Search Results (245)

Background: Homeobox transcription factors regulate developmental programs, cellular plasticity, and tumor progression, yet the role of H2.0-like homeobox (HLX) in prostate cancer (PCa) remains poorly defined. We investigated the clinical significance of HLX and its relationship to the pro-metastatic transcription factor TBX2. Methods: Transcriptomic and clinical datasets from TCGA, MET500, and SU2C/PCF cohorts were analyzed to assess HLX expression, clinicopathologic associations, and its relationship with TBX2. Functional studies in human PCa cell lines included TBX2 gain- and loss-of-function, HLX knockdown, chromatin immunoprecipitation (ChIP), and expression analyses. Shared HLX- and TBX2-associated pathways were evaluated by Reactome enrichment analysis, and Hallmark Gene Set Enrichment Analysis compared castration-resistant prostate cancer (CRPC) bone metastases with high versus low HLX expression (GSE77930; n = 5/group). In vivo relevance was assessed in an orthotopic TBX2 dominant-negative PCa xenograft model. Results: Human PCa datasets showed that HLX expression was elevated in PCa versus normal prostate tissue and associated with higher Gleason grade, lymph node involvement, aggressive molecular subtypes, and shorter disease-free survival. HLX expression also positively correlated with TBX2 across human PCa cohorts. HLX- and TBX2-associated transcriptional programs converged on extracellular matrix organization, cell adhesion, NOTCH, and VEGF-MAPK signaling pathways. Furthermore, HLX-high CRPC bone metastases were enriched for epithelial–mesenchymal transition, NOTCH, TGF-β, inflammatory, angiogenic, hypoxic, and KRAS signaling pathways. Mechanistic studies showed that HLX knockdown suppressed extracellular matrix-associated genes and key NOTCH pathway components. ChIP demonstrated direct TBX2 binding to the HLX promoter, and genetic modulation of TBX2 expression established HLX as a downstream target of TBX2. Consistent with these findings, reduced HLX expression in orthotopic TBX2 dominant-negative xenografts was associated with loss of metastatic progression. Conclusions: HLX is a candidate biomarker of aggressive PCa and a direct transcriptional target of TBX2. These findings identify a previously unrecognized TBX2–HLX regulatory axis associated with metastatic transcriptional programs and aggressive disease in advanced PCa. Full article

Background: As a member of the T-box transcription factor family, TBX18 was found to be involved in ESCC progression, while its role in regulating radiotherapy resistance in ESCC remains unclear. This study was designed to investigate the molecular mechanisms underlying the regulation of radioresistance in ESCC by TBX18. Methods: Sphere formation assay, Transwell invasion assay, and wound healing assay were conducted to show the influence of TBX18 on tumor stemness and epithelial–mesenchymal transition (EMT). Western blot, immunofluorescence, chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter assay were preformed to identify regulatory networks. A nude mouse xenograft tumor model was established to assess the regulatory effect of TBX18 and SIX1 on radioresistance of ESCC in vivo. Results: TBX18 expression was positively associated with stemness markers, including CD44, CD271, and SOX2. TBX18 promoted stemness-associated phenotypes, EMT, migration, invasion, and radioresistance in ESCC cells. Mechanistically, TBX18 directly bound to the SIX1 promoter and transcriptionally activated SIX1 expression. In turn, SIX1 enhanced TBX18 protein stability by suppressing ubiquitin–proteasome-mediated degradation, thereby forming a positive feedback loop. Functional rescue experiments demonstrated that the TBX18/SIX1 axis coordinately maintained stemness and EMT phenotypes and attenuated radiotherapy-induced apoptosis. In vivo studies further confirmed that TBX18 knockdown enhanced radiosensitivity, whereas SIX1 overexpression partially reversed this effect. In addition, immunohistochemical analysis revealed that TBX18 and SIX1 were significantly upregulated in ESCC tissues and positively correlated with each other. Full article

