Rs2262251 in lncRNA RP11‐462G12.2 is associated with nonsyndromic cleft lip with/without cleft palate

Nonsyndromic cleft lip with/without cleft palate (NSCL/P) is one of the most common human congenital defects. Rs2262251 (G>C) in long noncoding RNA (lncRNA) RP11‐462G12.2 is in high linkage disequilibrium with rs8049367, which was identified in our previous genome‐wide association study on NSCL/P, and is a potential causative single‐nucleotide polymorphism (SNP) for NSCL/P. To test these hypotheses, rs2262251 was evaluated in another cohort of 1,314 cases and 1,259 controls. Rs2262251 was associated with NSCL/P risk (p = .003). However, no association was detected for cleft palate only. SNP rs2262251 affected the structure and expression of lncRNA RP11‐462G12.2 in HEK293 and HEPM cells and in lip tissues from patients with NSCL/P. Overexpression of the rs2262251 G allele contributed to reducing the number of cells in the G0/G1 phase, inhibiting cell apoptosis, and promoting cell proliferation in vitro. The rs2262251 C allele regulated the expression of miR‐744‐5p and its target gene IQSEC2, both of which were expressed in human lip tissues, and showed reverse correlation during mouse lip development. Taken together, these findings suggest that rs2262251 is associated with the risk of NSCL/P and participates in a lncRNA–miRNA–mRNA regulatory axis in which miR‐744‐5p and IQSEC2 combine to control NSCL/P development.     

Exploratory genotype–phenotype correlations of facial form and asymmetry in unaffected relatives of children with non‐syndromic cleft lip and/or palate

Family relatives of children with nonsyndromic cleft lip with or without cleft palate (NSCL/P) who presumably carry a genetic risk yet do not manifest overt oral clefts, often present with distinct facial morphology of unknown genetic etiology. This study investigates distinct facial morphology among unaffected relatives and examines whether candidate genes previously associated with overt NSCL/P and left–right body patterning are correlated with such facial morphology. Cases were unaffected relatives of individuals with NSCL/P (n = 188) and controls (n = 194) were individuals without family history of NSCL/P. Cases and controls were genotyped for 20 SNPs across 13 candidate genes for NSCL/P (PAX7, ABCA4‐ARHGAP29, IRF6, MSX1, PITX2, 8q24, FOXE1, TGFB3 and MAFB) and left–right body patterning (LEFTY1, LEFTY2, ISL1 and SNAI1). Facial shape and asymmetry phenotypes were obtained via principal component analyses and Procrustes analysis of variance from 32 coordinate landmarks, digitized on 3D facial images. Case–control comparisons of phenotypes obtained were performed via multivariate regression adjusting for age and gender. Phenotypes that differed significantly (P < 0.05) between cases and controls were regressed on the SNPs one at a time. Cases had significantly (P < 0.05) more profile concavity with upper face retrusion, upturned noses with obtuse nasolabial angles, more protrusive chins, increased lower facial heights, thinner and more retrusive lips and more protrusive foreheads. Furthermore, cases showed significantly more directional asymmetry compared to controls. Several of these phenotypes were significantly associated with genetic variants (P < 0.05). Facial height and width were associated with SNAI1. Midface antero‐posterior (AP) projection was associated with LEFTY1. The AP position of the chin was related to SNAI1, IRF6, MSX1 and MAFB. The AP position of the forehead and the width of the mouth were associated with ABCA4–ARHGAP29 and MAFB. Lastly, facial asymmetry was related to LEFTY1, LEFTY2 and SNAI1. This study demonstrates that, genes underlying lip and palate formation and left–right patterning also contribute to facial features characteristic of the NSCL/P spectrum.     

Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss‐of‐function vs missense variants

Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is a prevalent, complex congenital malformation. Genome‐wide association studies (GWAS) on NSCL/P have consistently identified association for the 1p22 region, in which ARHGAP29 has emerged as the main candidate gene. ARHGAP29 re‐sequencing studies in NSCL/P patients have identified rare variants; however, their clinical impact is still unclear. In this study we identified 10 rare variants in ARHGAP29, including five missense, one in‐frame deletion, and four loss‐of‐function (LoF) variants, in a cohort of 188 familial NSCL/P cases. A significant mutational burden was found for LoF (Sequence Kernel Association Test, p = 0.0005) but not for missense variants in ARHGAP29, suggesting that only LoF variants contribute to the etiology of NSCL/P. Penetrance was estimated as 59%, indicating that heterozygous LoF variants in ARHGAP29 confer a moderate risk to NSCL/P. The GWAS hits in IRF6 (rs642961) and 1p22 (rs560426 and rs4147811) do not seem to contribute to the penetrance of the phenotype, based on co‐segregation analysis. Our data show that rare variants leading to haploinsufficiency of ARHGAP29 represent an important etiological clefting mechanism, and genetic testing for this gene might be taken into consideration in genetic counseling of familial cases.     

Correlating high‐resolution magic angle spinning NMR spectroscopy and gene analysis in osteoarthritic cartilage

Osteoarthritis (OA) is a common multifactorial and heterogeneous degenerative joint disease, and biochemical changes in cartilage matrix occur during the early stages of OA before morphological changes occur. Thus, it is desired to measure regional biochemical changes in the joint. High‐resolution magic angle spinning (HRMAS) NMR spectroscopy is a powerful method of observing cartilaginous biochemical changes ex vivo, including the concentrations of alanine and N‐acetyl, which are markers of collagen and total proteoglycan content, respectively. Previous studies have observed significant changes in chondrocyte metabolism of OA cartilage via the altered gene expression profiles of ACAN, COL2A1 and MMP13, which encode aggrecan, type II collagen and matrix metalloproteinase 13 (a protein crucial in the degradation of type II collagen), respectively. Employing HRMAS, this study aimed to elucidate potential relationships between N‐acetyl and/or alanine and ACAN, COL2A1 and/or MMP13 expression profiles in OA cartilage. Thirty samples from the condyles of five subjects undergoing total knee arthroplasty to treat OA were collected. HRMAS spectra were obtained at 11.7 T for each sample. RNA was subsequently extracted to determine gene expression profiles. A significant negative correlation between N‐acetyl metabolite and ACAN gene expression levels was observed; this provides further evidence of N‐acetyl as a biomarker of cartilage degeneration. The alanine doublet was distinguished in the spectra of 15 of the 30 specimens of this study. Alanine can only be detected with HRMAS NMR spectroscopy when the collagen framework has been degraded such that alanine is sufficiently mobile to form a distinguished peak in the spectrum. Thus, HRMAS NMR spectroscopy may provide unique localized measurements of collagenous degeneration in OA cartilage. The identification of imaging markers that could provide a link between OA pathology and chondrocyte metabolism will facilitate the development of more sensitive diagnostic techniques and will improve methods of monitoring treatment for patients suffering from OA. Copyright © 2015 John Wiley & Sons, Ltd.     

Identification of key genes and pathways in castrate-resistant prostate cancer by integrated bioinformatics analysis

ObjectiveTo identify hub genes and pathways involved in castrate-resistant prostate cancer (CRPC).MethodsThe gene expression profiles of GSE70768 were downloaded from Gene Expression Omnibus (GEO) datasets. A total of 13 CRPC samples and 110 tumor samples were identified. The differentially expressed genes (DEGs) were identified, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis was performed. Protein-protein interaction (PPI) network module analysis was constructed and performed in Cytoscape software. Weighted correlation network analysis (WGCNA) was conducted to determine hub genes involved in the development and progression of CRPC. The gene expression profiles of GSE80609 were used for validation.ResultsA total of 1738 DEGs were identified, consisting of 962 significantly down-regulated DEGs and 776 significantly upregulated DEGs for the subsequent analysis. GO term enrichment analysis suggested that DEGs were mainly enriched in the extracellular matrix organization, extracellular exosome, extracellular matrix, and extracellular space. KEGG pathway analysis found DEGs significantly enriched in the focal adhesion pathway. PPI network demonstrated that the top 10 hub genes were ALB, ACACB, KLK3, CDH1, IL10, ALDH1A3, KLK2, ALDH3B2, HBA1, COL1A1. Also, WGCNA identified the top 5 hub genes in the turquoise module, including MBD4, BLZF1, PIP5K2B, ZNF486, LRRC37B2. Plus, the Venn diagram demonstrated that HBA1 was the key gene in both GSE70768 and GSE80609 datasets.ConclusionsThese newly identified genes and pathways could help urologists understand the differences in the mechanism between CRPC and PCa. Besides, it might be promising targets for the treatment of CRPC.     

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gastric cancer

Background and objective

The underlying molecular mechanisms of gastric cancer (GC) have yet not been investigated clearly. In this study, we aimed to identify hub genes involved in the pathogenesis and prognosis of GC.

Exploring the interaction between FGF Genes and T-box genes among chinese nonsyndromic cleft lip with or without cleft palate case-parent trios

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Genetic variants causing syndromic orofacial clefts can also contribute to the etiology of NSCL/P. The purpose of the present study was to explore gene–gene (G × G) interaction using common single nucleotide polymorphic (SNP) markers in fibroblast growth factor (FGF) family and its receptors and T-box genes, which were associated with syndromic orofacial clefts. Our study was conducted in 806 Chinese NSCL/P case-parent trios drawn from an international consortium. A total of 252 SNPs in FGF8, FGF10, FGFR1, FGFR2, and TBX5 passed the quality control criteria and were included in the analysis. The interactions between SNPs in different genes were assessed using Cordell's method, which fitted a conditional logistic regression model. The analysis was performed using the R-package trio (Version 3.8.0). Bonferroni correction was used to adjust for multiple comparisons, and the overall significance threshold was set as P = 1.98 × 10⁻⁴ (0.05/252). Conditional logistic regression revealed the most significant interaction between rs2330542 in FGF10 and rs1946295 in TBX5, which remained significant (P = 9.63 × 10⁻⁶) after Bonferroni correction. The relative risk of allele C in rs2330542 (FGF10) was 1.02 (95%CI 0.81–1.28), while the relative risk was 1.42 (95%CI 1.03–1.97) when the exposure was a combination of allele C in rs2330542 and allele A in rs1946295 (TBX5). Our findings confirmed the importance of considering G × G interaction when exploring the genetic risk factors of NSCL/P. Further investigations are warranted to validate the potential interaction and reveal the biological function of FGF10/FGFR2/TBX5. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.     

Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate

Nonsyndromic orofacial cleft (NSOFC) is a complex disease of still unclear genetic etiology. To investigate the contribution of rare epithelial cadherin (CDH1) gene variants to NSOFC, we target sequenced 221 probands. Candidate variants were evaluated via in vitro, in silico, or segregation analyses. Three probably pathogenic variants (c.760G>A [p.Asp254Asn], c.1023T>G [p.Tyr341*], and c.2351G>A [p.Arg784His]) segregated according to autosomal dominant inheritance in four nonsyndromic cleft lip with or without cleft palate (NSCL/P) families (Lod score: 5.8 at θ = 0; 47% penetrance). A fourth possibly pathogenic variant (c.387+5G>A) was also found, but further functional analyses are needed (overall prevalence of CDH1 candidate variants: 2%; 15.4% among familial cases). CDH1 mutational burden was higher among probands from familial cases when compared to that of controls (P = 0.002). We concluded that CDH1 contributes to NSCL/P with mainly rare, moderately penetrant variants, and CDH1 haploinsufficiency is the likely etiological mechanism.     

Integrated bioinformatics analysis for differentially expressed genes and signaling pathways identification in gastric cancer

Background: Gastric cancer (GC) has a high mortality rate in cancer-related deaths worldwide. Currently, the pathogenesis of gastric cancer progression remains unclear. Here, we identified several vital candidate genes related to gastric cancer development and revealed the potential pathogenic mechanisms using integrated bioinformatics analysis.Methods: Two microarray datasets from Gene Expression Omnibus (GEO) database integrated. Limma package was used to analyze differentially expressed genes (DEGs) between GC and matched normal specimens. DAVID was utilized to conduct Gene ontology (GO) and KEGG enrichment analysis. The relative expression of OLFM4, IGF2BP3, CLDN1 and MMP1were analyzed based on TCGA database provided by UALCAN. Western blot and quantitative real time PCR assay were performed to determine the protein and mRNA levels of OLFM4, IGF2BP3, CLDN1 and MMP1 in GC tissues and cell lines, respectively.Results: We downloaded the expression profiles of {"type":"entrez-geo","attrs":{"text":"GSE103236","term_id":"103236"}}GSE103236 and {"type":"entrez-geo","attrs":{"text":"GSE118897","term_id":"118897"}}GSE118897 from the Gene Expression Omnibus (GEO) database. Two integrated microarray datasets were used to obtain differentially expressed genes (DEGs), and bioinformatics methods were used for in-depth analysis. After gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analysis, we identified 61 DEGs in common, of which the expression of 34 genes were elevated and 27 genes were decreased. GO analysis displayed that the biological functions of DEGs mainly focused on negative regulation of growth, fatty acid binding, cellular response to zinc ion and calcium-independent cell-cell adhesion. KEGG pathway analysis demonstrated that these DEGs mainly related to the Wnt and tumor signaling pathway. Interestingly, we found 4 genes were most significantly upregulated in the DEGs, which were OLFM4, IGF2BP3, CLDN1 and MMP1. Then, we confirmed the upregulation of these genes in STAD based on sample types. In the final, western blot and qRT-PCR assay were performed to determine the protein and mRNA levels of OLFM4, IGF2BP3, CLDN1 and MMP1 in GC tissues and cell lines.Conclusion: In our study, using integrated bioinformatics to screen DEGs in gastric cancer could benefit us for understanding the pathogenic mechanism underlying gastric cancer progression. Meanwhile, we also identified four significantly upregulated genes in DEGs from both two datasets, which might be used as the biomarkers for early diagnosis and prevention of gastric cancer.     

Collagen type IV‐related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families

Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype–phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next‐generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV‐related glomerular basement membrane nephropathies.     

5,10-亚甲基四氢叶酸还原酶基因多态性及补充叶酸与非综合征性唇腭裂的相关性

背景：对于5, 10-亚甲基四氢叶酸还原酶(5, 10-methylene tetrahydrofolate reductase, MTHFR)基因C677T位点多态性与唇腭裂相关性的研究国内外结果不一,未见结合干预因素叶酸影响的相关报道。 目的：探讨河南地区汉族人群MTHFR基因C677T位点多态性及补充叶酸与非综合征性唇腭裂的发病关系。 方法：选取2008-09/2010-03在郑州大学第一附属医院及郑州市第一人民医院整形外科就诊的非综合征性唇腭裂患者110例,采用PCR-RFLP法检测外周血中MTHFR基因C677T位点基因型并与40例健康对照比较频数差异。同时结合母孕期是否补充叶酸进行统计学分析。 结果与结论：病例组和对照组C677T基因型及等位基因频率比较差异均具有显著性意义(P < 0.01),且有家族史的患者TT基因型及T等位基因频率高于无家族史患者(P < 0.05)。对母孕期是否补充叶酸进行比较,发现非综合征性唇腭裂与叶酸摄入呈负相关(χ²=4.304,r=-0.169,P  < 0.05)。结果提示MTHFR基因C677T位点突变与河南汉族人群非综合征性唇腭裂的发生相关,母孕期补充叶酸能降低非综合征性唇腭裂的发病风险。     

Association of COL4A1 gene polymorphisms with cerebral palsy in a Chinese Han population

The basement membrane (BM) is an extracellular matrix associated with overlying cells and is important for proper tissue development, stability, and physiology. COL4A1 is the most abundant component of type IV collagen in the BM, and COL4A1 variants can present with variable phenotypes that might be related to cerebral palsy (CP). We postulated, therefore, that variations in the COL4A1 gene might play an important role in the etiology of CP. In this study, six single nucleotide polymorphisms (SNPs) in the COL4A1 gene were genotyped among 351 CP patients and 220 healthy controls from the Chinese Han population. Significant association was found for an association between CP and rs1961495 (allele: p = 0.008, odds ratio (OR) = 1.387, 95% confidence interval (CI) = 1.088–1.767) and rs1411040 (allele: p = 0.009, OR = 1.746, 95% CI = 1.148–2.656) SNPs of the COL4A1 gene. Multifactor dimensionality reduction analysis suggested that these SNPs had interactive effects on the risk of CP. This study is the first attempt to investigate the contribution of polymorphisms in the COL4A1 gene to the susceptibility of CP in a Chinese Han population. This study shows an association of the COL4A1 gene with CP and suggests a potential role of COL4A1 in the pathogenesis of CP.     

Association of single nucleotide polymorphisms in TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 with the risk of nonsyndromic cleft lip with or without cleft palate in a sample of the Iranian population,a preliminary report

Several lines of evidence support an association between tropomyosin 1 (TPM1) and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present study aimed to investigate the association between TPM1 polymorphisms and the risk of NSCL/P in an Iranian population. This case‐control was done on 105 NSCL/P patients and 110 unrelated healthy controls. TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 polymorphisms were genotyped by the polymerase chain reaction‐restriction fragment length polymorphism method. The finding showed that rs11071720 polymorphism significantly increased the risk of NSCL/P in homozygous codominant (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.14–5.69, p = 0.023, TT vs. CC), recessive (OR = 2.33, 95% CI = 1.06–5.18, p = 0.021, TT vs. CT + CC), and allele (OR = 1.53, 95% CI = 1.02–2.30, p = 0.030, T vs. C). The rs12148828 polymorphism was associated with protection against NSCL/P in codominant (OR = 0.27, 95% CI = 0.15–0.48, p < 0.001, TC vs. TT) and allele (OR = 0.38, 95% CI = 0.22–0.64, p < 0.001, C vs. T). Regarding rs3803499, the findings proposed that this polymorphism significantly increased the risk of NSCL/P in codominant (OR = 3.86, 95% CI = 1.19–12.56, p = 0.025, CC vs. TT) and recessive (OR = 3.74, 95% CI = 1.09–14.15, p = 0.018, CC vs. CT + TT). No significant association was practical between rs1972041 polymorphism and NSCL/P. In conclusion, the findings proposed that TPM1 polymorphisms may contribute to the etiology of NSCL/P in a sample of the Iranian population.     

Identified the novel resistant biomarkers for taxane-based therapy for triple-negative breast cancer

Developing treatment strategies for triple-negative breast cancer (TNBC) has become an important clinical challenge. Currently, taxane-based chemotherapy is one of the standard treatments for TNBC. However, determining the key factor of taxane-resistance is urgently in need for clinical treatment for breast cancer. We used GEO data to generate paclitaxel resistance in two basal-like TNBC cell lines (SUM149 and MDA-MB-468). Seventy-one common upregulated differentially expressed genes (DEGs) and 11 downregulated DEGs were found to be related to paclitaxel resistance. By constructing protein-protein interactions, 28 hub proteins with a degree cutoff criterion of ≥1 were found. Nine hub genes (COL4A6, COL4A5, IL6, PDGFA, LPAR1, FYB, IL20, IL18R1 and INHBA) are involved in important signaling pathways. We found that upregulated PDGFA and downregulated COL4A6 were significantly associated with an insensitive response to neoadjuvant paclitaxel-based therapy. A Kaplan-Meier plot was created to check the prognostic values of 11 hub DEGs in terms of recurrence-free survival. High expressions of PDGFA and LAMB3 were correlated with poor recurrence-free survival, while low levels of FYB, IL18R1, and RASGRP1 indicated poorer relapse-free survival. Our results suggest that PDGFA, COL4A6, LPAR1, FYB, COL4A5, and RASGRP1 might be candidate target genes for taxane-based therapy in basal-like TNBC.     

The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer

Fanelli M F, Chinen L T D, Begnami M D, Costa W L Jr, Fregnami J H T, Soares F A & Montagnini A L
(2012) Histopathology  61, 153–161 The influence of transforming growth factor‐α, cyclooxygenase‐2, matrix metalloproteinase (MMP)‐7, MMP‐9 and CXCR4 proteins involved in epithelial–mesenchymal transition on overall survival of patients with gastric cancer Aims: Determination of prognostic parameters that are predictive of survival of gastric cancer (GC) may allow better identification of patients who could benefit from current chemotherapy regimens. To assess the correlation between tumour progression and epithelial–mesenchymal transition (EMT), we assayed the expression levels of selected molecules involved in EMT [CD44, transforming growth factor (TGF)‐α, cyclooxygenase‐2 (COX‐2), matrix metalloproteinase (MMP)‐7, MMP‐9 and C‐X‐C chemokine receptor (CXCR4)], and correlated these with overall patient survival (OS) and disease stage. Methods and results: Medical records and pathological biopsy results of 137 patients with GC were evaluated retrospectively. Spearman’s correlation analysis showed that expression of CXCR4 was correlated significantly with the expression of all other proteins studied. In contrast, COX‐2 expression correlated significantly with the expression of only MMP‐7 (P = 0.011), MMP‐9 (P = 0.015) and CXCR4 (P = 0.013). We observed significant negative correlations between OS and the expression of TGF‐α (P = 0.017), COX‐2 (P < 0.001), CXCR4 (P = 0.010), MMP‐7 (P = 0.020) and MMP‐9 (P = 0.015). On multivariate analysis, only COX‐2 was an independent prognostic factor for OS [hazard ratio (HR) = 3.34; 95% confidence interval (CI): 1.43–9.75; P = 0.002). Conclusions: COX‐2, TGF‐α, MMP‐7, MMP‐9 and CXCR4 are associated with poor OS in gastric cancer.     

Dysregulation of X-linked gene expression in Klinefelter's syndrome and association with verbal cognition.

Klinefelter's Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini-Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression-cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = -0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition-gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis.     

The clinical significance and potential molecular mechanism of integrin subunit beta 4 in laryngeal squamous cell carcinoma

The relationship between integrin beta 4 (ITGB4) expression and laryngeal squamous cell carcinoma (LSCC) remains unclarified. The object of the present study was to explore the clinical significance and potential molecular mechanism of ITGB4 in LSCC. The protein level of ITGB4 was significantly higher in 46 LSCC patients than in 26 non-LSCC tissues detected by in-house immunohistochemistry. Consistently, ITGB4 mRNA level was also greatly upregulated based on microarray and RNA-seq data (standard mean difference, SMD = 1.62, 95 % CI: 1.23–2.00). And the area under curves (AUC) of summary receiver operator characteristic (SROC) was 0.87 (95 % CI: 0.84–0.90) based on 172 cases of LSCC and 59 cases of non-cancerous controls. Ninety genes were intersected by the ITGB4 related genes and LSCC differential expressed genes (DEGs) from all available microarray and RNA-seq datasets. Based on Gene Ontology (GO) analysis, the top terms of biological process (BP), cellular component (CC) and molecular function (MF) for the 90 ITGB4 related DEGs were extracellular matrix organization, basement membrane and extracellular matrix structural constituent, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that ITGB4 related DEGs mainly participated in the pathways of ECM-receptor interaction, Focal adhesion and Small cell lung cancer. Moreover, the Protein-Protein Interaction (PPI) network indicated that ITGA3, ITGA5, ITGB4, MET, LAMA3, and COL4A1 might be the core genes of LSCC development related to ITGB4. In conclusion, high ITGB4 expression may lead to the occurrence and development of LSCC via various signaling pathways.     

克氏综合征基因表达谱分析

目的 对克氏综合征（Klinefelter syndrome）患者进行基因表达谱分析,探讨其基因差异表达与临床表型之间的关系.方法 采用第二代高通量测序方法对7例克氏综合征患者和7例对照男性外周血全基因组mRNA进行深度测序,运用定量RT-PCR方法对30例克氏综合征患者及30例对照男性进行验证.结果 测序结果根据FDR≤0.001和｜ log2 Ratio≥1 ｜的标准,两组比较存在差异表达基因216个,差异具有统计学意义.其中X染色体基因9个,占4％,与X染色体失活相关的XIST差异表达最明显;常染色体基因207个,占96％,其中NR4A3、ZKSCAN4、HBEGF、EREG、AREG、NR4A2、CCR5差异表达明显.NR4A3主要.与2型糖尿病有关,HBEGF主要参与促性腺激素分泌过程.Y染色体不存在显著差异表达基因.结论 克氏综合征患者不仅多余X染色体基因差异表达,还有大量常染色体基因差异表达,这可能是克氏综合征临床表型多样化的原因.