bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical features of pneumatosis intestinalis induced by alpha- glucosidase inhibitor in patients with type 2 diabetes mellitus: a single center retrospective study
Authors: Wu Guanlin , He Weiheng , Rao Huimin , Lu Lin , He Xinran , Hou Xuewen 
Published: February 2025

PurposePneumatosis intestinalis (PI) is a rare but significant side effect associated with the use of alpha-glucosidase inhibitor (αGI) in the treatment of diabetes. This study aims to analyze the clinical features of PI induced by αGIs in patients with type 2 diabetes mellitus.MethodsWe conducted a retrospective analysis of patients diagnosed with PI between January 2018 and December 2023. Data collected included demographic characteristics, clinical symptoms and signs, laboratory findings, imaging results, endoscopic manifestations, treatments, and outcomes. Clinical characteristics were compared between patients who used acarbose and those who did not.ResultsA total of 48 patients with PI were included in the study, of whom 22 had used acarbose and 26 had not. The acarbose taken group was significantly older than the acarbose untaken group. Additionally, the prevalence of coronary heart disease and hypertension was markedly higher in patients taking acarbose. Importantly, total bilirubin levels were lower in those with PI who were on acarbose therapy.ConclusionOur findings highlight the need for increased vigilance regarding the potential development of PI in older diabetic patients with cardiovascular conditions following αGI administration. Timely intervention is crucial to prevent adverse outcomes. This study offers valuable insights for the future management of αGI in diabetes treatment.
Serum adropin levels as a potential biomarker for predicting diabetic kidney disease progression
Authors: Chen I-Wen , Lin Cheng-Wei , Lin Chia-Ni , Chen Szu-Tah 
Published: February 2025

BackgroundTo investigate the value of serum adropin in predicting chronic kidney disease (CKD) progression in subjects with type 2 diabetes (T2D).Materials and methodsSerum adropin levels were measured in normal control and T2D patients with various stage of CKD. CKD progression was defined as ≥ 30% decline from the baseline estimated glomerular filtration rate. Logistic regression analysis was applied to assess the association between adropin levels and CKD progression.ResultsThe study included 58 subjects with T2D (18 early CKD and 40 advanced CKD) and 9 subjects without diabetes (control). Subjects with T2D had significantly higher adropin levels than controls (6393.10 ± 1611.84 vs. 3470.30 ± 1284.41 pg/ml; P &lt; 0.001). Meanwhile, T2D patients with advanced CKD had higher adropin levels than those with early CKD (6848.89 ± 1287.04 vs. 5380.25 ± 1826.44 pg/ml; P = 0.003). Among T2D patients, subjects experienced CKD progression had higher adropin levels than those without (7520.15 ± 843.21 vs. 6151.16 ± 1661.61 pg/mL, P =0.003). Thus, adropin predicts CKD progression in T2D patients with 86% sensitivity and 70% specificity at 6872.24 pg/ml cutoff value. The association with CKD progression was still significant after adjusting for age, gender and body mass index (adjusted odds ratio = 27.188, 95% confidence interval 1.415-522.527, P =0.029).ConclusionsThe above findings suggest that serum adropin could be applied as a potential biomarker for predicting CKD progression in subjects with T2D. Further research is needed to validate these results and explore the underlying mechanisms.
Embryonic heat conditioning induces paternal heredity of immunological cross- tolerance: coordinative role of CpG DNA methylation and miR-200a regulation
Authors: Ravi Padma Malini , Kisliouk Tatiana , Druyan Shelly , Haron Amit , Cline Mark A. , Gilbert Elizabeth R. , Meiri Noam 
Published: February 2025

