Search Results (647)

Recent reports have shown that polymorphisms in the TRPS1 and TRIB1 genes are associated with plasma lipid levels and the risk of cardiovascular disease. This study evaluates the associations of TRPS1 and TRIB1 polymorphisms with subclinical atherosclerosis (SA) and plasma lipid levels in Mexican individuals. This study included 1406 Mexican mestizo individuals (417 individuals with SA and 989 healthy controls). Genotyping of TRPS1 and TRIB1 polymorphisms was performed using TaqMan assays in a real-time PCR system. To analyze whether these polymorphisms are associated with SA and plasma lipid levels, we used logistic regression (OR [95% CI]), adjusted for confounding factors. The AA genotype of the TRPS1 rs2737229 A/C polymorphism showed a significant association with the risk of developing SA under multiple genetic models [codominant: OR = 1.61 (95% CI: 1.10–2.36), p = 0.048; recessive: OR = 1.42 (1.02–1.99), p = 0.039; additive: OR = 1.26 (1.05–1.53), p = 0.015]. Similarly, the TT genotype of the TRIB1 rs2954029 T/A polymorphism was also significantly associated with the risk of developing SA [codominant: OR = 1.63 (1.10–2.43), p = 0.033; recessive: OR = 1.64 (1.13–2.37), p = 0.009]. In a sub-analysis of SA individuals, individuals with homozygous AA for the TRPS1 rs2737229 polymorphism had higher LDL cholesterol levels [135 mg/dL (110–148)] than those with homozygous CC [118 mg/dL (99–139)] (p < 0.003). The analysis of the TRIB1 rs2954029 polymorphism showed that carriers of the TT genotype had increased glucose levels [97 mg/dL (87–118)] compared to carriers of the AA genotype [91 mg/dL (84–99)] (p < 0.002). In summary, our findings showed that, in Mexican Mestizos, the AA genotype of the TRPS1 rs2737229 A/C SNP and the TT genotype of the TRIB1 rs2954029 A/T polymorphism are associated with a higher risk of developing SA and elevated levels of glucose and LDL cholesterol. Full article

Melanoma is characterized by a high mutational burden making it an established model for studying tumor neoantigens and developing strategies for personalized immunotherapy. In this study, a reproducible bioinformatics pipeline was developed and implemented for the identification and prioritization of candidate neoantigens derived from non-synonymous somatic mutations in melanoma, using genomic data from the MSK-IMPACT cohort (mel-mskimpact-2020; n = 696) and comparative reference information from TCGA-SKCM. From the somatic mutation annotation file (MAF), 16,311 non-synonymous mutations were filtered, from which 50,480 mutant 8–11-mer peptides were generated using a sliding-window approach centered on the mutated position. Peptide–HLA class I binding affinity was predicted using MHCflurry 2.0 across six representative alleles (HLA-A*02:01, HLA-A*24:02, HLA-B*35:01, HLA-B*39:05, HLA-C*04:01, and HLA-C*07:02). Candidate prioritization was initially based on predicted binding percentile (rank ≤ 2), identifying 12,209 peptide–HLA combinations with high predicted binding affinity. To refine candidate selection, additional computational analyses were incorporated, including proteasomal cleavage prediction using NetChop 3.1 and estimation of T-cell epitope immunogenicity using the Immune Epitope Database (IEDB) immunogenicity predictor. Furthermore, a direct comparison between mutant (MUT) and corresponding wild-type (WT) peptides was performed using Δaffinity and Δrank metrics to evaluate the predicted impact of somatic mutations on HLA binding. The analysis revealed a predominance of peptides associated with the HLA-B locus, particularly the allele HLA-B*35:01, among the interactions with the lowest predicted binding percentiles. Several high-ranking peptide candidates were derived from genes with known roles in melanoma biology, including PLCG2, GATA3, AKT1, PTEN, PTCH1, and SMO. Overall, the integrative computational framework implemented in this study enables the systematic prioritization of candidate neoantigens derived from non-synonymous mutations in melanoma. This pipeline provides a reproducible strategy for exploring tumor neoantigen repertoires and may serve as a foundation for subsequent experimental validation and for studies related to neoantigen-based immunotherapies and immunopeptidomics. Full article

Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, plays a crucial role in epigenetic regulation and cytoskeletal dynamics, while participating in host anti-infective immune responses. However, its precise functions and mechanisms during Chlamydia muridarum (C. muridarum) infection remain incompletely defined. Our study demonstrated that C. muridarum respiratory infection upregulates HDAC6 expression at the infection site and in immune organs. Comparative analysis of wild-type (WT) and HDAC6-deficient (HDAC6^−/−) mice in this infection model revealed that HDAC6 deficiency exacerbates disease progression, including significant weight loss, severe pulmonary inflammation, and impaired C. muridarum clearance. Relative to WT mice, HDAC6^−/− mice exhibited elevated Signal Transducer and Activator of Transcription 6 (Stat6) and GATA Binding Protein 3 (Gata3) mRNA expression, enhanced pathological Th2 responses with increased IL-4 secretion, and no significant differences in protective Th1 or Th17 responses following C. muridarum infection. Concurrently, these mice displayed enhanced M2 macrophage polarization, as evidenced by upregulated CD206 and Arg-1 expression, whereas M1 marker expression remained unchanged. The vitro studies confirmed that HDAC6^−/− bone marrow-derived macrophages (BMDMs) promote M2 polarization, characterized by increased Arg-1, IL-10, and TGF-β production, and further co-culture experiments showed that C. muridarum -stimulated HDAC6^−/− BMDMs drive Th2 differentiation. These findings elucidate the critical role of HDAC6 in regulating Th2-M2 immune responses during C. muridarum respiratory infection and suggest targeted modulation of HDAC6 as a novel therapeutic strategy for chlamydial respiratory infection. Full article

The features of patients with multiple urothelial tumors remain to be elucidated. We intend to differentiate primary upper tract urothelial carcinoma with synchronous urothelial bladder cancer (UTUC + sUBC) and UTUC with metachronous UBC (UTUC + mUBC) cases to determine whether these temporal patterns reflect biologically distinct processes. A subgroup analysis of a retrospective cohort of UTUC (n = 114) was performed comparing UTUC + sUBC (n = 14) with UTUC + mUBC (n = 29). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan–Meier analyses estimated the progression-free survival (PFS) and overall survival (OS) of both UTUC subgroups, and the log-rank test was used to assess differences between subgroups. Our study reveals no significant differences in phenotype or genomic profile between synchronous and metachronous UTUC-UBC cases (p > 0.05). Nevertheless, patients with synchronous UBC revealed significantly worse outcomes in PFS (2y-PFS 23.1% vs. 52.1%, p = 0.029) and OS (2y-OS 40.4% vs. 84.4%, p = 0.016) than those with metachronous disease. These discrepancies could arise from as yet-uncharacterized molecular features or microenvironmental influences. Full article

Background and Clinical Significance: Bladder cancer is common, with urothelial carcinoma (UC) comprising most cases in Western countries. Metastases usually involve pelvic structures, lymph nodes, and organs such as the liver, lungs, bones, and adrenal glands. Identifying unusual metastatic sites is critical for accurate diagnosis and treatment planning. Case Presentation: A 65-year-old man with a history of high-grade (G3) UC and carcinoma in situ, previously treated with TURBT, second-look resection, and SWOG-protocol BCG, presented with a new bladder lesion (pT1). Staging CT revealed extravesical spread and a 1.5 cm pancreatic body nodule. EUS-guided biopsy confirmed metastatic UC with concordant immunohistochemistry (GATA3+), excluding primary pancreatic cancer. The patient was referred for systemic therapy with immune checkpoint inhibitors and Enfortumab Vedotin. Conclusions: This case demonstrates the rare occurrence of pancreatic metastasis from bladder UC. EUS-guided biopsy with immunohistochemistry is essential to distinguish secondary lesions from primary pancreatic tumors. Accurate diagnosis is crucial to guide systemic therapy, particularly with emerging immunotherapy and antibody–drug conjugates. Full article

