposure in ornamental supply chains induces a depauperate microbiome state, compromising host resilience and physiological homeostasis during environmental transitions. This dysbiosis provides a microbiological explanation for widespread post-purchase die-off, highlighting a major animal welfare and biosecurity concern. High-throughput sequencing offers quick, in-depth microbiome health assessment, essential for developing interventions to improve husbandry and reduce antimicrobial reliance in the global ornamental fish trade. Full article

Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6^nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6^nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences. Full article

Background/Objectives: Prostate cancer is the most diagnosed and third most deadly cancer among men in Europe. Metastatic castration-resistant prostate cancer (mCRPC) is incurable and resistant to standard androgen ablation therapy. More biomarkers are needed to select patients for novel personalized treatments. Previous whole-genome RNA sequencing results indicated a possible role for cluster of differentiation 24 (CD24) and neuropeptide Y (NPY) as diagnostic or prognostic biomarkers in androgen receptor-positive (AR⁺) mCRPC. Methods: We analyzed tissue microarrays representing 127 primary prostate cancers (with matched adjacent benign prostatic glands) and 124 metastases (from 34 patients) using immunohistochemistry to detect CD24 or NPY. Results: CD24 was more highly expressed in primary prostate cancer than in adjacent benign tissue for nuclear (p: <0.001), cytoplasmic (p: <0.001), and membranous staining (p: <0.001), while NPY showed no difference. Average NPY scores were lower in prostate cancers that later recurred (geometric mean 17.6, 95% CI: 9.5–32.5) compared to those that did not (38.7, CI: 23.2–64.4; p: 0.044, d: 0.773). In mCRPC, CD24 was detectable in 76% of cores at the cell membrane and in 58% in the nucleus. NPY was detectable in the cytoplasm of 17%. Scores for NPY and nuclear (but not membranous) CD24 were higher in AR⁺ mCRPC. In the RNA sequencing results, CD24 did not correlate with AR or kallikrein-related peptidase 3 (KLK3), while NPY positively correlated with AR (r_s: 0.313; p: <0.004) and KLK3 (r_s: 0.400; p: <0.004). NPY and CD24 scores did not correlate with neuroendocrine mCRPC markers. Nuclear and membranous CD24 showed differential expression by metastatic site. Conclusions: We did not find strong evidence to support the use of CD24 or NPY alone as clinical biomarkers. Membranous and nuclear CD24 were expressed in the majority of mCRPC specimens, while NPY expression was more limited. NPY and nuclear CD24 were more highly expressed in AR⁺ mCRPC than AR⁻ neuroendocrine disease, and nuclear CD24 displayed site-specific expression, suggesting a potential role for nuclear CD24 in promoting AR⁺ mCRPC. Full article

Credit scoring is the industry-standard methodology for quantifying the creditworthiness and default risk of individual loan applicants. However, assessing the risk at the portfolio level—across different branches or regions—requires more than just aggregating individual scores. This paper presents a simple, pragmatic model for evaluating overall commercial bank portfolio risk by analyzing accumulated credit scores, facilitating effective inter-branch benchmarking. The proposed model is validated using credit score data from two distinct regions of the bank. Logistic regressions by region show that both northern and southern banks maintain low overall risk profiles due to strong portfolio credit scores. However, a nuanced analysis reveals regional discrepancies: the southern region appears riskier when segmented by credit score groupings (indicating a higher concentration of lower-tier borrowers), whereas the northern region exhibits higher risk when analyzed against a broader set of factors, such as approved amounts, maximum potential exposure, and approved versus book rates. This research suggests that portfolio risk is not one-dimensional; effective risk management requires analyzing both individual scores and the interaction of loan characteristics, particularly when comparing regional performance. Full article

