A multicenter study on the DNA mismatch repair (MMR) genes enabled us to study the profiling of germline variants in MMR genes of colorectal cancer (CRC) patients with MMR deficiency (dMMR). The clinicopathological differences between Lynch syndrome (LS) patients and sporadic dMMR CRC patients were compared by Student's t-test and χ2 test. The molecular profiling of germline variants in MMR genes in Chinese CRC patients with dMMR is clarified. A total of 326 CRC patients with dMMR were enrolled. Next-generation sequencing (NGS) and Sanger sequencing were performed using tumor-adjacent tissues of enrolled patients. Four MMR genes (MLH1, MSH2, MSH6, and PMS2) are included in the NGS panel. A total of 113 germline variants were detected, including 81 pathogenic and likely pathogenic variants. The clinicopathologic differences between CRC patients with/without LS were observed in age, family history, lesion location, and dMMR patterns. The CRC cohort with IHC-MSH6 negative alone shows the highest prevalence rate of LS. MLH1 was detected with the most germline variants. The mutational hotspot region of MLH1 is Exon 8, Exon 4 for MSH6, Exon 11 for PMS2, and Exon 7 for MSH2. Several germline hotspots were labeled on each MMR gene sequence by fixed-size bin analysis. In addition, some variants were novel discovered based on the presence or absence of the RS number and allele frequency record. Our study classified the clinicopathological features between sporadic CRC patients and LS patients. More importantly, the molecular profiling of the MMR gene germline variant was experimentally elucidated, which deepens the knowledge of MMR genes and provides a new perspective for the subsequent studies on the landscape of germline variants of Chinese LS patients.

Osteoporosis (OP) and its associated complications have emerged as critical public health challenges worldwide, primarily due to the high rates of disability and mortality they cause. In terms of its complex pathogenesis, epigenetic mechanisms play significant roles. Against this backdrop, this study aims to clarify the current research trends and hotspots in OP. Literature was retrieved from the "Web of Science," "PubMed," and "Scopus." Subsequently, publication counts, country distribution, regional collaborations, and keyword analyses were conducted by using the "Bibliometrix" and "ggplot2" packages in R Studio. For visualization analysis, institutional cooperation and keyword relationships were examined using "CiteSpace" and "VOSviewer." A total of 464 publications were included in this analysis. The five most frequently cited keywords were "postmenopausal osteoporosis (PMOP)," "expression," "mesenchymal stem-cells (MSCs)," "osteogenic differentiation," and "differentiation." Keyword co-occurrence analysis further identified "expression," "PMOP," and "MSCs" as predominant research themes. Moving forward, the findings suggest that future research will focus on elucidating the role of miRNAs in the epigenetic mechanisms of OP and identifying potential therapeutic targets. Regarding global collaboration, China led in international partnerships, particularly with the United States. Epigenetic mechanisms constitute a core regulatory factor in OP, serving as the critical link between genetic predisposition and environmental influences. Emerging research emphasizes the combined analysis of epigenetics and metabolomics, artificial intelligence (AI)-based prediction of epigenetic regulatory networks, and gene editing therapies targeting epigenetic factors. Furthermore, therapeutic strategies-including gene therapy, stem cell-based interventions, and small-molecule targeted compounds-represent pivotal future directions for OP therapeutics.

ObjectiveTo develop a prognostic nomogram for Wilms’ tumor (WT) integrating genetic and clinical factors to improve evaluation accuracy and clinical utility.MethodsRNA sequencing (RNA‐seq) data from 125 WT patients and single‐cell RNA (scRNA‐seq) data from 2437 samples were analyzed using bioinformatics tools for data processing, including normalization and scaling with SCTransform, and cell clustering with Seurat. Principal component analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP) were utilized for data visualization. Differential gene expression analysis identified pivotal genes for the Genetic Feature Prognostic Model for WT (GPM‐WT). Univariate Cox regression analysis refined this model by incorporating clinical prognostic indicators. Survival analysis, Cox regression, and ROC curve assessments evaluated these models’ prognostic capabilities. Immune cell infiltration and drug sensitivity were quantified, linking these to patient risk categories.ResultsSix prognostic lymphocyte genes (KLRC1, APOC2, GBP2, SLA, MLLT3, and SIGLEC5) were identified for GPM‐WT. Clinical factors, age and sex, were integrated to refine the model. The Lymphocyte Gene and Clinical Features Prognostic Nomogram (LGCPN‐WT) effectively distinguished high from low‐risk groups, predicting 2–5‐year survival rates with area under the curve (AUC) values of 0.771, 0.774, 0.751, and 0.785. Elevated immune cell infiltration and enhanced drug sensitivity characterized the high‐risk group, exhibiting significant responsiveness to chemotherapy, targeted, and immunotherapy treatments (p < 0.05).ConclusionsThe study developed an integrated LGCPN‐WT model, significantly enhancing survival prediction accuracy and clinical utility for WT, thus supporting personalized treatment approaches.

