📋 Browse Articles

Many studies have revealed the observational associations between lipoprotein(a) (Lp(a)) concentrations and the incidence of cardiovascular diseases (CVDs). However, the causal associations remain unclear. Public summary data were analyzed using a Mendelian randomization (MR) design to assess the causal associations between Lp(a) levels and risks of nine CVDs and evaluate the potential impact of aspirin on Lp(a) levels. The principal analysis was conducted employing the random-effects inverse-variance weighted (IVW) method. Furthermore, the weighted median and MR-Egger approaches were used as the sensitivity analysis. Additionally, the significantly associated single nucleotide polymorphisms (SNPs) in salicylic acid (INTERVAL and EPIC-Norfolk, n = 14,149) were chosen to assess the potential effects of aspirin on lowering Lp(a) levels. The IVW analysis showed that the per standard deviation (SD) increment in Lp(a) level was causally associated with a higher risk of coronary artery disease (odds ratio (OR), 1.237; 95% confidence interval (CI), 1.173-1.303), atrial fibrillation (OR, 1.030; 95% CI, 1.011-1.050), heart failure (OR, 1.074; 95% CI, 1.053-1.096), hypertension (OR, 1.006; 95% CI, 1.004-1.008), and peripheral artery disease (OR, 1.001; 95% CI, 1.001-1.001) (all A causal nexus was discerned between Lp(a) levels and an increased risk of conditions including coronary artery disease, atrial fibrillation, heart failure, hypertension, and peripheral artery disease. Furthermore, administering aspirin may be a potential therapeutic to reduce these CVD risks among individuals with elevated Lp(a) levels. Show less

Polycystic ovary syndrome (PCOS) is a multifactorial disorder influenced by both environmental and genetic factors. The aim of this study was to evaluate associations between selected polymorphisms ( A total of 50 women (25 with PCOS and 25 healthy controls) were included. Genetic variants were identified using Polymerase Chain Reaction (PCR)-based methods. The frequencies of genotypes and alleles were compared between groups. Clinical symptoms such as irregular menstruation, hirsutism, acne, androgenetic alopecia, and overweight were assessed in relation to genotype. No significant differences were found in genotype distributions for Although most analyzed variants were not directly associated with PCOS in this cohort, the observed link between Show less

Certain parents of children with febrile seizures have a high sense of perceived vulnerability, which may lead to overprotective behaviors. This study aimed to measure the latent profile types of perceived vulnerability in parents of children with febrile seizures and investigate the factors affecting these different profiles. A cross-sectional study was conducted from October 2023 to December 2024. Participants were surveyed using a general data questionnaire, the child vulnerability scale (CVS), parents' perception of uncertainty scale (PPUS), and perceived social support scale (PSSS). Latent profile analysis (LPA) was conducted to identify different types of perceived vulnerability among parents of children with febrile seizures. The influencing factors for each profile were identified using univariate and multivariate logistic regression analysis. In total, 400 participants were included in this study. The perceived vulnerability among parents of children with febrile seizures was divided into three latent profiles: "General Low Perceived Vulnerability Group" (37.9%), "Moderate Perceived Vulnerability Group" (32.8%), and "High Perceived Vulnerability Group" (29.3%). Multivariate analysis indicated that relationship with children, parents' age, educational attainment, marital status, body temperature during febrile seizures, PPUS, and PSSS were the factors affecting perceived vulnerability in parents of children with febrile seizures. The perceived vulnerability in parents of children with febrile seizures exhibited significant heterogeneity. To minimize the perceived vulnerability, medical professionals should provide tailored mental health counseling and intervention based on vulnerability characteristics. Show less

Nero Siciliano (NS) is an autochthonous pig breed reared in northeastern Sicily; despite its high-quality meat products, NS is currently endangered. This study aimed to evaluate the genetic variability at nine loci within candidate genes for meat traits-Melanocortin 4 Receptor ( Show less

Obesity, a pandemic, worldwide afflicts almost one billion people. Obesity and ageing share several pathological pathways leading to neurological disorders. However, due to a lack of suitable animal models, the long-term effects of obesity on age-related disorders- cognitive impairment and dementia have not yet been thoroughly investigated. Therefore, the current investigation focuses on developing a suitable model to explore the effects of obese-ageing. It also aims to determine whether obesity affects cognitive abilities in an age-dependent manner, and to identify a potential biomarker(s) for cognitive decline. Cognitive tests were carried out on 6-months and 1-year-old melanocortin-4 receptor (Mc4r)-deficient-obese and lean (wildtype) mice. Additionally, brains and sera were harvested for molecular, histological and serological analyses from 6, 12, and 24-months-old mice. Finally, RT-PCR was carried out after hippocampal mRNA sequencing. The cognitive tests revealed that 1-year-old obese mice have cognitive impairment along with underlying neurodegenerative changes, such as enlarged lateral ventricles. Serum neurofilament light chain (sNfL) levels were also elevated. Lipid accumulation and neuroinflammation were apparent besides, a compromised blood-brain barrier (BBB) indicated by altered junction protein gene expression. Differentially-expressed genes associated with cognitive decline were identified by mRNA sequencing of hippocampi. One such gene, Secreted Phosphoprotein 1 (Spp1) had markedly increased expression in cognitively-impaired obese mice. Our findings present an obese-aged mouse model of cognitive decline with neuroinflammation, reduced BBB-integrity and predisposing neurodegenerative changes. Obese-ageing accelerates the progression of cognitive impairment. Furthermore, Spp1 appears to be a potential biomarker for early diagnosis of neuropathological disorders. Show less

Apolipoprotein C-III (apoC-III) is transported on chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a) [Lp(a)]. Olezarsen, a hepatic-targeted antisense oligonucleotide targeting APOC3 mRNA, lowers apoC-III and triglycerides and reduces pancreatitis events. This study evaluated the reduction of apoC-III in specific lipoprotein pools after treatment with olezarsen. Participants with familial chylomicronemia syndrome (FCS) in the Balance study received olezarsen 80 mg (n = 22), 50 mg (n = 21), or placebo (n = 23). Triglycerides, apoC-III, and lipoprotein-associated apoC-III was measured at baseline and days 85, 169, 253, and 365 using chemiluminescent ELISAs. Lipoprotein-associated apoC-III levels were measured in 4 lipoprotein pools, apoC-III-total apoB (apoB-48+apoB-100), apoC-III-apoA-I (HDL), apoC-III-apoB-100 (VLDL + LDL), and apoC-III-apo(a) (Lp(a)). The placebo-adjusted average percent changes from baseline to day 365 were calculated. The average percent changes from baseline to day 365 in apoC-III were -61.9 % and -74.7 % and for triglycerides -37.8 % and -55.7 % with olezarsen 50 mg and olezarsen 80 mg, respectively. The corresponding olezarsen-placebo average differences (95 % CI) in apoC-III-total apoB levels were -47.1 % (-64.1, -32.6) and -65.8 % (-81.5, -49.8), respectively and apoC-III-apoA-I by -53.6 % (-79.3, -29.4) and -76.1 % (-104.1, -55.4), respectively (p<0.001 for all). ApoC-III-apoB-100 was reduced by -12.5 % (-28.1, 2.1) (p = 0.0768) and -29.9 % (-46.1, -16.0) (p = 0.0006) and apoC-III-apo(a) by -15.7 % (-47.5, 10.6) (p = 0.18) and -39.1 % (-70.2, -16.1) (p = 0.0024), with olezarsen 50 mg and olezarsen 80 mg respectively. In adults with FCS, olezarsen significantly lowers apoC-III in all major lipoprotein pools, particularly in total apoB and apoA-I. Tracking changes in apoC-III among various lipoprotein pools elucidates the action of olezarsen on apoC-III and may inform future studies of pancreatitis and cardiovascular risk with apoC-III-targeted therapies. Show less

Obesity is a multifactorial disease caused by an interaction between genetic, environmental and behavioral factors. Polymorphisms of the two genes Circadian Locomotor Output Cycles Kaput (CLOCK) rs1801260 and Melanocortin-4-receptor (MC4R) rs17782313, are associated with obesity. Knowledge is limited on the interaction between CLOCK, MC4R and obesity. The aim was to explore the interactions between the CLOCK and MC4R gene variants on markers related to obesity. There were 423 subjects with information on two genetic variants of two genes (CLOCK and MC4R). Their interaction was evaluated with: chronotype, sleeping duration, emotional eating, food timing, stress, dietary intake, appetite, physical activity (assessed by questionnaires), anthropometric measures of obesity (assessed by physical measurements), and also hormonal factors (assessed by ELISA). Generalized Linear Models were applied. Our results revealed that significant differences were observed between the genotypes of CLOCK rs1801260 for weight, Body Mass Index (BMI), Glucagon-like peptide-1 (GLP-1), cortisol, energy, fat, sleep duration, chronotype, appetite, depression, stress, emotional eating, physical activity, breakfast, lunch, and dinner time (p˂0.05). Also, significant differences were observed between the genotypes of MC4R rs17782313 for weight, BMI, Waist Circumference (WC), Waist to Hip Ratio (WHR), ghrelin, energy, carbohydrate, fat, appetite, depression, stress, breakfast time, and emotional eating (p˂0.05). Our findings also showed significant interactions between the CLOCK (CC)∗MC4R (CT) genotypes for higher appetite, stress and CLOCK (CT)∗ MC4R (CC) genotypes for higher fat and energy intake and CLOCK (CC)∗MC4R (CC) genotypes for higher weight, BMI, energy and fat intake, appetite, emotional eating, stress, ghrelin, cortisol and lower sleep duration and GLP-1 (p˂ 0.05). Due to the non-significance of the interaction in CLOCK (CT)∗ MC4R (CT) genotypes, it seems that the presence of a healthy arm in the CLOCK and MC4R polymorphism is necessary for the proper function of the genes. Thus, these results highlight that gene variants and their interaction should be considered in obesity assessment. Show less

Gender-associated variations in phenotypic expression and their consequences are established in numerous cardiac circumstances. However, their impact is questionable in the case of HCM. To investigate the demographic and clinical profiles of the HCM patients. Also, to compare the echocardiographic features according to the HCM subtypes in the study populace. The present study was conducted at the DMCH, Ludhiana, from March 2019 to May 2021, using a prospective observational and non-blinded design. The data regarding demographic and clinical profile are gathered for the specified duration. The clinical features are confirmed through the Echocardiography. The gathered data are analyzed through chi-square to determine the differences among the groups with the aid of the SPSS tool. The demographic profiles and clinical assessment of 103 patients are analyzed. The subjective assessment reveals that HCM is predominantly in males in a ratio of 2.1:1. Dyspnea is a chief complaint of both genders (77.67%). Apical type is prevalent in male HCM patients. MYBPC3 and MYH7 are the general mutations found in the genetic tests. SCD is found in patients possessing this type of genetic mutation. The non-obstructive type is more common than the obstructive type. HCM is a chronic disease and causes morbidity as well as mortality globally. HCM patients are vulnerable to SCD and stroke. These risk factors rely on the diagnosis associated with age, gender, obstruction, obesity, and coronary diseases. Hence, the present research on the demographic characteristics of HCM patients promotes awareness regarding the complications among the Indian populace. Show less

This study aims to explore the association between plasma metabolites and chronic kidney disease progression in individuals with type 2 diabetes. We performed a comprehensive metabolomic analysis in a prospective cohort study of 5144 multi-ancestral individuals with type 2 diabetes in Singapore, using eGFR slope as the primary outcome of kidney function decline. In addition, we performed genome-wide association studies on metabolites to assess how these metabolites could be genetically influenced by metabolite quantitative trait loci and performed colocalisation analysis to identify genes affecting both metabolites and kidney function. Elevated levels of 61 lipids with long unsaturated fatty acid chains such as phosphatidylethanolamines, triacylglycerols, diacylglycerols, ceramides and deoxysphingolipids were prospectively associated with more rapid kidney function decline. In addition, elevated levels of seven amino acids and three lipids in the plasma were associated with a slower decline in eGFR. We also identified 15 metabolite quantitative trait loci associated with these metabolites, within which variants near TM6SF2, APOE and CPS1 could affect both metabolite levels and kidney functions. Our study identified plasma metabolites associated with prospective renal function decline, offering insights into the underlying mechanism by which the metabolite abnormalities due to fatty acid oversupply might reflect impaired β-oxidation and associate with future chronic kidney disease progression in individuals with diabetes. Show less

Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition. Show less

Lipoprotein (a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. In this study we aimed at assessing the effect of currently available lipid-lowering therapies (LLTs) on Lp(a) plasma levels. A meta-analysis was performed according to the PRISMA guidelines. Databases were searched up to May 2025. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) comparing the effect of lipid-lowering drugs vs placebo (addition of the same drug to both intervention and control group was acceptable); (4) reporting the effects on Lp(a) levels; (5) intervention duration of more than 3 weeks. The between-group (treatment-placebo) Lp(a) absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 145,314 subjects from 147 RCTs were included. Statins, bempedoic acid, ezetimibe, omega-3 fatty acids, and fibrates did not affect Lp(a) concentration. Lp(a) levels were significantly reduced by PCSK9 monoclonal antibodies (PCSK9mAbs, -6.37 mg/dL [-7.26 to -5.47], a 29% reduction from baseline), inclisiran (-4.76 mg/dL [-5.83 to -3.69], a 22% reduction from baseline), CETP inhibitors (CETPi, -6.77 mg/dL [-8.67 to -4.88], a 46% reduction from baseline), and niacin (-7.06 mg/dL [-9.27 to -4.85], a 37% reduction from baseline). In the subgroup analysis by baseline Lp(a) levels, a larger absolute reduction of Lp(a) levels was observed with increasing baseline levels of Lp(a) for PCSK9mAbs, inclisiran, and CETPi. Among available LLTs, PCSK9mAbs, inclisiran, CETPi, and niacin significantly decreased Lp(a) levels. Further research is necessary to understand whether this effect would translate into a clinically relevant cardiovascular benefit. Show less