BackgroundEnhancing an organism’s survival hinges on the development of balanced and adaptable stress response systems. While the initial stress-response set-points in the hypothalamus may be genetically determined, they are further influenced by epigenetic factors during embryonic development. A debate persists regarding the heritability of such behavioral traits. The chick in ovo heat conditioning model offers a unique insight into this fundamental question, where manipulation during embryonic development can induce heat resilience and even cross-tolerance to promote immunological resilience. In this study, we conducted an analysis of thermal manipulation during embryogenesis to demonstrate paternal heredity and investigate its transmission through sperm DNA methylation in coordination with miR-200a action.ResultFirst-generation embryos underwent in ovo heat conditioning (EHC), creating a cohort of embryonic EHC and control chicks. These chicks were then subjected to an intracranial lipopolysaccharide (LPS) challenge. Conditioning rendered the chicks immune resilient, as evidenced by their fibril effect. Male offspring were raised to maturity, and their sperm was analyzed for methylome patterns, revealing significant differences between treatments, particularly in immune and development related genes. Additionally, sperm from EHC males was used for artificial insemination of naïve Cobb hens, resulting in untreated offspring that displayed immune resilience upon LPS challenge, indicating transgenerational effects. Overlap analysis of sperm methylome and differentially methylated sites (DMS) of offspring hypothalamus revealed inheritance of altered methylation associated with specific genes. Several of these genes are potential effectors of miR-200a, whose expression profile in the hypothalamus during LPS challenge was conserved across both generations. To evaluate the role of miR-200a in cross-tolerance acquisition, miR-200a was intracranially injected, and RNA-seq analysis of the hypothalamus revealed genes involved in the regulation of developmental and metabolic processes, stress, and immune response.ConclusionThis study demonstrates paternal trait heredity by revealing that EHC induces cross-tolerance with the immunological system, rendering chicks resilient to LPS that transgenerationally transmit this to untreated offspring. Additionally, analysis of sperm methylation patterns in EHC mature chicks led to identification of genes associated with neuronal development and immune response, indicating potential neural network reorganization. Finally, miR-200a emerges as a regulator potentially involved in mediating the cross-tolerance effect.
GNA15 predicts poor outcomes as a novel biomarker related to M2 macrophage infiltration in ovarian cancer
Authors: Liu Qin , Sun Yabing , Zhang Tao , Lin Wanrun , Zhang Jing , Zhang Huijuan , Zheng Wenxin , Xu Hong , Zhou Feng 
Published: February 2025

BackgroundThe exploration of genetic signatures within the ovarian cancer (OC) tumor microenvironment (TME) remains limited. M2-like tumor-associated macrophages (M2-like TAMs) are pivotal in OC progression and therapy. This study aims to establish a novel prognostic signature and identify M2-like TAM-related biomarkers in OC using RNAseq-based transcriptome analysis.MethodsPrognostic M2-like TAM-related genes were identified through univariate Cox regression, consensus clustering, and LASSO regression. Immune landscape analysis was conducted to assess immune cell composition and immune checkpoint genes in high- and low-risk groups. Subsequently, in vitro cell experiments and OC cohorts were performed.ResultsGene set enrichment analysis revealed that GNA15 is involved in immune responses like leukocyte transendothelial migration and FcγR-mediated phagocytosis. GNA15 was up-regulated in cisplatin-resistant OC cells, and its in vitro down-regulation decreased cell proliferation. An eight-gene prognostic model, including M2-like TAM-related genes, independently predicted poor outcomes in OC. GNA15 emerged as a hub gene positively correlated with M2-like TAMs infiltration, predicting unfavorable outcomes across OC cohorts. Moreover, GNA15 expression correlated positively with CD163 expression, suggesting its role in macrophage polarization.ConclusionGNA15 plays an immunosuppressive role in OC progression linked to M2-like TAMs polarization and stands as a potential prognostic marker in OC.
NOX4 modulates breast cancer progression through cancer cell metabolic reprogramming and CD8+ T cell antitumor activity
Authors: Xiong Yingying , Weng Yiming , Zhu Shan , Qin Jian , Feng Jia , Jing Xiaopeng , Luo Chao , Gong Wei , Sun Rui , Peng Min 
Published: February 2025