Background: Clear cell renal cell carcinoma (ccRCC) constitutes 75–80% of all renal cell carcinomas and exhibits aggressive behavior with high metastatic potential. Common metastatic sites include lungs, bones, lymph nodes, and liver, while urinary bladder involvement is exceedingly rare. Early detection of atypical metastases is critical for risk stratification, surgical planning, and systemic therapy selection. Methods: We report a 69-year-old male presenting with recurrent, painless gross hematuria and dysuria. Contrast-enhanced computed tomography revealed a left renal mass with bilateral pulmonary nodules, regional lymphadenopathy, and a bladder lesion. The patient underwent transurethral resection (TUR) of the bladder lesion, followed by robot-assisted left nephro-adrenalectomy with para-aortic lymphadenectomy. Histopathology and immunohistochemistry (PAX8+, CD10+, CAIX+, CK7−, GATA3−) confirmed ccRCC with synchronous bladder metastasis. Postoperatively, combined immune checkpoint inhibitor (ICI) therapy and tyrosine kinase inhibitors (TKIs) were initiated. Results: TUR provided symptomatic relief and diagnostic confirmation. Robot-assisted surgery enabled precise, oncologically safe excision of the primary tumor and regional metastases with minimal blood loss and no perioperative complications. Pathological staging was pT3aN1M1, ISUP grade 2, with lymphovascular invasion, confirming advanced disease requiring systemic therapy. Early initiation of ICI plus TKI therapy targeted residual micrometastases to potentially prolong survival. Conclusions: This case highlights the rare occurrence of ccRCC with synchronous bladder metastasis and underscores the importance of comprehensive imaging, detailed morphologic and immunohistochemical evaluation, and a multidisciplinary approach. Robot-assisted cytoreductive surgery combined with modern systemic therapy represents an effective strategy for advanced ccRCC, emphasizing the need for individualized treatment and long-term follow-up in atypical metastatic scenarios. Full article

Congenital heart defects (CHDs) represent the most common category of congenital malformations and constitute a significant cause of infant morbidity and mortality. Despite advances in prenatal imaging, such as fetal echocardiography, early detection remains challenging, particularly in pregnancies without identified risk factors. Recent studies suggest that maternal circulating non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), may serve as promising non-invasive biomarkers for the prenatal diagnosis of CHDs. Following a review of the most relevant clinical and preclinical studies, it was found that maternal circulating RNA, particularly microRNAs and lncRNAs, shows potential as non-invasive biomarkers for detecting fetal congenital heart defects. Among microRNAs, miR-146a-5p demonstrated the highest diagnostic accuracy for ventricular septal defects (VSDs), while panels of lncRNAs, such as LINC00598, LINC01551, and GATA3-AS1, exhibited high performance for atrial septal defects (ASDs). In addition, miR-19b, miR-29c, and miR-375 were associated with both VSDs and ASDs, suggesting a shared role in septal development. However, the studies displayed variability in biomarker selection and analytical methodologies. The findings indicate that maternal circulating microRNAs and lncRNAs hold significant potential as non-invasive biomarkers for the early detection of CHDs. Nonetheless, methodological heterogeneity and small sample sizes highlight the need for standardized protocols and larger multicenter studies prior to clinical implementation. These observations support the future integration of RNA biomarkers with fetal echocardiography to enhance early CHD screening and to inform prenatal counseling. Full article

Pituitary neuroendocrine tumors (PitNETs) constitute a significant proportion of primary intracranial neoplasms and were historically differentiated based on clinical hormone excess syndromes and tinctorial properties. The 5th edition of the WHO classification introduces a paradigm shift towards the lineage-based taxonomy based on the cell-specific expression of transcription factors (TFs). This overview focuses on the biological justifications and diagnostic value of the core TFs of Pituitary-Specific Positive Transcription Factor 1 (PIT1), T-Box Pituitary Transcription Factor (TPIT), and Steroidogenic Factor 1 (SF1), which signify the somatotroph, lactotroph, thyrotroph, corticotroph, and gonadotroph lineages, respectively. By focusing on TF expressions instead of hormone immunoreactivity, pathologists can better subtype clinically non-functioning tumors, effectively relegating the previously overutilized null cell category to about 1% of cases. The TF-based classification is also essential in discriminating high-risk histotypes of silent corticotroph tumors, sparsely granulated somatotrophs, and immature PIT1-lineage PitNETs, which are linked to a higher invasiveness and recurrence. We suggest a practical, stepwise immunohistochemical diagnostic algorithm with the integration of ancillary markers (e.g., GATA3 and ERα) to refine lineage assignment. New molecular correlates such as GNAS and USP8 mutations also add to this framework and guide the use of individualized treatment involving somatostatin analogs or dopamine agonists. And lastly, we discuss the ongoing issues of diagnosis of triple-negative and multilineage tumors and the growing importance of DNA methylation profiling and artificial intelligence in standardized reporting and improving precision management. Full article