The tumor immune microenvironment (TIME) and its impact on the prognoses and treatment of lung adenocarcinoma (LUAD) represent a major focus of research in this field. The present study primarily elucidates the role of RGS17 in TIME of LUAD. A comprehensive array of analytical methods was employed to assess the gene expression levels, including RT-qPCR, Western blots assay and Immunohistochemistry. The assessment of cell apoptosis and viability was conducted through the utilization of Flow cytometry, Colony formation, or CCK-8 assays. To comprehensively evaluate glycolysis, the glucose consumption, lactate production and extracellular acidification rate (ECAR) were detected. RGS17 was highly expressed in LUAD patients, which predicted adverse prognosis of LUAD patients. Functionally, RGS17 promoted LUAD tumor growth by hindering the anti-tumor immune response. Specifically, knockdown of RGS17 in tumor cells was observed to result in increased CD8 + T cell infiltration into the tumors, thereby impeding LUAD tumor growth. Furthermore, tumor-secreted RGS17 impeded CD8 + T cell function by reducing IFN-γ and Granzyme B secretion, thus impeding the anti-tumor immune response. Mechanically, RGS17 impeded glycolysis in CD8 + T cells by regulating the PI3K/AKT pathway. Tumor-secreted RGS17 impairs CD8 + T cell cytotoxicity in LUAD through impeding glycolysis mediated by PI3K/AKT pathway, thereby promoting tumor growth. Show less

A female patient from India was diagnosed with diabetes at 16 years of age and presented to a tertiary care diabetes clinic nine months later with hyperglycemia and dyslipidemia (hypercholesterolemia and hypertriglyceridemia), while on insulin and statin therapy. The striking feature was the presence of lipodystrophy on both her upper and lower limbs. Both her elder brother and mother showed the presence of dyslipidemia and a normal phenotype on cascade screening. All three of them had a normal BMI. Managing the case was challenging due to the suboptimal response of dyslipidemia to the various combinations of medication. Genetic testing revealed a rare mutation in the LPL gene, causing familial combined hyperlipidemia (FCH) with an unusual association of lipodystrophy. A similar heterozygous mutation was found in the mother. We report the first case of FCH with lipodystrophy from India and share the challenges encountered during the three years of follow-up. Show less

Lipid ratio is a balance between atherogenesis and antiatherogenesis. it is an important predictive marker of carotid plaque. The lipid ratios, which include non-high-density lipoprotein cholesterol (non-HDL-C)/high-density lipoprotein cholesterol (HDL-C), remnant cholesterol (RC)/HDL-C, apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1), low-density lipoprotein cholesterol (LDL-C)/HDL-C, ApoB/HDL-C, total cholesterol (TC)/HDL-C, triglycerides (TG)/HDL-C, were included and analyzed. Sex differences in the relationship between lipid ratios and carotid plaque were discussed. The risk of carotid plaque was found to be significantly associated with the Non-HDL-C /HDL-C, RC/HDL-C, ApoB/ApoA1, LDL-C /HDL-C, ApoB/HDL-C, TC/HDL-C in females but not in males. The ApoB/HDL risk presented the highest relationship with carotid plaque in females only. The predictive value of the aforementioned lipid ratios for carotid plaque was observed in females only. Show less

Altering inflammation can impact the recovering heart's structure and function following myocardial infarction (MI). MAP kinase-activated protein kinase 2 (MK2) regulates the stability of several pro-inflammatory cytokines. Hence, this study was to determine if MK2 deficiency impaired the inflammatory phase of post-MI wound repair. Myocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2 Show less

This study aims to investigate how Bifidobacterium breve BBr60 improves obesity-related metabolic disorders by modulating the gut microbiota-SCFAs axis, thereby affecting inflammatory factors and metabolic hormones. A randomized, double-blind, placebo-controlled trial was conducted. A total of 75 individuals with obesity subjects (BMI ≥ 28) were enrolled and randomly assigned to either the BBr60 intervention group (10 billion CFU daily) and the placebo group. After the 12-week intervention, 65 participants (BBr60: n = 33; placebo: n = 32) completed the study and were included in the primary analysis. All participants received standardized nutritional counseling aimed at a moderate energy intake (~ 1800 kcal/day, including a daily intake of 25 g of dietary fiber.). Every week, we call participants at a fixed time to inquire about their weekly diet and weight changes, and provide dietary suggestions for the following week based on the inquiry results. Participants were instructed to maintain their usual physical activity levels throughout the study. The composition of the gut microbiota was analyzed by 16 S sequencing, fecal SCFAs were detected by GC-MS, and serum levels of IL-27, IL-1β, and metabolic hormones were measured using ELISA technology. Metabolic indicators such as body weight, body fat percentage, and HOMA-IR were also assessed. The BBr60 intervention significantly increased fecal butyrate levels (p < 0.001), accompanied by a decrease in IL-1β levels (p < 0.05) and an upregulation of IL-27 (p < 0.01). In terms of metabolic hormones, leptin (LEP), adiponectin (ADPN), connecting peptide (C-P), pancreatic polypeptide (PP), peptide YY (PYY), Glucose-dependent insulinotropic polypeptide (GIP), and Glucagon-Like Peptide-1 (GLP-1) were all significantly elevated (p < 0.05), while Homeostasis Model Assessment for Insulin Resistance(HOMA-IR) was significantly reduced in the BBr60 group (p < 0.05). In the control group, C-P, PP, and GIP were significantly increased (p < 0.05), whereas LEP, ADPN, PYY, GLP-1, and HOMA-IR showed no difference before and after the 12-week period. Correlation analysis indicated that butyrate levels were significantly positively correlated with GLP-1 and IL-27, and negatively correlated with IL-1β. Bifidobacterium breve BBr60, by remodeling the gut microbiota-SCFAs axis, inhibits the pro-inflammatory factor IL-1β, activates the anti-inflammatory signal IL-27, and synergistically regulates the metabolic hormone network (such as GLP-1, ADPN), significantly improving obesity-related metabolic disorders. This study provides a theoretical basis and intervention targets for the clinical application of probiotics targeting the "microbiota-SCFAs-inflammation/hormone axis," and future research can explore precise probiotic treatment regimens based on individual microbiota characteristics. Show less

Prostate cancer is an adenocarcinoma that involves epithelial-mesenchymal transition (EMT) for metastasis. To uncover novel insights into the development of prostate tumors and to identify important genes and putative microRNAs (miRs) for patient care, this study performed an in-depth bioinformatics analysis using dbDEMC3.0 (Zhejiang University, Hangzhou, China), MIENTURNET (University of Rome Tor Vergata, Rome, Italy), and DIANA-miTED (University of Thessaly, Thessaly, Greece) to explore miRs regulating tumorigenesis, proliferation, and potential therapeutic targets. A total of 373 differently expressed miRs were examined in this study, of which 87 had significant upregulation and 85 had significant downregulation. Our results from the MIENTURNET software showed that miR-141-3p, miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-203a-3p, miR-429, miR-34a-5p, and miR-509-3-5p interact with the transcription factors CDH1, CDH2, SNAI1, ZEB1, and ZEB2, which play a significant role in the core EMT regulatory network. The Encyclopedia of RNA Interactomes (ENCORI) miR-target interaction co-expression analysis observed that miR-34a-5p had a strong interaction with CDH1 as compared to other genes. The results of DIANA-plasmiR analysis showed that miR-34a-5p is a useful prognostic and diagnostic biomarker. Our results suggest that this study advances our knowledge of the molecular mechanism underlying prostate adenocarcinoma and that the interaction between the EMT gene and differentially expressed miR (DEmiR) in prostate adenocarcinoma may represent a target for prostate cancer diagnosis and treatment. Show less

Coronavirus disease 2019 (COVID-19) has been widely associated with intense systemic inflammation, endothelial injury, and a high incidence of thrombotic complications, which together contribute to disease severity and poor clinical outcomes. While endothelial dysfunction, dysregulated cytokine production, and oxidative stress are recognized features of severe COVID-19, the direct impact of circulating factors from infected individuals on endothelial cell behavior remains insufficiently characterized. Here, we examined how serum from patients with severe COVID-19 and from convalescent individuals modulates endothelial activation, inflammatory responses, and oxidative stress using human umbilical vein endothelial cells as an in vitro model. Venous blood samples were collected from individuals with severe COVID-19 (n = 13), convalescent patients (n = 11), and healthy volunteers (n = 7) during the initial phase of the COVID-19 pandemic. Human umbilical vein endothelial cells (HUVEC) were maintained in culture and exposed to 15% serum from each study group after a period of serum deprivation. The expression of genes associated with endothelial activation, thrombosis, inflammation, and oxidative stress was analyzed by quantitative real-time PCR at defined time points. In addition, the endothelial secretory profile was evaluated in cell culture supernatants using multiplex bead-based immunoassays. Statistical analyses were performed using one-way ANOVA followed by appropriate post hoc tests, receiver operating characteristic (ROC) curve analysis to assess the discriminatory capacity of biomarkers, and multivariate linear regression to identify factors associated with disease severity. We investigated the role of the endothelium in modulating the cytokine storm in severe COVID-19. HUVEC were stimulated with serum from patients with severe COVID-19, convalescent individuals, and healthy volunteers. Stimulation with serum from severe cases induces significant increases in These findings suggest that HUVEC serves as a promising biological sensor for detecting inflammatory responses in COVID-19 patients and shows the crucial role of the endothelium in sustaining the cytokine storm that contributes to patient severity and mortality. Show less