Gene inactivation in model organisms has identified numerous genes and signaling pathways involved in mammalian cardiac outflow tract (OFT) development. Human genetics data have implicated the VEGFR3 gene in OFT development, but when and where it is required is unknown. In this study we determined the sensitivity of the developing murine heart to reduced Vegfr3 gene dosage, and we tested whether its requirement is dependent upon TBX1, a known regulator of Vegfr3 expression in cardiac and lymphatic endothelial cells. We found that in the mouse, a single copy of the Vegfr3 gene was sufficient for normal heart development in most cases. Mutation of a single copy of the Tbx1 gene greatly enhanced the sensitivity of heart development to Vegfr3 dosage reduction and led to the formation of cardiac defects. In addition, deletion of Vegfr3 in the Tbx1 expression domain also led to severe cardiac OFT abnormalities. We used RNAscope to reveal the location of Vegfr3 and Tbx1 transcripts in midterm mouse embryos. This revealed co-localization of these transcripts in the endothelium of the aortic sac, caudal pharyngeal arch arteries and proximal OFT, suggesting that these are potential sites of genetic interaction between Vegfr3 and Tbx1 that are critical for murine heart development. Full article

A series of novel heterometallic rare-earth chloroterephthalate metal–organic frameworks with the general formula (Tb_xGd_1−x)₂(Cl-1,4-bdc)₃·5H₂O (x = 0–1) were synthesized via direct precipitation from aqueous solutions. The structural and photophysical properties of these compounds were studied in detail. All compounds exhibit bright luminescence upon UV excitation into the ligand absorption band due to an efficient antenna effect. The photoluminescence quantum yield shows a non-monotonic dependence on the concentration of the terbium ion with a maximum value of 71% achieved for the compound containing equal molar fractions of the lanthanide ions. The (Tb_0.5Gd_0.5)₂(Cl-1,4-bdc)₃·5H₂O sample was evaluatedfor its utility in both qualitative and quantitative analysis of selected metal ions and in latent fingerprint development. It was shown to enable the detection of Cr(III), Fe(III), and Cu(II) ions through luminescence quenching, with the emission intensity being concentration-dependent. This behaviour highlights the compound’s potential as a basis for analytical protocols and materials aimed at the quantitative determination of these metal ions. Full article

Background: One of the key hallmarks of aging is the age-related decline in immune system function, accompanied by a chronic low-grade inflammation, or “inflammaging”. Simultaneously, a reduced capacity of immune cells to recognize and eliminate pathogens, along with immune exhaustion, is also defined as a sign of aging. Cynomolgus macaques (Macaca fascicularis) belong to a group of non-human primates evolutionarily close to humans and are often used for preclinical research. Methods: In this study, we performed mRNA sequencing of bone marrow and peripheral blood samples from young (5 years old) and old (over 19–21 years old) cynomolgus macaques to identify key markers of immunosenescence. Results: Although an increase in p16 expression was detected, we did not observe the increase in the senescence-associated secretory phenotype (SASP) cytokines reported in previous studies. Instead, we observed a transcriptional profile characterized by increased lymphocyte cytotoxic activity combined with a decrease in proinflammatory signaling, reduced markers of myeloid cells, and lowered sensitivity to pathogen-associated patterns. Similar changes were detected in both blood and bone marrow: decreased expression of naive T-cell markers (CCR7, LEF1, SELL, and FOXO1), reduced markers of the myeloid lineage—neutrophils and monocytes (CD177, CD14, CD163, FPR1, FPR2, and CXCR1)—and downregulation of genes belonging to different pattern-recognition receptor families (TLR1, TLR2, TLR4, TLR5, TLR6, TLR8, TLR10, IFIH1, CLEC4E, NOD2, NLRC4, NLRP12, NLRX1, and NAIP). In contrast, the group of old animals showed increased expression of markers associated with terminally differentiated cytotoxic lymphocytes (CD8+ T cells and NK cells): GZMB, PRF1, KLRK1, FASLG, TBX21, CCR5, and GNLY. Conclusions: Our findings offer new perspectives on the molecular mechanisms of age-associated immune dysregulation in non-human primates, serving as a baseline for selecting key candidate genes in subsequent functional investigations. Full article

Down feathers and contour feathers are two distinct feather types with vastly different structures and functions coexisting in the same individual. However, the molecular mechanism underlying these differences remains unclear. In this study, skin tissue containing intact feather follicles was collected from four anatomically defined regions of healthy Beijing ducks (Anas platyrhynchos domesticus) for transcriptomic sequencing: the breast and abdomen, which generate down feathers, and the wingtips and rump, which produce contour feathers. To mitigate bias arising from site-specific effects, we established paired comparisons between contour feathers and down feathers across different regions. Across all comparisons, 36 core differentially expressed genes (DEGs) were consistently identified. These encompassed nine HOX family transcription factors across three paralogous clusters, ZIC family members (ZIC1 and ZIC4), WNT4, TBX4, BMP5, cytoskeletal and sarcomeric genes (MYOZ2, ACTN2, DES, SMPX), extracellular matrix regulators (ASPN, MGP, FMOD), and lipid metabolism-related genes (MOGAT2, PNPLA2), among others. Pathway enrichment analysis revealed that transcriptomic variations in different feather follicles involve gene modules functioning in positional identity, cytoskeletal organization, extracellular matrix remodeling and lipid metabolism, with potential neuroendocrine modulation. The transcriptomic dataset established here facilitates future studies on the molecular mechanisms of feather differentiation and offers a reference for molecular breeding to enhance down feather yield and quality of Beijing ducks. Full article

Cleft lip and palate (CL/P) are among the most common congenital craniofacial anomalies, arising from disruptions in facial development during early embryogenesis. These conditions show significant clinical and genetic heterogeneity and are broadly classified into syndromic and nonsyndromic forms. The objective of this review is to summarize current knowledge on the embryological, genetic, and molecular mechanisms underlying CL/P and to highlight their clinical implications. A comprehensive review of the literature was conducted, focusing on studies in developmental biology, human genetics, and genomics related to CL/P. Emphasis was placed on both syndromic and nonsyndromic forms, including findings from genome-wide association studies, gene mutation analyses, and investigations of gene–environment interactions. Syndromic clefting is frequently associated with pathogenic variants in genes such as IRF6, TP63, and TBX22, which play key roles in epithelial differentiation, transcriptional regulation, and palatal development. In contrast, nonsyndromic CL/P results from complex interactions between multiple genetic variants and environmental factors. Genome-wide association studies have identified numerous susceptibility loci, many located in noncoding regulatory regions active during craniofacial development. Environmental influences, including maternal nutrition, smoking, alcohol exposure, and folate metabolism, have been shown to significantly modify risk. CL/P is a multifactorial condition involving intricate interactions between genetic and environmental factors. Advances in genomics and developmental biology have enhanced understanding of its etiology and are contributing to improved risk assessment, diagnosis, and the development of future precision medicine approaches. Full article

Background: Variant interpretation in clinical genomics requires integration of population-specific allele frequencies, curated database annotations, and phenotype evidence. However, variants annotated as pathogenic or likely pathogenic in reference databases may have different allele frequencies across populations, and electronic medical record (EMR) data may provide useful but incomplete clinical context. Methods: In this study, we used the China Medical University Hospital Genetic Biobank (CMUH-GB) and linked EMRs to evaluate ClinVar-annotated candidate variants in a Taiwanese Han population. Genotyped array variants were filtered by quality control, mapped to ClinVar, and prioritized if annotated as pathogenic or likely pathogenic and observed with an alternative allele frequency greater than 0.0001 in CMUH-GB. Results: After an updated annotation review, EMR linkage, exclusion of known rare-disease cases or ineligible loci, and retention of variants with clinically relevant EMR phenotypes, 11 candidate variants were analyzed. These variants were located in SCN5A, KCNH2, FBP1, PAH, ACADS, TBX6, BRCA1, LDLR, GP6, and SLC4A11. Several candidate variants showed substantially higher allele frequencies in CMUH-GB and the Taiwan Biobank than reported in some external population datasets. Genotype–phenotype association analyses were performed using additive genetic models with covariate adjustment and Benjamini–Hochberg false discovery rate correction. No interpretable association remained statistically significant after correction. SCN5A rs794728912 models for long QT syndrome and cardiac conduction defects were not estimable because no cases were observed among alternative-allele carriers, resulting in sparse-event separation. A nominal GP6 association with coagulation defects did not remain significant after correction. These findings support population-specific reassessment prioritization of selected ClinVar-annotated variants but do not constitute formal ACMG/AMP reclassification. Conclusions: Our study highlights the value and limitations of integrating hospital-based genotyping data with EMR-derived phenotypes for ancestry-aware variant interpretation in underrepresented populations. Full article

Several protocols have been reported for inducing parathyroid differentiation from human pluripotent stem cells in vitro. However, the efficiency of terminal differentiation into mature parathyroid cells remains limited. In this study, we performed comparative transcriptomic analyses of parathyroid lineage-induced human induced pluripotent stem (iPS) cells to clarify their developmental stage identity. Comparative analyses with adult parathyroid adenoma, used as a surrogate reference for mature parathyroid cells, and thymuses revealed that the differentiated cells exhibited gene expression patterns consistent with early-stage parathyroid and thymus development, including TBX1, which is required for fate determination of the parathyroid–thymic primordium. On the other hand, the expression of mature parathyroid marker genes, such as PTH, GCM2, and the calcium-sensing receptor (CaSR), remained markedly lower than that in parathyroid adenoma. Under the differentiation conditions and durations examined, application of modified differentiation protocols did not significantly enhance the expression of mature parathyroid markers, although pharyngeal pouch developmental gene expression was maintained. Our findings indicate that current in vitro differentiation systems effectively induce the parathyroid–thymic primordium stage, while a developmental bottleneck at the transition from the primordium toward parathyroid lineage commitment remains. Full article

The zig-zag eel (Mastacembelus armatus) exhibits sexual dimorphism in growth patterns. Identifying the genes involved in sex differentiation is a crucial step toward achieving single-sex breeding and serves as a vital foundation for elucidating the XY sex determination mechanism in M. armatus. This study measured the morphological characteristics of male and female M. armatus and found that males were significantly superior to females in body weight and nearly all morphological indices. Subsequently, whole-transcriptome sequencing was performed on the gonads of adult males and females, identifying 11,714 DEmRNAs, 3442 DElncRNAs, 416 DEcircRNAs, and 620 DEmiRNAs, including male sex differentiation genes such as Sox30, Tbx1, Sox9, and Gata4, and female sex differentiation genes like Sox3, Foxl2, and Wnt4a. Functional enrichment analysis identified pathways associated with sex differentiation, including the TGF-beta signaling pathway, the steroid hormone biosynthesis, the Hippo signaling pathway, and the Wnt signaling pathway, etc. A ceRNA network was constructed based on differentially expressed mRNAs and ncRNAs, revealing that the sex differentiation-related genes Sox3, Sox9, Sox30, Tbx1, and Wt1 are regulated by one or multiple pairs of lncRNA/circRNA-miRNA pairs. The study results will provide molecular targets for research on sex-controlled breeding in M. armatus and lay an important theoretical foundation for clarifying its sex differentiation mechanisms. Full article