IntroductionBreast cancer is the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Although NADPH oxidase 4 (NOX4) has been implicated in various oncogenic processes, its exact function in breast cancer progression, metabolic reprogramming, and immune modulation remains unclear.MethodsWe used murine 4T1 and EO771 breast cancer models to generate NOX4 knockout (KO) cell lines via CRISPR/Cas9. In vitro assays (cell proliferation, colony formation, wound healing, and Seahorse metabolic analyses) and in vivo orthotopic tumor studies assessed the impact of NOX4 loss. Transcriptomic changes were identified through RNA sequencing and gene set enrichment analysis. We performed MYC knockdown in NOX4 KO cells to investigate its mechanistic role. Flow cytometry characterized tumor-infiltrating immune cells. Finally, NOX4-overexpressing cells were tested for survival benefit and response to dual-checkpoint immunotherapy (anti-PD-1/anti-CTLA-4).ResultsNOX4 deletion accelerated tumor growth in vivo and enhanced proliferation, colony formation, and migratory capacity in vitro. Metabolic profiling showed that NOX4 KO cells had elevated glycolysis and fatty acid oxidation, along with increased mitochondrial mass. Transcriptomic and enrichment analyses revealed MYC pathway activation in NOX4 KO cells; suppressing MYC reversed these hyperproliferative and metabolic changes. Immunologically, NOX4 KO reduced CD8+ T cell infiltration and function, partially due to lowered CCL11/CCL5 levels, while PD-L1 expression was upregulated. In contrast, NOX4 overexpression improved survival in mice and synergized with checkpoint blockade, demonstrating a positive effect on anti-tumor immunity.DiscussionThese findings show that NOX4 constrains breast cancer aggressiveness by limiting MYC-driven metabolic adaptations and supporting CD8+ T cell-mediated immunity. Loss of NOX4 promotes a more malignant phenotype and dampens T cell responses, whereas its overexpression prolongs survival and enhances checkpoint inhibitor efficacy. Therapeutically targeting the NOX4–MYC axis and leveraging NOX4’s immunomodulatory capacity could offer promising strategies for breast cancer management.
Attitudes of medical students in Croatia toward rural medicine education and practice
Authors: Mrduljaš-Ðujić Nataša , Radić Ivana , Bašić Marković Nina , Vrgoč Toni , Buljubašić Maja 
Published: February 2025

IntroductionRecruiting and retaining doctors in rural areas is challenging. In Croatia, medical school curricula lack content on rural medicine and specialized training for rural practice. This study explores the opinions and attitudes of first- and sixth-year medical students in all four medical schools in Croatia regarding working in rural areas.MethodsAn online questionnaire was administered to Croatian medical students in their first and final years between January 2022 and February 2023. Responses were obtained from 690 participants from the Universities of Osijek, Rijeka, Split, and Zagreb. The cross-sectional study included 13 questions, with 5 on socio-demographic data. Data were analyzed using descriptive statistics and non-parametric tests (chi-square) to assess group differences.ResultsCompared to first-year students, final-year students feel less prepared by their education for rural practice (χ2 = 84.287; P = 0.000) but are more interested in working in rural areas (χ2 = 26.810; P = 0.000). Most students believe rural doctors need additional financial incentives, with this belief significantly stronger among final-year students (χ2 = 14.192; P = 0.000). Both groups agree that rural doctors face poor working conditions (χ2 = 1.524; P = 0.217). No statistically significant differences were found regarding job interest outside city centers (χ2 = 2.041; P = 0.564) or choosing rural medical practice (χ2 = 4.795; P = 0.187) among medical students from the Universities of Osijek, Rijeka, Split, and Zagreb. Students from rural settlements were more often interested in jobs outside the city center (72.1%) compared to those from smaller towns (60.6%), [χ2(1) = 5.142, p = 0.023] and larger cities (44.1%), [χ2(1) = 28.978, p = 0.000].ConclusionAlthough Croatian medical students show interest in working in rural areas, their education lacks sufficient preparation for the unique challenges of rural practice. They view the current conditions for rural doctors as inadequate and believe that additional financial incentives are necessary. Interest in rural practice is consistent across medical faculties in Croatia, with students living in rural areas showing a higher interest in working there.
Characterization of adult T-cell leukemia/lymphoma patients with specific skin lesions in a tertiary dermatological service in Brazil
Authors: Valente Mariana , Sanches José Antonio , Nukui Youko , Cury-Martins Jade , Souza Bruno Castro , Pereira Juliana , Miyashiro Denis 
Published: February 2025