Chronic heart failure (CHF) is frequently complicated by depression, which worsens prognosis but remains underdiagnosed due to symptom overlap and a lack of objective screening tools. Although biomarkers reflecting lipid metabolism, insulin resistance, inflammation, and neuro-immuno-endocrine imbalance have been implicated in both CHF and depression, their predictive value for psychiatric outcomes in CHF patients is unclear. This study aimed to develop and validate interpretable machine learning (ML) models for predicting depression risk in CHF patients via the use of clinical and biomarker data. We retrospectively enrolled 3, 110 CHF patients admitted between January 2015 and December 2024 at Guang'anmen Hospital. Demographic, clinical, and laboratory indicators, including apolipoprotein B (ApoB), the triglyceride-glucose (TyG) index, and a novel glycated TyG (gTyG) index, were collected. Logistic regression and restricted cubic spline analyses were used to assess dose-response associations between biomarkers and depression. Eight ML algorithms were trained and evaluated, with model interpretability assessed via SHapley Additive exPlanation (SHAP). Among the 3, 110 patients, 37.3% had comorbid depression. Elevated ApoB and gTyG indices were strongly associated with depression risk in both the unadjusted and fully adjusted models (ApoB Q4 vs. Q1: OR 5.41, 95% CI 3.72-7.87; gTyG Q4 vs. Q1: OR 2.88, 95% CI 1.88-4.41; both P < 0.001), demonstrating clear nonlinear dose-response relationships. The TyG index was associated with depression in the crude analyses but lost significance after adjustment. Among the ML models, the RF model achieved the best performance (AUC 0.933 in training, accuracy 0.814, sensitivity 0.939). SHAP analysis revealed that the ApoB and gTyG indices were the most influential predictors. A user-friendly web application was developed for individualized risk prediction. This study demonstrated that the ApoB and gTyG index are robust biomarkers for predicting depression risk in CHF patients. The RF model provided the highest predictive accuracy and interpretability, highlighting its potential utility for early risk stratification and targeted intervention. The incorporation of these biomarkers into routine clinical practice may facilitate timely identification and management of depression in CHF patients, ultimately improving patient outcomes. Show less

We report herein a phase Ib trial to determine the safety, tolerability, and antitumor activity of erdafitinib, a pan-FGFR tyrosine kinase inhibitor, with fulvestrant and palbociclib in patients with hormone receptor-positive/HER2-negative metastatic breast cancers (NCT03238196). Thirteen patients were enrolled on the escalation phase in a traditional 3 + 3 trial design to determine the maximum tolerated dose (MTD). Subsequently, 22 patients were treated at the established MTD during the expansion phase. All patients had received prior treatment with cyclin-dependent kinase-4/6 inhibitors and endocrine therapy, and 29 showed FGFR pathway alterations in their tumors. The MTD of erdafitinib was 6 mg taken orally once daily when combined with palbociclib and fulvestrant. The triple combination showed clinically manageable tolerability. Most common adverse events were neutropenia, likely attributable to palbociclib, and oral mucositis and hyperphosphatemia, attributable to erdafitinib. Three patients showed a partial response, one of them lasting more than 2.5 years, despite lacking detectable FGFR1 to FGFR4 somatic alterations. FGFR1 amplification was not associated with response to FGFR inhibition, but high FGFR1 protein expression, measured by IHC, correlated with longer progression-free survival within the FGFR1-amplified cohort. There was no correlation between FGFR1 copy number and FGFR1 protein levels in specimens from metastatic sites, potentially highlighting the need for a more recent metastatic tumor biopsy for biomarker evaluation. The trial endpoint was met establishing the MTD of erdafitinib at 6 mg. Whereas the triplet regimen may pose tolerability challenges, alterative doublets with selective FGFR1 inhibitors in patients with FGFR1-dependent tumors, possibly administered in sequence, are worthy of further investigation. Show less

Posterior pituitary tumors (PPTs) are rare, non-neuroendocrine neoplasms derived from pituicytes of the neurohypophysis or infundibulum. According to the 2025 WHO classification, PPTs comprise four distinct but related low-grade entities: pituicytoma, granular cell tumor of the sellar region, spindle cell oncocytoma, and ependymal pituicytoma. All share nuclear TTF-1 expression, confirming their common origin, but differ in morphology, immunophenotype, and ultrastructure. Histologically, pituicytomas consist of bipolar spindle cells in fascicles; granular cell tumors show polygonal cells with PAS-positive, diastase-resistant cytoplasmic granules; spindle cell oncocytomas display oncocytic change and abundant mitochondria; and ependymal pituicytomas exhibit perivascular pseudorosettes and EMA positivity in apical or dot-like patterns. Immunohistochemically, all are S100 and vimentin positive, and negative for pituitary hormones and lineage-specific transcription factors. Clinically, PPTs are typically non-functioning but may be associated with corticotroph or somatotroph hyperfunction. Imaging features are nonspecific. Surgical resection is the treatment of choice, although hypervascularity and adherence-especially in spindle cell oncocytomas-can hinder complete excision. Radiotherapy is reserved for recurrences. Molecular analyses reveal recurrent alterations in MAPK/PI3K pathways (e.g., HRAS, BRAF, FGFR1, NF1, TSC1) and suggest a shared histogenesis. Copy number imbalances correlate with reduced progression-free survival in some subtypes. Despite a generally favorable prognosis, recurrence-particularly in spindle cell oncocytomas-necessitates long-term follow-up. The WHO 2025 update provides a unified framework for classification, diagnosis, and prognostic stratification of these rare tumors. Show less

Regorafenib is an oral multi-tyrosine kinase (RTK) inhibitor. It exhibits high selectivity for VEGFR1/2/3, while also inhibiting PDGFRβ, FGFR1, and oncogenic signaling cascades involving c-RAF/RAF1 and BRAF. These pathways are highly expressed in meningiomas, particularly in high-grade meningiomas. The MIRAGE trial (NCT06275919) is a multicenter, open-label, controlled, randomized phase 2 clinical trial evaluating grade 2/3 meningioma patients who have progressed following surgery and radiotherapy. A total of 94 participants are being randomized (1:1) to receive either regorafenib (160 mg orally for 3 weeks on, 1 week off) or local standard-of-care therapies (e.g., bevacizumab, hydroxyurea, somatostatin analogs). Major inclusion criteria include histological confirmation of grade 2 or grade 3 meningioma according to the WHO 2021 classification, radiologically documented progression according to RANO criteria with at least 1 measurable lesion (minimum 10 × 10 mm) on baseline MRI, ineligibility for further surgery and/or radiotherapy, and a WHO performance status of 0-1. The primary endpoint is 6-month progression-free survival (6m-PFS) and secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and health-related quality of life. Exploratory analysis will also be performed. MIRAGE, initiated in September 2024, is an academic trial promoted by the Istituto Oncologico Veneto, IOV-IRCCS, and will recruit patients across 15 neuro-oncology centers in Italy with an estimated study duration of 18 months. MIRAGE is a phase 2 trial designed to determine the role of regorafenib in prolonging the PFS of grade 2-3 meningioma patients ineligible for further surgery and/or radiotherapy. ClinicalTrials.gov NCT06275919. Registered before start of inclusion, 7 February 2024. EuCT no. 2024-510954-28. Show less

The limited response rate to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of lung adenocarcinoma (LUAD). In our study, we identified a lactate-based chemical barrier surrounding FAP Show less

Lung adenocarcinoma (LUAD) is a leading cause of cancer‑related death due to its aggressive nature and metastatic potential. The present study aimed to explore the expression of phospholipid phosphatase 2 (PPAP2C) in LUAD, and its effect on cell migration and invasion, with a particular focus on its association with the ERK/JNK signaling pathway and epithelial‑mesenchymal transition (EMT). The expression of PPAP2C in LUAD was analyzed using data from The Cancer Genome Atlas database. Pearson's correlation coefficient analysis was used to assess the correlation between PPAP2C and genes such as MAPK1, MAPK3, MAPK8, CDH1, CDH2 and SNAI1. Subsequently, the PPAP2C gene was silenced in A549 and H1299 LUAD cell lines using siRNA vectors, followed by assessments of gene expression, cell migration, invasion and protein interaction using reverse transcription‑quantitative PCR, western blotting, wound healing assay, Transwell invasion assay, molecular docking analysis, co‑immunoprecipitation and immunofluorescence staining. The results showed that PPAP2C was significantly upregulated in LUAD tissues compared with that in normal tissues. In addition, high levels of PPAP2C were significantly correlated with MAPK3, MAPK8, CDH1 and SNAI1. Notably, PPAP2C silencing significantly inhibited cell migration and invasion. Additionally, it reduced the phosphorylation levels of ERK and JNK proteins. PPAP2C showed specific binding sites with ERK1, and co‑precipitated with ERK1 in both A549 and H1299 cells. Furthermore, PPAP2C silencing decreased the expression levels of N‑cadherin and Snail, while increasing E‑cadherin expression, thereby inhibiting EMT. In conclusion, PPAP2C may be highly expressed in LUAD tissues, and could promote cell migration and invasion by activating the ERK/JNK signaling pathway and inducing EMT. These findings provide a novel potential target for the diagnosis and treatment of LUAD. Show less