Lung organogenesis is orchestrated by dynamic epithelial–mesenchymal interactions during embryogenesis, yet the gene regulatory programs and signaling dynamics governing these processes in the pseudoglandular stage remain incompletely understood. In this study, we integrated spatial and single-cell transcriptomic data across embryonic developmental stages to systematically characterize epithelial and mesenchymal dynamics during lung development. To achieve more refined cell types at single-cell resolution in spatial transcriptomic data, we developed a bin-based deconvolution strategy that enabled high-precision cell-type assignment. We subsequently constructed a 3D spatiotemporal landscape of lung development and elucidated the molecular regulatory mechanisms underlying epithelial–mesenchymal maturation during lung morphogenesis. In addition, we analyzed transcription factor module activity, intercellular communication signaling, and predicted downstream target genes, while integrating public GWAS metadata to link developmental programs with lung cancer-related features. We observed pronounced stage-specific functional heterogeneity between the pseudoglandular and late embryonic stages. Notably, E13.5 emerged as a critical transition window, during which progenitor states shifted toward more mature cellular phenotypes. We reconstructed epithelial–mesenchymal interactions and uncovered coordinated rewiring of ligand–receptor signaling and transcriptional networks across developmental stages. Regulatory network analysis further identified temporally coordinated transcription factor modules centered on Tbx3, Tbx5, Gli1, Gata4/5, Foxa1/2, and Cebpa, which collectively orchestrated branching morphogenesis, epithelial patterning, and tissue stabilization. Integration with lung cancer genome-wide association data demonstrated that embryonic lung progenitor states exhibit strong associations with lung cancer-related transcriptional programs, particularly involving epithelial–mesenchymal plasticity and RNA-splicing pathways. Furthermore, TP53/HNRNP-mutant lung adenocarcinomas displayed embryonic-like molecular features associated with cytoskeletal remodeling and progenitor-state reactivation. Together, our study provided a spatiotemporally resolved framework of embryonic lung development and identifies a critical transition window linking lung morphogenesis, regulatory network remodeling, and cancer-associated epithelial plasticity. Full article

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease of the pulmonary vasculature characterized by obliterative remodeling of small pulmonary arteries, leading to sustained elevation of pulmonary vascular resistance, right ventricular failure, and premature death. The diagnostic gold standard remains right heart catheterization, requiring a mean pulmonary artery pressure greater than 20 mmHg at rest, a pulmonary arterial wedge pressure of 15 mmHg or below, and a pulmonary vascular resistance exceeding 2 Wood units. PAH is an autosomal dominant disorder with markedly incomplete penetrance of approximately 20–30%, indicating that germline mutations alone are insufficient to cause disease. Disease manifestation requires additional “second hits”, including chronic hypoxia, systemic inflammation, hemodynamic stress, hormonal influences, and common genetic modifiers such as single-nucleotide polymorphisms (SNPs). This genetic and environmental complexity underpins the broad clinical heterogeneity observed across PAH subtypes, which include idiopathic PAH, heritable PAH, and disease associated with connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure. This review provides a comprehensive and critical appraisal of the molecular-genetic architecture of PAH. Thirty genes have now been implicated in disease pathogenesis, spanning seven functional categories: receptors of the TGF-β/BMP signaling family (BMPR2, ACVRL1, ENG, BMPR1B); circulating BMP ligands (GDF2, BMP10); transcription factors (TBX4, SOX17, KLF4, FOXF1, SMAD1, SMAD4, SMAD9); membrane and polyamine transporters (ATP13A3, AQP1); potassium channel regulators (KCNA5, KCNK3, ABCC8); metabolic and mitochondrial genes (EIF2AK4, NFU1, GGCX); signaling receptors and structural proteins (NOTCH3, KDR, CAV1, PLEKHH2); vasoactive and extracellular matrix regulators (KLK1, CBLN2, CD248); and epigenetic regulators (TET2, TOPBP1). Among these, BMPR2 is the dominant contributor, accounting for 53–86% of heritable PAH and 14–35% of idiopathic cases. The remaining genes each account for fewer than 5% of cases individually, collectively reflecting a broad landscape of rare and ultra-rare genetic contributions. For each gene, we critically evaluate the strength of genetic evidence, pathogenic mechanisms, degree of mechanistic resolution, and clinical relevance. We further discuss the contribution of emerging technologies, including whole-genome sequencing, single-cell and spatial transcriptomics, multi-omics integration, iPSC-derived vascular models, and artificial intelligence, to expanding the PAH genetic architecture beyond single-gene discovery. A key theme across this landscape is convergence: despite mechanistic diversity at the gene level, most PAH-associated variants ultimately impair endothelial quiescence, promote smooth muscle proliferation, and drive apoptosis resistance through disruption of BMP signaling amplitude, transcriptional stability, ion channel homeostasis, metabolic integrity, or epigenetic regulation. This convergence supports both a unified therapeutic rationale and a precision medicine framework for genotype-stratified intervention in PAH. Full article

