Yang Shen

Cardiomyopathies are genetically heterogeneous myocardial diseases that can lead to heart failure, arrhythmias, and sudden cardiac death. OBSCN encodes obscurin, a giant sarcomere-associated protein involved in sarcomere organization, cytoskeletal coupling, calcium handling, and cell–cell adhesion signaling. This review synthesizes current evidence on OBSCN variants in cardiomyopathy, focusing on their spectrum, phenotypic associations, and potential pathogenic mechanisms. Curated variants were systematically interpreted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines. Putative truncating variants predominated among variants of uncertain significance, and hypertrophic cardiomyopathy was the most frequently reported phenotype. Co-occurring variants in established or candidate cardiomyopathy-associated genes were reported for some OBSCN variants, particularly missense variants. However, co-occurrence alone does not establish an independent pathogenic contribution, oligogenic inheritance, or a genetic modifier effect. Potential mechanisms include obscurin insufficiency, destabilization of sarcomeric scaffolding, impaired sarcoplasmic reticulum coupling, dysregulated calcium homeostasis, altered mechanotransduction, and defective intercellular adhesion. Overall, OBSCN is an emerging but incompletely characterized cardiomyopathy-associated gene, and truncating variants warrant further clinical and mechanistic investigation.

Despite the high global incidence of asthma and atrial fibrillation (AF), the causal relationship between the two conditions remains unclear. Emerging observational evidence suggests a potential association; however, conflicting results and limited mechanistic insights necessitate a comprehensive evaluation. This study aims to determine the causal relationship between asthma and the risk of AF and to explore the underlying molecular mechanisms. We performed a meta-analysis of observational studies to assess the association between asthma and AF risk, followed by a two-sample Mendelian randomization (MR) analysis to infer causality. Bioinformatics analyses using data from the Gene Expression Omnibus (GEO) were conducted to identify differentially expressed genes (DEGs) and enriched pathways. Potential therapeutic targets were validated through drug-gene interaction screening. The meta-analysis of eight observational studies involving 1,067,774 participants demonstrated that asthma was associated with a 21% increased risk of AF (odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.07-1.36, p = 0.003). Two-sample MR analyses of European populations revealed that genetically predicted asthma was causally associated with increased AF risk (inverse-variance weighted (IVW) OR = 1.001, 95% CI: 1.000-1.002, p = 0.019), whereas no significant association was observed in East Asian cohorts. Transcriptomic analyses identified carboxypeptidase A3 (CPA3) as a shared upregulated gene in both asthma and AF, potentially involved in renin-angiotensin system dysregulation. Drug-gene interaction screening suggested osilodrostat and metyrapone as potential therapeutic candidates targeting CPA3. Our study provides evidence that genetic predisposition to asthma is significantly associated with an increased risk of AF in the European population. Transcriptomic data analyses suggest that CPA3 and its interactions with therapeutic drugs could serve as potential biomarkers, offering new opportunities to improve prognosis in patients with coexisting asthma and AF.

Background: Triptolide (TP) exhibits various pharmacological activities. Our previous studies have confirmed the efficacy of TP against lung adenocarcinoma (LUAD). However, the potent pharmacological activity of TP is underpinned by its complex mechanisms. Exploring its potential mechanisms is of great value for promoting the clinical application of TP and extending its clinical use. Methods: Differentially expressed genes (DEGs) associated with LUAD were analyzed and acquired from the TCGA database, while DEGs related to TP were obtained through RNA sequencing. Hub genes were identified through LASSO and random forest models. The efficacy of TP against LUAD was validated using tumor‐bearing mouse models and A549 cells. The validation of hub genes was conducted using RT‐qPCR. The regulatory effect of hub genes on TP efficacy was validated through overexpression cell models. Furthermore, the potential mechanisms by which TP improves gemcitabine (GEM) resistance were explored using a GEM‐resistant cell line in combination with the overexpression model. Results: This study validated the therapeutic effect of TP against LUAD in vivo and in vitro. Bioinformatics revealed that the mechanism of TP's effect against LUAD might be associated with amino acid‐related biological processes. Five hub genes were screened and identified by combining bioinformatics methods and experiments. The overexpression model validated that PSAT1 plays an effective role in the efficacy of TP and in alleviating GEM resistance. Conclusion: This study preliminarily demonstrated that the anti‐LUAD effect of TP was associated with the PSAT1‐regulated serine biosynthesis pathway, and that TP effectively improves GEM resistance by inhibiting PSAT1 expression.

The TTN gene encodes a crucial structural protein within cardiac sarcomeres, and its variants may contribute to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy; however, phenotype and genotype are different. Whole‐exome sequencing (WES) was conducted on a Chinese proband diagnosed with HCM. In silico splicing prediction tools and minigene assays were employed to investigate the impact of the identified variant on mRNA splicing. A literature review was performed to retrieve and analyze previously reported splicing variants in the TTN gene associated with HCM. A 42‐year‐old male proband presented with nonobstructive HCM and paroxysmal atrial arrhythmias. A novel homozygous TTN variant was found, predicted to cause a 14‐base pair deletion at a splice acceptor site. Two asymptomatic offspring were found to carry the heterozygous variant. Based on variant interpretation guidelines, the variant met the PM2_supporting criterion and was classified as a variant of uncertain significance (VUS). The predicted aberrant splicing effect was subsequently confirmed by the minigene splicing assay, demonstrating altered pre‐mRNA splicing leading to an in‐frame insertion/deletion (p.Arg32498_Glu32504delinsGln). Functional verification confirmed that this mutation conforms to the PM4 criterion, suggesting that it can be reclassified as a tepid VUS (scoring 3 points). The functional result might provide pathogenic evidence. We also reviewed 28 previously reported splicing variants in TTN associated with HCM. Of these, 57.1% (16/28) localized to the I‐band region, whereas 21.4% (6/28) were situated in the A‐band domain of titin. Notably, 21.4% (6/28) co‐occurred with pathogenic variants in other sarcomeric genes ( MYH7 or MYBPC3 ), correlating with more severe clinical phenotypes. Reclassification and reinterpretation of the variants revealed that none met the level of likely pathogenic or higher. The present case contributes a homozygous splice‐site variant with experimentally confirmed aberrant splicing and an in‐frame protein alteration in titin. The focus of this report is the Mendelian genetic basis of the proband′s cardiomyopathy phenotype, and our data provide additional case‐level and functional evidence for a possible role of specific TTN splicing defects in HCM.