BackgroundCockayne syndrome (CS) is a rare, autosomal‐recessive, multisystem disorder characterized by microcephaly, failure to thrive, photosensitivity, leukodystrophy, muscle contracture, and intellectual disability. It is caused by deleterious variant in the ERCC6 and ERCC8 genes, which are involved in the transcription‐coupled nucleotide excision repair system. According to severity and age of onset, CS is categorized into four types: I, II, III, and cerebrooculofacioskeletal syndrome (COFS). However, some researchers consider COFS to be a distinct disease from CS, while others describe COFS as a severe form of CS.MethodsWhole‐exome sequencing (WES) and Sanger sequencing were used to identify potential pathogenic causative variant.ResultsWES data analysis revealed a nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene, which was co‐segregated using Sanger sequencing. Although this variant has been reported previously in association with both CS and COFS separately, this study’s patient manifested intermediate symptoms.ConclusionThis study’s findings expand the clinical spectrum of the variant (NM_000124: c.3862C>T, p.R1288X) and provide more supporting evidence that CS and COFS are phenotypic spectrums rather than different clinical conditions in which genetic and epigenetic factors probably play a pivotal role in the severity of symptoms.

BackgroundTemperature sensitivity has gained considerable attention in the era of precision medicine. This trait has long been used to identify cold–heat patterns (C-HPs), a diagnostic framework in Traditional Korean Medicine that categorizes individuals based on their thermal responses. C-HP helps understand an individual's inherent physical characteristics, which have been shown to be highly heritable and thus shaped by genetic factors. However, genetic markers that are significantly associated with this trait remain scarce. To address this gap, we aimed to identify candidate single-nucleotide polymorphisms (SNPs) based on previous genomewide association studies (GWASs) of related traits.MethodsGiven the limited research directly addressing C-HP, we incorporated genetic studies related to traits such as “Cold” or “Heat,” as well as thyroid hormone, which plays a key role in thermogenesis through the activation of various metabolic pathways. After selecting the SNPs reported in previous GWAS from the GWAS Catalog (EMBL-EBI), we validated these findings using 90 Korean patients reporting C-HP, with statistical significance assessed through residual permutations. Gene set enrichment analysis (GSEA) was performed using the GO Biological Process 2023 dataset to identify the pathways associated with C-HP. Furthermore, we compared our findings with control traits in order to confirm that the observed associations were specific to C-HP-related traits rather than random correlations. Principal component analysis (PCA) was conducted on candidate SNPs from the 1000 Genomes reference dataset to illustrate the ethnic variation for C-HP across five populations.ResultsOf 63 GWAS, we selected 548 SNPs for validation. Ultimately, 20 candidate SNPs associated with heat patterns and 19 candidate SNPs associated with cold patterns were identified. Of the heat-pattern SNPs, 18 were linked to thyroid hormone traits, with key SNPs including rs12409301 (CAPZB) and rs12855 (CDKN2C). For the cold-pattern trait, 16 SNPs were associated with thyroid hormones such as rs622474 (PDE4B) and rs11204752 (GOLPH3L). GSEA confirmed notable enrichment in vascular processes for the heat pattern and mitochondrial organization for the cold pattern. The most significant pathway was vascular smooth muscle cell development (p value = 1.28 × 10−5) in the heat pattern. The clear ethnic differences in C-HP were observed in the PCA of 1000 Genomes populations where East Asian and African populations formed distinct, well-separated clusters.ConclusionOur study suggested a total of 39 candidate SNPs as genetic markers for C-HP that are plausible in the context of temperature sensitivity. We hope that our findings will provide a valuable basis for further biological research and potential clinical applications of C-HP.

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.

Introduction Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance. Methods We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's p value was higher than 0.1. We used random models when the p value was less than 0.1. Results Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations. Conclusion This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.

Background Cysteine and Glycine Rich Protein 1 (CSRP1) belongs to the cysteine-rich protein family, which contains a unique double-zinc finger motif and is important for development and cellular differentiation. Abnormal expression of CSRP1 was reported within several malignancies such as prostate cancer and acute myeloid leukemia. Here, we explored function of CSRP1 within colon adenocarcinoma (COAD) for the first time. Methods The mRNA levels of CSRP1 in COADs were obtained from TCGA datasets. CSRP1 protein expressions in COADs were tested via immunohistochemistry staining. Patients' prognosis was evaluated using both univariate analysis and multivariate analysis. Two human COAD originated cancer cell lines, Caco-2, and HT-29, were used for cellular experiments including shRNA knockdown, proliferation assay, and migration assay. In vivo model was established using nude mice xenografts to further validate the role of CSRP1 in COAD progression. Results The mRNA levels of CSRP1 are elevated in COAD specimens from patients with more advanced tumor stages and higher Carcinoembryonic Antigen (CEA) levels. In addition, higher CSRP1 mRNA level indicates worse COAD prognosis. Consistently, higher CSRP1 protein expression is correlated with worse overall survival according to both univariate and multivariate analysis, indicating that CSRP1 is a new COAD prognostic factor. Furthermore, COAD cells transfected with CSRP1-shRNAs exhibit attenuated proliferation and migration capacities. Finally, growth of xenografts originated from CSRP1-knockdown cells is inhibited comparing to the control ones. Conclusions Expression of CSRP1 is positively correlated with COAD progression, which can promote tumor growth and migration. Higher CSRP1 can is a novel independent prognostic factor of COAD.

Objective This study aimed to identify circular RNA profiles (circRNAs) via high-throughput RNA sequencing and distinguish the differentially expressed (DE) circRNAs between stable and unstable plaques. Methods RNA sequencing was performed on unstable and stable carotid plaque samples obtained from patients with carotid artery stenosis. DE circRNAs were screened, and six DE circRNAs were verified using quantitative real-time PCR (qRT-PCR). Functional evaluation of the DE circRNAs was conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Results We screened 344 DE circRNAs in unstable plaques, consisting of 342 upregulated and 2 downregulated circRNAs. GO analysis showed that the host genes of the upregulated circRNAs were related to ER to Golgi transport vesicle membrane, endocytic vesicle membrane, and Ran GTPase binding. KEGG analysis revealed that the host genes of the upregulated circRNAs were primarily associated with protein processing in endoplasmic reticulum, lysine degradation, homologous recombination, epithelial cell signaling in Helicobacter pylori infection, and yersinia infection. The results of qRT-PCR verified three upregulated DE circRNAs and two downregulated DE circRNAs in unstable plaques. Conclusion Hsa-circ-0001523, hsa-circ-0008950, hsa-circ-0000571, hsa-circ-0001946, and hsa-circ-0000745 may be involved in regulating the stability of atherosclerotic plaques and serves as a therapeutic target for unstable plaques.

Introduction As the most malignant type of gliomas, glioblastoma is characterized with disappointing prognosis. Here, we aimed to investigate expression and function of NKD inhibitor of Wnt signaling pathway 1 (NKD1), an antagonist of Wnt-beta-catenin signaling pathways, in glioblastoma. Methods The mRNA level of NKD1 was firstly retrieved from TCGA glioma dataset to evaluate its correlation with clinical characteristics and its value in prognosis prediction. Then, its protein expression level in glioblastoma was tested by immunohistochemistry staining in a retrospectively cohort collected from our medical center (n = 66). Univariate and multivariate survival analyses were conducted to assess its effect on glioma prognosis. Two glioblastoma cell lines, U87 and U251, were used to further investigate the tumor-related role of NKD1 through overexpression strategy in combination with cell proliferation assays. Immune cell enrichment in glioblastoma and its correlation with NKD1 level was finally assessed using bioinformatics analyses. Results NKD1 shows a lower expression level in glioblastoma compared to that in the normal brain or other glioma subtypes, which is independently correlated to a worse prognosis in both the TCGA cohort and our retrospective cohort. Overexpressing NKD1 in glioblastoma cell lines can significantly attenuate cell proliferation. In addition, expression of NKD1 in glioblastoma is negatively correlated to the T cell infiltration, indicating it may have crosstalk with the tumor immune microenvironment. Conclusions NKD1 inhibits glioblastoma progression and its downregulated expression indicates a poor prognosis.