IntroductionHuman T-lymphotropic virus type-1 (HTLV-1) is endemic in some countries, including Brazil. HTLV-1 is the etiological agent of adult T-cell leukemia-lymphoma (ATLL), a rare and aggressive CD4+ T-lymphocyte malignancy. ATLL affects 1–5% of virus carriers. Dermatological involvement occurs in 40–70%. Diagnosis is based on clinicopathologic correlation and HTLV-1 serology. There are few therapeutic options so far.MethodsThis is an observational retrospective cohort study with ATLL patients followed in a tertiary hospital in São Paulo, Brazil. Data were collected at diagnosis. Survival curves using the Kaplan–Meier method were analyzed with log-rank test, univariate and multivariate analyses were performed with the Cox proportional hazards model.ResultsForty-four patients were studied, 24 females (54.5%), and 20 males (45.5%). The median age at diagnosis was 59.4 years. Classification at diagnosis was: 16 (36.4%) chronic (93.7% unfavorable, 6.2% favorable), 14 (31.8%) acute, 10 (22.7%) smoldering, four (9.1%) lymphoma, and none with primary cutaneous tumoral. Regarding skin lesions, 18 (40.9%) had plaques; 15 (34.1%) nodules/tumors; 11 (25.0%) papules; 10 (22.7%) erythroderma; seven (15.9%) patches; two (4.5%) ichthyosis; one (2.3%) purpuric lesions. Epidermotropism/exocytosis of lymphocytes was observed in 25 patients (62.5%), and Pautrier microabscesses in three (7.3%). Four patients (10.0%) had subcutaneous involvement, two (5.0%) folliculotropism, two (5.0%) angiocentrism, and one (2.5%) perineural involvement. Ten patients (25.0%) presented a lichenoid pattern. Thirty-four patients (79.1%) had increased lactate dehydrogenase; 20 (45.5%) lymphocytosis; six (13.6%) flower cells in peripheral blood; six (14.6%) hypercalcemia; five (12.2%) hypoalbuminemia. Beta-2 microglobulin was increased in all 24 cases investigated. Monoclonal T-lymphocytes were observed in the blood of 23 patients (76.7%) and the skin of 19 (76.0%). Thirty patients (68.2%) died. Median overall survival was 32.3 months. Acute and chronic unfavorable forms had worse prognoses, with median overall survival of 23.3 and 34.1 months, respectively (p = 0.0011). After multivariate analysis, Shimoyama classification (acute) and urea levels were associated with poorer prognoses.ConclusionWe described a large Brazilian cohort of ATLL with cutaneous involvement. Description of clinical, pathology, laboratory, and follow-up data, and factors associated with poorer survival is essential to provide better care and to improve the quality of life of these patients.
Exogenous cystine increases susceptibility of drug-resistant Salmonella to gentamicin by promoting oxidation of glutathione metabolism and imbalance of intracellular redox levels
Authors: Du Junyuan , Wu Zhiyi , Zhu Chunyang , Yang Heng , Zhao Feike , Fang Binghu 
Published: February 2025

IntroductionAntibiotic overuse has caused the development of bacterial resistance, which is a major threat to public health. Intracellular metabolic processes are essential for maintaining the normal physiological activities of bacteria, and an increasing body of research has demonstrated a significant association between metabolic alterations and the development of drug resistance. Numerous studies have demonstrated that the addition of adjuvants can counteract bacterial antibiotic resistance.MethodCystine treatment was verified in vitro to promote the lethal effect of gentamicin on Salmonella using in vitro bactericidal counting methods. The metabolic differences in Salmonella enterica Typhimurium standard strain ATCC 14028 with or without the addition of cystine were analyzed via untargeted metabolomics. The multifunctional electronic enzyme marker was used to determine intracellular reduced glutathione/oxidized glutathione (GSH/GSSG), ferrous iron on (Fe2+), and reactive oxygen species (ROS) levels. The expression of glutathione and stress genes was determined using real-time quantitative PCR.ResultWe confirmed that exogenous cystine increased the lethal effect of gentamicin against strain S. enterica Typhimurium (ATCC 14028) and other clinically resistant Salmonella serotypes. Exogenous cystine stimulated the metabolism of the cell and activated the glutathione pathway while altering the GSH/GSSG ratio, which placed bacteria in a state of redox imbalance with increased Fe2+ and ROS levels. Our results suggest that when bacterial redox levels are reprogrammed, bacterial susceptibility to antibiotics can also change.DiscussionThis study confirms that cystine enhances the antimicrobial efficacy of gentamicin against drug-resistant Salmonella. Through the application of metabolomics, the underlying metabolic mechanisms by which cystine exerts its effects on Salmonella have been elucidated, offering a novel perspective in the domain of metabolic reprogramming aimed at counteracting drug resistance. Furthermore, these findings reinforce the potential role of small-molecule metabolites as effective adjuvants to enhance antibiotic action.
Defining the high-risk category of patients with cutaneous melanoma: a practical tool based on prognostic modeling
Authors: Dudin Oleksandr , Mintser Ozar , Gurianov Vitalii , Kobyliak Nazarii , Kozakov Denys , Livshun Sofiia , Sulaieva Oksana 
Published: February 2025

IntroductionAlthough most cutaneous melanoma (CM) in its early stages is treatable, the risk of recurrence remains high and there is a particular ambiguity on patients prognosis. This drives to identification of prognostic biomarkers for predicting CM recurrence to guide appropriate treatment in patients with localized melanoma.AimThis study aimed to develop a prognostic model for assessing the risk of recurrence in patients with CM, enabling prompt prognosis-driven further clinical decision-making for high-risk patients.Materials and methodsThis case-control study included 172 patients with CM recurrence (high-risk group) and 30 patients with stable remission (low-risk group) 3 years after primary diagnosis. The impact of sex, age at diagnosis, anatomical site, histological characteristics (the histological type, pathological stage, ulceration; the depth of invasion, mitotic rate, lymphovascular invasion, neurotropism, association with a nevus, tumor-infiltrating lymphocyte density, tumor regression and BRAF codon 600 mutation status) on CM recurrence was evaluated.ResultsFive independent variables, including nodal status, a high mitotic rate, Breslow thickness, lymphovascular invasion, perineural invasion and regression features were identified as the most significant. A 5-factor logistic regression model was developed to assess the risk of melanoma recurrence. The sensitivity and specificity of the model were 86.1% and 72.7%, respectively.ConclusionThe developed model, which relies on routine histological features, allows the identification of individuals at high risk of CM recurrence to tailor their further management.
Brain compensatory activation during Stroop task in patients with mild cognitive impairment: a functional near-infrared spectroscopy study
Authors: Fan Chenyu , Li Hanfei , Chen Ke , Yang Guohui , Xie Hongyu , Li Haozheng , Wu Yi , Li Meng 
Published: February 2025

PurposeThis study investigated the disparities in brain activation patterns during the Stroop task among individuals with mild cognitive impairment (MCI) and those without any cognitive impairments (healthy controls, HCs) using functional near-infrared spectroscopy (fNIRS).MethodsWe analyzed the cortical activation patterns of 73 patients with MCI and 63 HC individuals as they completed the Stroop task, employing fNIRS. The regions of interest (ROIs) included the dorsal prefrontal cortex (dPFC), ventrolateral prefrontal cortex (VLPFC), and parietal lobe (PL). The Stroop task is divided into early stage (0–15 s) and late stage (15–30 s). We also measured participants’ behavior during the Stroop task, analyzed variations in cortical activation intensity at different experiment stages, and performed correlation analysis between Montreal Cognitive Assessment (MoCA) scores, Stroop performance, and oxygenation levels.ResultsOur analysis revealed that individuals with MCI and HC demonstrated elevated cortical activation in the dPFC, VLPFC, and PL areas while performing the Stroop task (q &lt; 0.05, FDR-corrected). The MCI group displayed longer response latencies compared to the HC group while demonstrating comparable accuracy performance across both congruent and incongruent Stroop trials. The MCI group showed compensatory activation in the VLPFC, and PL regions compared to the HC group during the late stage of the Stroop task (q &lt; 0.05, FDR-corrected). Correlational analysis revealed a negative association between MoCA scores and oxygenation levels in the dPFC, VLPFC, and PL regions during the late stage of the Stroop task (p &lt; 0.05). However, no correlation was found with behavioral performance.ConclusionMild cognitive impairment patients demonstrated effective compensation for their cognitive impairments at a partial behavioral level by engaging compensatory activation in the prefrontal, and parietal regions while performing the Stroop task.