Background: Elevated abdominal adipose tissue at time of diagnosis is associated with breast cancer mortality. We sought to understand the association between abdominal adipose tissue (subcutaneous, SAT and visceral, VAT) assessed via dual-energy X-ray absorptiometry (DXA) and breast cancer mortality in the prevention setting. Methods: Women enrolled in the Women’s Health Initiative study with baseline whole-body DXA scans were included in the study (n = 9767). Causes of death were adjudicated up to 27 years of follow-up. Competing risk models were used to examine independent associations between baseline VAT, SAT, per 100 cm², and breast cancer-specific deaths; findings were reported as sub-hazard ratios (SHR) and confidence intervals (CI). Time-varying analyses additionally included DXA at years 3 and 6. Covariates included demographic, lifestyle, and tumor factors. Results: Baseline VAT and SAT ranged from undetectable to 616.25 cm² and 55.26–952.46 cm², respectively. There were 738 incident breast cancer cases post-enrollment, and 87 breast cancer-related deaths. Median age at diagnosis was 62 years. In adjusted models, higher baseline VAT and SAT were significantly associated with higher risk breast cancer mortality (49% and 40%, respectively); time-varying models were similar. Conclusions: Higher VAT and SAT were similarly associated with breast cancer mortality in this group of postmenopausal women. Full article

Background: Periodontal disease is a chronic inflammatory condition characterized by progressive destruction of the supporting tissues of the teeth. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of immune and inflammatory responses; however, their coordinated expression patterns in periodontal disease remain incompletely understood. Objective: This study aimed to evaluate the expression of miR-141-3p, miR-146a-5p, and miR-148b-3p in periodontal disease and to explore their potential co-regulation in relation to periodontal inflammation. Methods: Gingival samples were collected from individuals with periodontal disease and periodontally healthy controls. miRNA expression levels were quantified by real-time quantitative PCR using TaqMan assays and normalized to miR-191-5p. Relative expression was calculated using the ΔΔCt method. Statistical analyses included group comparisons and correlation analyses to assess relationships among miRNA expression levels. Results: miR-146a-5p expression was significantly reduced in periodontal disease compared with healthy controls (p < 0.05), while miR-141-3p showed a consistent downward trend without reaching statistical significance. No significant differences were observed for miR-148b-3p expression between groups. Notably, strong positive correlations were identified among the three miRNAs, indicating coordinated expression patterns independent of disease stage or grade. Conclusions: The findings demonstrate altered expression of miR-146a-5p and coordinated regulation of miR-141-3p, miR-146a-5p, and miR-148b-3p in periodontal disease. These results support the concept that miRNAs act within regulatory networks rather than as isolated markers and contribute to a more nuanced understanding of miRNA-mediated regulation in periodontal inflammation. Full article

The improper disposal of domestic medical waste (DMW) constitutes a significant public health and environmental concern; however, limited studies exist concerning DMW disposal practices in South Africa. This study evaluated the knowledge and practices involving the disposal of domestic medical waste (DMW) in the City of Tshwane Metropolitan Municipality. The study investigated common disposal methods, levels of awareness of appropriate techniques, and associated health risks. Data were collected using structured questionnaires (Annexure A) with closed-ended questions, administered both physically at shopping complexes and electronically via LinkedIn, WhatsApp, and email to eligible participants. Data analysis was conducted using the Statistical Package for the Social Sciences (SPSS) Version 29 and Microsoft Excel, with results presented in graphical form. Findings revealed that 78.3% of residents disposed of DMW in general waste bins, while 85.8% reported discarding medicine bottles in the same manner, and only 5.2% returned unused medications to pharmacies. The findings highlight gaps in awareness, infrastructure, and policy, necessitating comprehensive education programs, improved waste management services, and policy revisions to include DMW. A proposed model emphasizes education, community involvement, infrastructure enhancement, and ongoing policy evaluation to address these challenges. These efforts aim to reduce health risks, mitigate environmental impacts, and promote safe DMW disposal practices, safeguarding public health and creating a sustainable environment. Full article