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, with nearly 80% of patients diagnosed at advanced stages due to the absence of early symptoms and the nonspecific nature of later clinical manifestations. This highlights the urgent need for robust molecular biomarkers that can refine patient stratification and guide personalized therapeutic approaches. A major determinant of OC aggressiveness is the epithelial-to-mesenchymal transition (EMT), a transcriptionally driven program that represses epithelial identity while promoting mesenchymal traits, thereby enhancing invasion, dissemination, recurrence, and resistance to therapy. EMT dysregulation is widespread in OC and fuels tumor heterogeneity, metastatic spread, and chemoresistance. To investigate the contribution of EMT-related genes in OC biology, we analyzed whole-genome sequencing and RNA-seq data from 419 patients in The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas, assessing their genomic and transcriptomic alterations. We integrated these findings with transcriptomic and drug-sensitivity data from the CTRPv2 portal, performing Pearson correlation analyses to identify therapeutic vulnerabilities associated with EMT gene expression. Our analysis identifies recurrent genomic and transcriptomic alterations across several EMT-associated genes. Notably, we identified a four-EMT gene signature (EFNA1, OVOL2, GATA3, and DSG2) whose expression correlates with differential sensitivity to VEGFR and EGFR inhibitors in OC cell lines. Overall, these results suggest that EMT-driven molecular changes contribute to the onset and progression of OC and highlight a subset of EMT genes as promising predictive biomarkers for targeted therapy responses. Full article

Boron (B) toxicity is one of the major abiotic stresses limiting wheat productivity in arid and semi-arid regions of the world. Thus, it is important to understand the molecular basis of tolerance in boron-tolerant wheat genetic resources for effective breeding. Wild emmer wheat is a valuable genetic resource for tolerance to multiple abiotic stresses; however, the molecular mechanisms behind boron toxicity tolerance in this species has not been sufficiently characterized. Here, we present the first RNA sequencing-based transcriptomic analysis of B toxicity response in a boron-tolerant Triticum dicoccoides genotype, PI362036. Shoot tissues exposed to high boron (10 mM B) for 7 days showed extensive transcriptional reprogramming with 2783 differentially expressed genes. Functional enrichment analyses showed that B toxicity significantly altered the genes associated with biosynthesis of secondary metabolites, metabolic pathways, ribosomal activity, carbon metabolism, RNA transport, photosynthesis–antenna proteins, and citrate cycle pathway. Several transcription factor families, including TIG, MYB, MYB-related families, NAC, C2H2-GATA, ARF, and AP2-EREBP families, showed significant differential regulation, emphasizing their regulatory roles in B stress adaptation. Collectively, this study provides the first comprehensive transcriptomic framework of boron toxicity tolerance in T. dicoccoides under short-term high boron exposure, identifying candidate genes and pathways that may be exploited for improving boron tolerance in cultivated wheat through targeted breeding strategies. Given that boron toxicity in agricultural systems primarily arises from excessive boron accumulation in soils and irrigation water, the identified pathways offer insight into early adaptive responses of shoot tissues to elevated boron availability. Full article

Chinese tongue sole (Cynoglossus semilaevis) is an important aquaculture species in China. Under high-temperature conditions, genetically female fish can undergo sex reversal and develop into phenotypic males (pseudomale fish). Previous studies have demonstrated that apoptosis might function in sex differentiation. Based on this, we identified and characterized the functions of six caspase genes (caspase1-like, caspase3a, caspase6, caspase8, caspase8-like, caspase9) in Chinese tongue sole. These six caspase genes were expressed in all analyzed tissues of both males and females. They were detected to be expressed in the gonads at various developmental stages, with expression levels peaking between 7 months and 2 years of age. In situ hybridization (ISH) analysis showed that the caspase genes were mainly localized in spermatocytes and oocytes. Promoter activity analysis indicated that with the exception of caspase3a, the remaining five caspase genes exhibited promoter activity and were regulated by transcription factors, including sp1 and gata4. High-temperature stimulation can significantly affect the expression of caspases in the gonads of both male and female fish, with female fish showing a more pronounced response. An siRNA-mediated knockdown experiment revealed that following caspase knockdown, the expression of sex differentiation-related genes, heat shock transcription factors (hsf), and heat shock proteins (hsp) in Chinese tongue sole was significantly altered. Based on these findings, we speculate that caspases play an important role in the sex differentiation process by responding to temperature stimuli. Full article

