Novel DCC variants in congenital mirror movements and evaluation of disease-associated missense variants

Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases. We re-evaluated the 15 known disease-associated DCC missense variants by determining minor allele frequency (MAF) and pathogenicity using four in silico tools combining previous pathogenicity scores and the ACMG/AMP standards and guidelines and classified them in three groups. Group I contains three DCC missense variants that are rather unlikely to be associated with a higher risk to CMM and/or ACC. The five variants in group II may represent susceptibility factors to altered midline crossing in the central nervous system. Group III includes seven variants absent in publically available databases and representing possible pathogenic alleles, with four predicted to have a severe impact on protein function. Based on this data and the variable expressivity and incomplete penetrance present in heterozygous carriers of a DCC variant, classification and clinical interpretation of missense variants is challenging in the absence of evidence of pathogenicity originated from functional studies. Evaluation of missense variants by MAF and a weighted combination of several computational algorithms is recommended.     

Vaccine-driven serotype-rearrangement is seen with latency in clinical isolates: Comparison of carried and clinical pneumococcal isolates from the same time period in Hungary

Young children – the main asymptomatic carriers of pneumococcus – are often the source of pneumococcal infections. PCV13 replaced PCV7 in 2010 in Hungary and it became a mandatory vaccine in 2014. In this work we surveyed the effect of vaccination in three groups: in healthy children under 7?years; in children of the same age but infected with pneumococcus (P1); in older patients (P2) who were very likely not vaccinated.Nasal swabs were taken from 522 healthy children to screen pneumococcal carriage between March 2015 and May 2016. In the same time period, 146 clinical isolates were collected, mainly from mucosal infections. Serotypes, antibiotic susceptibility and clonality of the isolates was determined and compared.The carriage rate was 39.1%. Regarding carriage, the serotype distribution showed the total disappearance of serotypes 3 and 6A compared to former Hungarian studies. The prevalence of PCV13 serotypes was only 5.8% represented by three serotypes (19F, 19A, 9V). Of note, serotype 19A (a very resistant and invasive type) also decreased significantly. In the patient groups, PCV13 prevalence was higher: 17.5% (P1) and 32.6% (P2). Although serotype 3 was present in P1 (7.9%), the leading serotype was 23B (22.2%), a non-vaccine type (NVT). P2 showed the most diverse serotype distribution, but serotype 3 was predominant here (15.7%). Pneumococcal isolates from the patients were more resistant towards the tested antibiotics compared to those from carriers.PCV13 seems to be highly successful in reducing the prevalence of vaccine serotypes. The serotype-rearrangement can be seen also among clinical isolates, albeit somewhat later in time. Fortunately, the replacing serotypes are less invasive and less resistant, but, most worrisome, serotype 19F can be found again with increased frequency among carriage isolates and mucosal infections. Further surveillance is needed to carefully monitor such successful, antibiotic resistant “refugees”.     

Canalopatias cardíacas: o papel das mutações nos canais de sódio

Introduction and objectives

The importance of sodium channels for the normal electrical activity of the heart is emphasized by the fact that mutations (inherited or de novo) in genes that encode for these channels or their associated proteins cause arrhythmogenic syndromes such as the Brugada syndrome and the long QT syndrome (LQTS). The aim of this study is to conduct a review of the literature on the mutations in the sodium channel complex responsible for heart disease and the implications of a close relationship between genetics and the clinical aspects of the main cardiac channelopathies, namely at the level of diagnosis, risk stratification, prognosis, screening of family members and treatment.

Characteristics and sputum conversion of tuberculosis (TB) patients in Kalutara,Sri Lanka

Background

Tuberculosis (TB) is an infectious bacterial disease; remains as one of the important public health problem affecting every part of the world. Substantial number of TB cases are reported from Sri Lanka every year irrespective of its strong preventive health system. The aim of this analysis is to describe the characteristics of TB patients and to assess the factors associated with sputum conversion. This analysis was based on the data from the District Chest Clinic of Kalutara district, Sri Lanka.

Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature

BACKGROUND: In the Dukes' B and C stages of colorectal carcinoma there are considerable variations in the observed courses of the disease. Since post-operative chemotherapy in patients with Dukes' C (node-positive) colon carcinoma has been demonstrated to be effective in improving overall-survival, a more exact prognosis assessment gains additional significance and therapeutic relevance. DISCUSSION: One also hopes to derive improved prognostic factors from the clarification of the molecular pathogenesis. Because of its frequency and the accessibility and recognizability of its developmental stages colorectal carcinoma is among the best investigated of all solid tumors. Despite a multitude of suggested molecular candidate markers none of these changes has yet been able enter the everyday life of the clinic. However, it is to be expected that some of the molecular alterations presently discussed will gain importance before long in the clinical treatment of patients with colorectal carcinoma. CONCLUSION: Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.     

UNC5H3和DCC在胃癌中的表达与增殖的关系及其预后

目的 探讨UNC5H3和DCC在胃癌组织的表达,与临床病理特征和增殖的关系以及与患者生存和预后的关系。 方法 应用组织芯片和免疫组织化学技术,分析60例胃癌组织中UNC5H3、DCC和Ki-67的表达,并对其表达进行相关分析。利用图像分析软件Image-Pro Plus 6.0测量切片积分吸光度,对结果进行验证。采用Kaplan-Meier限乘法计算生存率。建立Cox回归模型,评价UNC5H3和DCC作为胃癌患者预后的独立影响因素的可行性。结果 在60例胃癌组织中,UNC5H3、DCC和Ki-67的阳性表达率分别为43.3%、53.3%和60.0%。UNC5H3和DCC与淋巴转移和远处转移之间,差异有显著性(P<0.05)。UNC5H3和DCC表达与Ki-67表达相互之间无相关性（P>0.05）。用Kaplan-Meier生存曲线经 Log-rank检验发现,UNC5H3的阳性表达与胃癌患者生存之间存在相关性（P<0.05）。DCC的阳性表达与胃癌患者生存之间无相关性（P>0.05）。经Cox回归分析,UNC5H3和DCC的表达与胃癌患者预后无明显相关性。结论 依赖性受体UNC5H3和DCC共同参与了胃癌的发生进展,检测UNC5H3和DCC可作为反映胃癌临床病理学特点的指标,检测UNC5H3可作为胃癌患者生存期的指标,但UNC5H3和DCC的表达不是判断胃癌患者预后的独立影响因素。     

No association between the Arg201Gly polymorphism of the DCC gene and colorectal cancer.

BACKGROUND AND AIMS: In one small study, the DCC Arg201Gly polymorphism has been observed more frequently in colorectal cancer cases compared with controls. We wondered whether these results could be replicated in a much larger study. METHODOLOGY: The DCC Arg201 Gly polymorphism was genotyped in 625 unselected Caucasian colorectal cancer patients and 220 controls. Association analysis was used to search for a difference between patients and controls. Subgroup analyses were performed for site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. RESULTS: The association analyses revealed no difference in Arg201Gly genotype frequency between patients and controls, neither overall nor for different subgroups according to site of tumour, gender, age at diagnosis, family history of colorectal cancer and modified Dukes classification. CONCLUSION: No association was observed between the Arg201Gly polymorphism of DCC and colorectal cancer risk.     

大肠癌组织APC／MCC和DCC基因杂合缺失的研究

为评估ＡＰＣ／ＭＣＣ和ＤＣＣ基因在大肠癌发生和发展中的作用，采用聚合酶链反应（ＰＣＲ）技术，并配合限制性片段长度多态现象（ＲＦＬＰ）分析，对４１例大肠癌患者的组织ＡＰＣ／ＭＣＣ（位于染色体５ｑ２１）和ＤＣＣ基因（位于染色体１８ｑ２１．３）杂合缺失（ＬＯＨ）进行研究。ＡＰＣ基因ＬＯＨ率为２８．０％（７／２５），ＭＣＣ基因ＬＯＨ率为３６．４％（８／２２），两者综合分析ＬＯＨ率为３８．９％（１４／３８）。ＤＣＣ基因ＬＯＨ率为５５．３％（２１／３８）。ＤＣＣ基因在有淋巴结转移组的ＬＯＨ率（８０．０％）显著高于无淋巴结转移组（３９．１％）（Ｐ＜０．０５），在ＤｕｋｅｓＣ、Ｄ期组的ＬＯＨ率（７１．４％）显著高于Ａ、Ｂ期组（３５．３％）。以上结果提示，ＡＰＣ／ＭＣＣ和ＤＣＣ基因的ＬＯＨ是大肠癌常见的基因改变，ＤＣＣ基因ＬＯＨ的测定有可能成为大肠癌病人预后估计的指标。     

Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.