The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy. Show less

Emerging evidence suggests that the genetic architecture of Alzheimer's (AD) and Parkinson's diseases (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African Admixed, East Asian, and European populations by implementing Population Attributable Risk (PAR) comparisons on summary statistics from genome-wide association studies (GWAS). PAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African Admixed, East Asian, and Latino individuals. For both AD, Show less

Endometriosis can lead to decreased endometrial receptivity, reduced rates of implantation, and diminished ovarian reserve. Currently, more than 50% of infertile women are found to suffer from endometriosis. However the etiology and pathogenesis of endometriosis are still poorly understood. Epithelial-mesenchymal transition (EMT) has been confirmed to be involved in endometriosis. PYK2 is a non-receptor tyrosine kinase that affects cell proliferation, survival, and migration by regulating intracellular signaling pathways. PYK2 plays a regulatory role in the EMT process by affecting the expression of genes associated with EMT through the influence of transcription factors. Snail1 (Snail1) plays a key role in the EMT process and is highly expressed in endometriosis tissues. On the other hand, Snail1 affects the invasive and metastatic ability of endometriosis cells mainly by regulating the EMT process. However, the upstream mechanisms that regulate the process of Snail1 protein stability in endometriosis are not clear. We identified a non-receptor tyrosine kinase, proline-rich tyrosine kinase 2 (PYK2 or PTK2B), and examined the expression of PYK2 in endometriosis. The relevant plasmids were constructed. This study enrolled 20 patients with laparoscopically confirmed endometriosis meeting ASRM diagnostic criteria, collecting ectopic lesions (14 ovarian endometriotic cysts and 6 deep infiltrating nodules) along with matched eutopic endometrial tissues (15 proliferative phase, 5 secretory phase) as controls. All tissue specimens underwent immunohistochemical analysis. Human endometrial stromal cells (HESC) were isolated from normal endometrium of 3 control patients for in vitro meconium induction. Ectopic endometrial stromal cells (EESC) were obtained from 5 ectopic lesions. Protein extracts from both ectopic tissues and cells were subjected to Western blot and co-immunoprecipitation (Co-IP) interaction validation. Functional assays (proliferation/migration/invasion) were performed using EESC and 11Z cell lines with triplicate biological replicates. Co-IP experiments were performed to verify the interaction between PYK2 and Snail1, as well as to determine the specific location of this interaction. Additionally, we examined the effect of PYK2 on endometriosis cells in vitro and whether VS-6063 inhibits the biological functions of endometriosis cells. Endometriosis models were established in 20 five-week-old female C57BL/6 mice, randomly allocated into experimental (n = 10) and control (n = 10) groups. Statistical analyses were conducted using GraphPad Prism 7.0, employing parametric tests for normally distributed data and non-parametric methods otherwise, with Benjamini-Hochberg correction for multiple comparisons. PYK2 is highly expressed in endometriosis tissues. It acts as a new binding partner of Snail1 and enhances EMT in endometriosis by increasing the phosphorylation of Snail1. Additionally, PYK2 promotes the proliferation, migration, and invasion of endometriosis cells while inhibiting decidualization. We demonstrated that VS-6063 inhibited the proliferation, migration, and invasion of endometriosis cells in vitro, as well as the growth of endometriotic lesions in vivo. PYK2 is a novel binding partner of Snail1. PYK2 promotes the occurrence and development of endometriosis by up-regulating Snail1, which could be a promising therapeutic target for endometriosis. Show less

Snail is a zinc finger transcription factor encoded by the SNAI1 gene and triggers a cellular process termed epithelial-mesenchymal transition (EMT) upon its increased expression and/or functional activation. Snail expression and activity are regulated by various extracellular stimuli, including cytokines and environmental factors. Transforming growth factor-β (TGF-β) is a Snail inducer that functions via Smad3-mediated transcriptional activation. In the present study, we identified a distal enhancer that modulates TGF-β-induced SNAI1 expression. ChIP-seq and Hi-C analyses showed that the enhancer is located 46 kb downstream of the SNAI1 gene; in TGF-β-stimulated cells, it associates with Smad3 and interacts with the SNAI1 proximal promoter. Inhibiting the activity of the enhancer using CRISPRi attenuated TGF-β-induced SNAI1 expression, stress fiber formation, and cell motility enhancement, suggesting that the enhancer mediates TGF-β-induced EMT. The enhancer contains a Smad-binding CAGA motif and an activator protein-1 (AP-1) binding motif that function in transcriptional activation. Ras-responsive element binding protein 1 (RREB1), a transcription factor required for TGF-β-induced Snail expression, regulated the basal activity of the enhancer but not its inducibility by TGF-β. In contrast to the enhancer, the association of Smad3 with the proximal promoter was not evident. These findings suggest that the proximal promoter and the distal enhancer respond to distinct signaling cues, integrate them, and cooperatively function to drive SNAI1 expression. Show less