Cardiorenal syndrome (CRS) involves bidirectional pathophysiology between cardiovascular and renal dysfunction. The visceral adiposity index (VAI), a sex-specific composite metric, serves as an indicator of visceral adipose accumulation and associated cardiometabolic risk. This cross-sectional study aims to investigate the previously underexplored association between CRS and VAI. We analyzed National Health and Nutrition Examination Survey (NHANES) data from 33,605 adults. Logistic regression models and restricted cubic splines (RCS) were utilized to examine the association. Machine learning (ML) models (XGBoost, SVM, and GLM) were developed and evaluated using receiver operating characteristic curves, Youden's J, and F1 score. The model interpretability was evaluated by Shapley Additive exPlanations (SHAP). The logistic regression analysis, adjusted for confounders, demonstrated a positive association between VAI and CRS. Higher VAI was independently associated with increased risks of CRS (OR = 1.29, 95% CI = 1.13-1.49). Quartile analysis demonstrated a 53% elevated risk in the highest versus lowest VAI quartile (Q4 vs Q1: OR = 1.53, 95% CI = 1.15-2.03). The RCS did not indicate significant nonlinearity (P for non-linear = 0.98), suggesting a linear association between VAI and CRS. Subgroup analyses revealed that hypertension status exhibited a significant interaction. The XGBoost model demonstrated superior predictive performance. The SHAP plot of XGBoost revealed that age, VAI, and hypertension were the three most important features for predicting CRS. Elevated VAI is independently associated with an increased risk of CRS. We introduce the first explainable ML-driven CRS prediction benchmark using VAI within a nationally representative population.

Potentially modifiable cardiovascular risk factors, including hypertension, diabetes, obesity, alcohol consumption, and smoking initiation, are associated

Cardiorenal syndrome (CRS) is a complex clinical condition characterized by the simultaneous dysfunction of the heart and kidneys. The atherogenic index of plasma (AIP), calculated as the logarithm of the ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C), has emerged as a potential biomarker for cardiovascular risk. This study investigates the association between AIP and CRS, aiming to explore the potential linkage between AIP and CRS. Data were sourced from the National Health and Nutrition Examination Survey spanning 2005-2018, involving 35,365 participants after applying exclusion criteria. The primary exposure variable was AIP, categorized into quartiles, while the primary outcome variable was CRS, defined by the coexistence of cardiovascular disease (CVD) and chronic kidney disease (CKD). Statistical analyses, considering sample weights, included ANOVA, Chi-square tests, logistic regression models, and restricted cubic spline (RCS) analysis to examine nonlinear relationships. The weighted logistic regression analysis showed a positive correlation between AIP and CRS across all models. In the fully adjusted model, the highest AIP quartile had a significantly increased odds ratio (OR) for CRS (Q4: OR = 1.62; 95% CI: 1.21-2.15). RCS analysis confirmed a positive correlation between AIP and CRS, with TG positively and HDL-C negatively correlated with CRS. Subgroup analysis indicated a significant interaction with hypertension, showing a stronger association in non-hypertensive individuals. Higher AIP levels are associated with an increased prevalence of CRS, with a notable hypertension-specific interaction indicating a higher effect in individuals without hypertension.

Background: Snail family transcriptional repressor 2 (SNAI2) is a transcription factor that induces epithelial to mesenchymal transition in neoplastic epithelial cells. It is closely related to the progression of various malignancies. However, the significance of SNAI2 in human pan-cancer is still largely unknown.Methods: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases were taken to examine the SNAI2 expression pattern in tissues and cancer cells. The link between SNAI2 gene expression levels and prognosis, as well as immune cell infiltration, was investigated using the Kaplan-Meier technique and Spearman correlation analysis. We also explored the expression and distribution of SNAI2 in various tumor tissues and cells by the THPA (Human Protein Atlas) database. We further investigated the relationship between SNAI2 expression levels and immunotherapy response in various clinical immunotherapy cohorts. Finally, the immunoblot was used to quantify the SNAI2 expression levels, and the proliferative and invasive ability of pancreatic cancer cells was determined by colony formation and transwell assays.Results: We discovered heterogeneity in SNAI2 expression in different tumor tissues and cancer cell lines by exploring public datasets. The genomic alteration of SNAI2 existed in most cancers. Also, SNAI2 exhibits prognosis predictive ability in various cancers. SNAI2 was significantly correlated with immune-activated hallmarks, cancer immune cell infiltrations, and immunoregulators. It’s worth noting that SNAI2 expression is significantly related to the effectiveness of clinical immunotherapy. SNAI2 expression was also found to have a high correlation with the DNA mismatch repair (MMR) genes and DNA methylation in many cancers. Finally, the knockdown of SNAI2 significantly weakened the proliferative and invasive ability of pancreatic cancer cells.Conclusion: These findings suggested that SNAI2 could be used as a biomarker in human pan-cancer to detect immune infiltration and poor prognosis, which provides a new idea for cancer treatment.