Ewing sarcoma (ES) is a bone malignancy primarily, well known by its t(11;22)(q24;q12) chromosomal translocation. Despite high initial treatment success, ES frequently recurs, likely due to micrometastatic disease present at diagnosis but undetected during primary treatment. This study aims to characterize transcriptomic differences between primary and metastatic ES to identify genes and pathways associated with the metastatic phenotype. Using the Search Tag Analyze Resource for National Center for Biotechnology Information’s Gene Expression Omnibus, seven independent gene expression series were identified, yielding 37 metastatic and 82 primary ES tumor samples. Differentially expressed genes were defined using a significance threshold of p < 0.05 and absolute experimental log ratio > 0.1 and were analyzed using Ingenuity Pathway Analysis. This integrative transcriptomic analysis identified 753 significant molecules. Metastatic ES was characterized by upregulation of lung-associated surfactant proteins and secretoglobin family members, along with downregulation of genes involved in extracellular matrix organization. Additional genes of interest included SLC6A14, CXCL14, and TBX3, which have been implicated in tumor progression in other malignancies. These findings provide a computationally derived molecular profile associated with metastatic ES and highlight candidate genes and pathways that warrant further validation. This integrative approach offers a framework for future studies focused on understanding metastatic biology in rare pediatric cancers. Full article

The diagnostic field of prostate cancer (PCa) has undergone a significant evolution with the widespread integration of multiparametric magnetic resonance imaging (mpMRI) and mpMRI-targeted biopsies (TBx). This approach has been shown to improve the detection of clinically significant prostate cancer (csPCa) while reducing the overdiagnosis of low-risk disease. However, a conceptual and clinical challenge, which can be referred to as the “Precision Paradox,” has emerged. By directing biopsy cores almost exclusively into the most suspicious MRI lesions, clinicians may inadvertently overrepresent the biological significance of a limited high-grade component. This can lead to grade migration and pathological downgrading at the time of radical prostatectomy (RP). Although downgrading does not automatically equate to clinical overtreatment, it introduces prognostic uncertainty that complicates risk stratification for active surveillance (AS) and focal therapy. This conceptual commentary provides a critical perspective on this diagnostic issue. We synthesize recent meta-analyses to evaluate the true rates of grade mismatch associated with TBx and combined biopsy approaches. Furthermore, we discuss the spatial limitations of biopsy sampling, the pathological mechanisms driving grade discordance, and the clinical relevance of minor high-grade components such as cribriform architecture. Finally, we highlight the role of multi-omics and validated genomic biomarkers in risk models, ultimately fostering improved shared decision-making in the modern mpMRI era. Full article

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with known metabolic or anti-inflammatory effects. However, their direct roles in adipocyte browning and the mechanisms via β3-adrenergic receptor (β3-AR) signaling are not well defined, and this study addresses this gap. Methods: To evaluate browning potential, 3T3-L1 adipocytes were treated with catalpol and rhoifolin during differentiation. The expression of browning markers and lipid metabolism or catabolism transcription factors was analyzed using Western blotting and quantitative real-time polymerase chain reaction. The involvement of the β3-AR and adenosine monophosphate–activated protein kinase (AMPK) signaling pathways was further validated using specific agonists and antagonists. Results: Both compound treatments significantly upregulated beige-specific (Cd137, Cited, Tbx1, Cidea, Fgf21, Tmem26) and mitochondrial biogenesis markers (Cox4, Nrf1, Tfam), accompanied by a marked increase in thermogenic markers (UCP1, PGC-1α, Prdm16). Concurrently, lipolysis-related genes such as Atgl, Hsl, and Plin1 were elevated, while lipogenesis targets (Fasn, Lpl, Srebf1, Acaca) were downregulated through activation of the β3-AR signaling pathway. Conclusions: These findings suggest that catalpol and rhoifolin, key phytochemicals of YST, promote WAT browning and lipolysis. Our findings indicate that these compounds induce browning and modulate metabolism via the β3-AR pathway. These results serve as a cornerstone for natural anti-obesity therapy, pending further validation in vivo and clinical studies. Full article