A monitor and control framework for quantum-key-distribution (QKD) networks equipped with switching capabilities was developed. On the one hand, this framework provides real-time visibility into operational metrics. Specifically, it extracts essential data, such as the switching capabilities of QKD modules, the number of keys stored in buffer queues of the QKD links, and the respective key generation and consumption rates along these links. On the other hand, this framework allows software-defined networking (SDN) applications to operate on the collected information and address the cryptographic needs of the network. The SDN applications dynamically adapt the configuration of the switched network to align with its changing demands, e.g., prioritizing key availability on critical paths, responding to link failures, or reallocating generation capacity to prevent bottlenecks. This contribution demonstrates that the combination of switched QKD, centralized control, and global optimization strategies enables efficient, policy-driven operation of QKD networks. The cryptographic resources are allocated to maximize performance and resilience while remaining aligned with the specific policies set by network administrators. Full article

Background: Overweight women are at increased risk of metabolic dysfunction, muscle loss, and reduced physical function during middle age. Resistance training (RT), combined with a high-protein diet and omega-3 supplementation, may help mitigate these risks; however, their combined effects remain unclear. Objective: To examine whether omega-3 supplementation enhances the effects of RT combined with a high-protein diet on body composition, muscular performance, and selected biochemical markers in overweight women. Methods: Fifty-four overweight women (40–53 years) were randomly assigned to RT plus omega-3 supplementation with a high-protein diet (RO), RT plus placebo with a high-protein diet (RP), or a non-training control group (C). The RT intervention was performed three times per week for 8 weeks. Body composition, muscular performance, and circulating markers related to muscle metabolism and clinical safety were assessed before and after the intervention. Results: Forty-four participants completed the study. Both intervention groups demonstrated significant reductions in body mass and fat mass, alongside increases in skeletal muscle mass (SMM) and improvements in muscular strength, endurance, and power compared with the C group (p < 0.001). Markers related to muscle metabolism improved in both RT groups, with greater changes observed in the RO group. Clinical safety markers remained within normal ranges, with no between-group differences. Conclusions: Eight weeks of RT combined with a high-protein diet effectively improved body composition, muscle function, and anabolic signaling in overweight women. Short-term omega-3 supplementation selectively modulated biochemical markers but did not provide additional improvements in SMM, performance, or clinical safety markers, suggesting that its benefits may be limited without longer-term or higher-dose interventions. Full article

The importance of micronutrient status in human food choice remains a fundamental issue needing further investigation. The objectives of the present paper are to present and discuss historic and current research together with a general model incorporating this interaction and to suggest future research to address the questions this poses. By definition, essential nutrients must be consumed in sufficient amounts to meet an individual’s requirements. While data indicate that complex neuroendocrine mechanisms provide negative-feedback control of energy and protein intake to support homeostasis, corresponding mechanisms controlling micronutrient intake are less well studied. In some contexts, they are explicitly assumed to be absent, specifically for models evaluating safety and risks of deficiencies. However, it may be hypothesized that for at least some micronutrients, mechanisms exist that aid attainment of requirements by altering preference for micronutrient-rich foods so as to increase ingestion of foods containing them, similar to how being thirsty increases the appeal of watermelon compared with dry food. If this hypothesis is correct, it may hold important implications for understanding the types and quantities of foods ingested. Greater appeal in foods richer in essential nutrients may reduce the risk of malnutrition. However, by extension, it may be posited that the use of supplements could confound the most healthful food choices. For example, obtaining vitamin C from supplements or fortified foods could then causally reduce the dietary intake of vegetables and fruits by reducing the appeal of these foods. The unintended consequence may be a lower intake of fiber, nitrate, and phytochemicals, food constituents that may contribute to health without being essential nutrients themselves. This hypothesis can and should be tested empirically, for example, through randomized placebo-controlled supplementation trials. If clear causal effects are documented, clinical and public health guidance will require critical evaluation and possible modification. Full article