Somatic copy-number alterations (CNAs) are pervasive in cancer, but routine targeted panels yield sparse CNA readouts unsuited for CNA signature analysis. We built a consensus framework that integrates four deconvolution algorithms to extract CNA signatures from panel data. Analysis of 24,870 tumors sequenced using MSK-IMPACT identified five reproducible signatures (CON1–CON5). CON5 mirrored near-diploid profiles, whereas the others captured distinct aneuploid patterns. Technical fidelity was confirmed by internal cross-validation and external validation in sarcoma and hepatocellular carcinoma cohorts. Clinically, these signatures were associated with overall survival across tumor types (hazard ratio 1.3–2.5; FDR < 0.01) and provided additive prognostic information beyond Fraction of Genome Altered. Associations with driver mutations (GATA3 in CON1, KRAS in CON5) supported biological specificity, and the signatures delineated resistance landscapes for chemotherapy, hormonal, targeted, and immunotherapy. By converting routine panel data into biologically interpretable prognostic features, our framework enables risk stratification and therapeutic guidance in precision oncology. Full article

Human iPSC-derived cardiomyocytes (iPSC-CMs) exhibit fetal-like mitochondrial networks and limited oxidative metabolism, constraining their translational utility. The key bottleneck is mitochondrial immaturity, resulting from blunted PGC-1α–NRF1/2–TFAM axis activation and insufficient nuclear–mitochondrial coordination, rather than sarcomeric or electrophysiological immaturity alone. This review synthesizes genome-guided interventions (CRISPRa and mtDNA editing) and complementary environmental strategies—including metabolic substrate switching, electromechanical stimulation, and extracellular vesicle (EV)-mediated mitochondrial transfer—to drive mitochondrial biogenesis and maturation in iPSC-CMs. We systematically reviewed studies (2005–2025) targeting (1) key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), (2) CRISPR-based transcriptional activators/repressors and mtDNA editors (DdCBE, mitoTALENs), and (3) maturation approaches such as metabolic conditioning, electromechanical stimulation, 3D tissue culture, and EV-mediated mitochondrial transfer. CRISPRa-mediated activation of PGC-1α, NRF1, and GATA4, combined with mtDNA base editors, enhances mitochondrial mass and OXPHOS function, while integration with environmental maturation strategies further promotes adult-like phenotypes. Integrative approaches that combine genome-guided interventions (CRISPRa, mtDNA editing) with environmental maturation cues yield the most adult-like iPSC-CM phenotypes reported to date. CRISPR-guided mitochondrial biogenesis thus represents a frontier for producing metabolically competent, structurally mature iPSC-CMs for disease modeling and therapy. Remaining translational challenges include efficient mitochondrial delivery, metabolic homeostasis, and multi-omics validation. We propose standardized workflows to couple nuclear and mitochondrial editing with maturation strategies. Full article

Transcription factors (TFs) are ubiquitously distributed in plants and play pivotal roles in regulating plant growth and development. The present study aims to elucidate the function of transcription factors (TFs) in highland barley’s response to selenium stress. The results show that 89, 218, 141, 92, 23, and 34 genes were identified from the bHLH, MYB, NAC, WRKY, GATA, and HSF families, respectively. We analyzed the physicochemical properties of the transcription factor family, including amino acid number and molecular weight, theoretical PI, instability index, hydrophilicity index, and subcellular location. The majority of proteins encoded by these gene families are hydrophilic and predominantly localized in the nucleus. Structural analysis demonstrates that each family contains conserved motifs and domains. Most bHLH genes, such as KAE8811666.1 and KAE8789390.1, contain bHLH_SF superfamily domains. 45 MYB genes possess the myb_SHAQKYF domain. Most NAC genes possess typical NAM domains. Most WRKY proteins showed the WRKY superfamily domain. The 22 members of GATA possess the ZnF_GATA domain. HSF gene family showed that 24 gene family members contained HSF domains. Systematic evolutionary analysis indicates that the bHLH and NAC families can each be divided into nine subfamilies, while the remaining four families are categorized into five to eight subfamilies, respectively. Based on transcriptome data, under low selenium treatment, 56.25%, 76%, 67.39%, 47.37%, 50%, and 56.25% of the genes belonging to the bHLH, MYB, NAC, WRKY, GATA, and HSF transcription factor families were significantly upregulated, respectively. In contrast, under high selenium treatment, the proportions of upregulated genes in these families were 81.25%, 80%, 65.22%, 63.16%, 75%, and 75%, respectively. Additionally, qRT-PCR results were consistent with the trends of the transcriptome expression data, corroborating the reliability and accuracy of the transcriptomic findings. These results elucidate the molecular characteristics and response patterns of six transcription factor families to selenium stress in highland barley, laying a foundation for further in-depth research on the functions of transcription factors in highland barley plants. Full article