ZIC1 Is Downregulated through Promoter Hypermethylation, and Functions as a Tumor Suppressor Gene in Colorectal Cancer

The transcription factor, Zinc finger of the cerebellum (ZIC1), plays a crucial role in vertebrate development. Recently, ZIC1 has also been found to participate in the progression of human cancers, including medulloblastomas, endometrial cancers, and mesenchymal neoplasms. However, the function of ZIC1 in colon cancer progression has not been defined. In this study, we demonstrate ZIC1 to be silenced or significantly downregulated in colon cancer cell lines. These effects were reversed by demethylation treatment with 5-aza-2′-deoxycytidine (Aza). ZIC1 expression is also significantly downregulated in primary colorectal cancer tissues relative to adjacent non-tumor tissues (p = 0.0001). Furthermore, methylation of ZIC1 gene promoter is frequently detected in primary tumor tissues (85%, 34/40), but not in adjacent non-tumor tissues. Ectopic expression of ZIC1 suppresses cell proliferation and induces apoptosis, which is associated with MAPK and PI3K/Akt pathways, as well as the Bcl-xl/Bad/Caspase3 cascade. To identify target candidates of ZIC1, we employed cDNA microarray and found that 337 genes are downregulated and 95 genes upregulated by ectopic expression of ZIC1, which were verified by 10 selected gene expressions by qRT-PCR. Taken together, our results suggest that ZIC1 may potentially function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in colorectal cancers

Characterizing mental health status of couples in high-risk pregnancy and its relevant characteristics

Objectives: Considering the increasing morbidity and mortality in high-risk pregnancies, it is essential to identify the mental health status of women during their pregnancy since this type of pregnancy is associated with the stress for the women and also their spouses. The present study was designed to determine the mental health status of the couples in high-risk pregnancies and its respective characteristics. Materials and Methods: This cross-sectional study was conducted on couples faced with high-risk pregnancy situations in hospitals and public health centers of Gorgan during 2016-2017. The sample size included 375 couples who were selected by cluster random sampling technique based on the inclusion criteria. Four questionnaires were used to collect the required data. Descriptive and analytical statistics were employed to analyze the obtained data. Results: The results of the study showed that 31.7 of mothers and 25.6 of fathers had mental disorders in high-risk pregnancy situations. Examining the mental health relevant characteristics, the findings indicated an inverse relationship among the following variables: duration of marriage (P = 0.041), number of children (P = 0.050), maternal age (P = 0.018), number of previous pregnancies (P = 0.032), age of the spouse (P = 0.013), gestational age (P = 0.12), social support (P = 0.001), and the mean score of pregnant women’ mental health. It was found that the above-mentioned factors were associated with an improved mental health. The mean scores for the spouse’s mental health (P = 0.000), the need for counseling (P = 0.12), opening the pregnancy file before the first trimester (P = 0.015), and concern (P = 0.000) were found to have a direct relationship with the mean score of the pregnant women’ mental health. Conclusions: Checking mental health during prenatal care is recommended to promote the mental health status of the couples encountered with high-risk pregnancy. © 2018 The Author (s)

A combinatorial oligogenic basis for the phenotypic plasticity between late-onset dilated and arrhythmogenic cardiomyopathy in a single family

Introduction: Primary dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are the two common and distinct forms of hereditary cardiomyopathies caused by defined pathogenic variants (PVs) typically in different sets of genes. DCM is characterized by left ventricular dilatation, dysfunction, and failure, whereas ARVC classically involves the right ventricle and is characterized by fibrofatty infiltration of the myocardium. DCM is caused primarily by the PVs in genes encoding sarcomere and cytoskeletal protein, while ARVC is mainly a disease of the desmosome proteins. DCM and ARVC exhibit partial phenotypic and genetic overlaps.Aim: To analyze the genetic basis of the phenotypic heterogeneity of cardiomyopathy in members of a single family.Methods and Results: We recruited, clinically characterized, and performed whole-exome sequencing in five affected, three probably affected, and two clinically unaffected members of a single family. The family members mainly exhibited late-onset DCM associated with conduction defects and arrhythmias. One family member who died suddenly was diagnosed with the classic ARVC at autopsy and another presented with isolated ventricular tachycardia. A novel splicing (truncating) and a rare missense variant in the TTN gene, likely in cis, co-segregated with the phenotype in all affected and probably affected family members and were likely the causal variants. Several PVs and LPVs in other genes involved in cardiomyopathies and arrhythmias were also identified that seem to modify the expression of the phenotype. Notably, LPVs in the DSP and PKP2 genes, which are known genes for ARVC, were identified in the family member who also carried the TTN variants but developed the classic ARVC.Conclusion: The findings indicate the causal role of the TTN variants, exhibiting an age-dependent penetrance in late-onset DCM, and highlight the potential modifying role of the concomitant LPVs in additional genes on the expression of the phenotype, including a phenotypic switch from the anticipated DCM to ARVC. The findings support an oligogenic basis of the cardiac phenotype in hereditary cardiomyopathies. A comprehensive genetic analysis involving all PVs and LPVs along with detailed phenotypic characterization is necessary to gain insights into the molecular pathogenesis of hereditary cardiomyopathies

Framework de avaliação da complexidade de projetos em portfólios de engenharia civil

A importância da complexidade para o desempenho dos negócios tem ganhado reconhecimento acadêmico e gerencial. A navegação de forma efetiva na complexidade é um diferencial para as organizações, incluindo as temporárias (projetos). Portanto, um melhor entendimento da complexidade em projetos e suas aplicações mostra-se necessário. No entanto, a literatura científica é carente de modelos para avaliar a complexidade nas organizações, especialmente, na área de construção civil. Assim, o objetivo deste artigo exploratório foi propor um modelo para avaliar a complexidade de projetos em portfólios de engenharia civil. O modelo foi criado a partir dos fatores de complexidade em projetos de engenharia identificados pela revisão bibliográfica, tratados pela técnica para tomada de decisão ANP (Analytic Network Process) e suportados pela Teoria da Complexidade. Como resultado, o modelo MID (multiplicidade, interdependência, diversidade) criado foi aplicado em um exemplo para priorizar o portfólio de projetos de uma empresa de construção civil. A pesquisa sugere que o modelo MID é mais amplo (avalia qualquer tipo de projeto), mais simples (estrutura mais enxuta) e mais diversificado (calcula a complexidade relativa e total) que o TOE Framework para priorização de portfólios na área de engenharia civil

RNA Sequencing and Pathway Analysis Identify Important Pathways Involved in Hypertrichosis and Intellectual Disability in Patients with Wiedemann–Steiner Syndrome

International audienceA growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann-Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease