结直肠癌组织中KIAA1522的表达 及临床意义

目的：检测KIAA1522蛋白在结直肠癌中的表达变化并评价其临床意义。方法：应用组织芯片-免疫组织化学染色技术,检测96例结直肠癌组织及其配对癌旁正常组织中KIAA1522蛋白的表达情况,并对其阳性表达率与结直肠癌临床病理指标及患者预后的关系进行统计学分析。结果：KIAA1522蛋白在癌旁正常结直肠上皮细胞中主要定位于细胞浆,阳性表达率为12.5%（12/96）,而在结直肠癌组织中KIAA1522蛋白阳性表达率为81.3%（78/96）,两者间差异显著（P < 0.05）。Kaplan-Meier生存分析结果显示,KIAA1522蛋白阳性表达与结直肠癌患者术后3年无瘤生存期短显著正相关（P=0.017,Log-rank检验）。多因素Cox回归分析结果表明,KIAA1522蛋白阳性表达是结直肠癌患者预后不良的独立预测因素（P=0.020）。卡方检验的分析结果显示,KIAA1522蛋白阳性表达与肿瘤的远处转移正相关（P=0.012,Fisher精确检验）。结论：KIAA1522在结直肠癌组织中的阳性表达与肿瘤的远处转移及患者术后生存期短显著相关,可能作为预测结直肠癌患者预后及转移的潜在分子标志。     

胶质瘤中BRAF基因异常的研究进展

BRAF是生长信号转导蛋白激酶RAF基因家族成员之一,调控丝裂原活化蛋白激酶/细胞外信号相关激酶通路,在细胞分裂、分化和发育中发挥重要作用。目前常见的BRAF基因异常包括BRAF基因突变和BRAF基因融合。近些年研究显示BRAF基因的异常改变可发生于多种胶质瘤类型,并且作为独特的分子遗传学特征为胶质瘤的诊断、预后及治疗提供重要依据。本文就BRAF基因在胶质瘤中的异常的形式、机制、检测以及临床诊治意义等研究进展做一综述。     

Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients

BackgroundIn the last two decades, with the advent of whole-exome and whole-genome sequencing, supplemented with linkage analysis, more than 150 genes responsible for X-linked intellectual disability have been identified. Some genes like NEXMIF remain an enigmatic entity, as often the carrier females show wide phenotypic diversity ranging from completely asymptomatic to severe intellectual disability and drug-resistant epilepsy.MethodsWe report three patients with pathogenic NEXMIF variants from an Indian family. All of them had language predominant developmental delay and later progressed to moderate intellectual disability with autistic features. We also reviewed the previously published reports of patients with pathogenic NEXMIF variants.ResultsTogether with the presented cases, 45 cases (24 symptomatic females) were identified from 15 relevant research items for analysis. Males have demonstrated a more severe intellectual disability and increasingly delayed walking age, autistic features, central hypotonia, and gastroesophageal reflux. In contrast, females have shown a predominant presentation with drug-resistant epilepsy and mild to moderate intellectual impairment. Notably, the affected females demonstrate a higher incidence of myoclonic, absence, and atonic seizures. The majority of the variants reported are nonsense or frameshift mutations, causing loss of function of the NEXMIF gene, while a considerable proportion possesses chromosomal translocations, microdeletions, and duplications.ConclusionsNEXMIF gene mutations should be suspected in all cases of X-linked ID and autism cases in males or even in refractory epilepsy cases in females.     

Forced expression of KIAA1199, a novel hyaluronidase,inhibits tumorigenicity of low-grade chondrosarcoma

Hyaluronan (HA) has been shown to play crucial roles in the tumorigenicity of malignant tumors. Chondrosarcoma, particularly when low-grade, is characterized by the formation of an extracellular matrix (ECM) containing abundant HA, and its drug/radiation resistance has become a clinically relevant problem. This study aimed to evaluate the effects of a novel hyaluronidase, KIAA1199, on ECM formation as well as antitumor effects on chondrosarcoma. To clarify the roles of KIAA1199 in chondrosarcoma, mouse KIAA1199 was stably transfected to Swarm rat chondrosarcoma (RCS) cells (histologically grade 1). We investigated the effects of KIAA1199 on RCS cells in vitro and an autografted model in vivo. HA binding protein (HABP) stainability and ECM formation in KIAA1199-RCS was markedly suppressed compared with that of control cells. No significant changes in messenger RNA expression of Has1, Has2, Has3, Hyal1, or Hyal2 were observed. KIAA1199 expression did not affect proliferation or apoptosis but inhibited migration and invasion of RCS cells. In contrast, the expression of KIAA1199 significantly inhibited the growth of grafted tumors and suppressed the stainability of alcian blue in tumor tissues. Although there was no direct inhibitory effect on proliferation in vitro, induction of KIAA1199 showed the antitumor effects in grafted tumor growth in vivo possibly due to changes in the tumor microenvironment such as inhibition of ECM formation. Forced expression of KIAA1199 exhibits antitumor effects on low-grade chondrosarcoma, which has chemo- and radio-therapy resistant features. Together, KIAA1199 could be a novel promising therapeutic tool for low-grade chondrosarcoma, mediated by the degradation of HA.     

维吾尔族和汉族女性乳腺癌与KIAA1199基因表达调控的关系

目的探讨维吾尔族和汉族女性乳腺癌与KIAA1199表达调控的关系。方法收集维吾尔族和汉族女性乳腺纤维腺瘤、乳腺癌患者的石蜡包埋组织标本150例(维吾尔族68例,汉族82例),另选取新鲜组织标本58例(维吾尔族21例,汉族37例),采用免疫组织化学和逆转录聚合酶链反应(RT-PCR)法检测KIAA1199蛋白和mRNA表达水平。结果乳腺纤维腺瘤细胞中KIAA1199蛋白表达上调率为31.9%,乳腺癌细胞中KIAA1199蛋白表达上调率为76.7%,差异有统计学意义(P<0.01),维吾尔族、汉族女性乳腺癌KIAA1199表达上调率的变化趋势具有共性(维吾尔族2=12.30,P<0.01;汉族2=15.19,P<0.01),其族群差异无统计学意义(P>0.05)。KIAA1199基因的转录表达水平在乳腺癌组织中明显上调,其mRNA相对含量为0.967±0.281,乳腺纤维腺瘤组织中KIAA1199 mRNA含量为0.475±0.176,差异有统计学意义(P<0.01)。结论 KIAA1199表达上调伴随着乳腺病变进程,可能成为乳腺癌分子预警指标。     

A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence

Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p < 10⁻⁴. The best novel signal was rs6701037 (p = 1.86 × 10⁻⁷) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p = 4.71 × 10⁻⁷) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p = 7.90 × 10⁻⁶). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p = 1.47 × 10⁻⁶) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p = 1.39 × 10⁻²) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p = 4.58 × 10⁻³, 2.1 × 10⁻⁴, and 2.86 × 10⁻³ for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p < 2 × 10⁻⁵) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040, THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence.