Showing papers by "Noam Shomron published in 2018"

Circulating MicroRNAs: a Potential Biomarker for Cardiac Damage, Inflammatory Response, and Left Ventricular Function Recovery in Pediatric Viral Myocarditis

Abstract: Viral myocarditis (VM) can be a life-threatening event resulting in cardiac failure, chronic cardiomyopathy, and death. VM typically includes three phases, i.e., acute, subacute, and resolution/chronic. We prospectively investigated cardiac- and inflammatory-associated plasma-circulating miRNA levels in eight pediatric patients with VM during the three stages of the disease. The level of cardiac-associated miR-208a was significantly elevated during the acute phase compared with the subacute and resolution/chronic phases. The level of cardiac- and inflammatory-associated miR-21 was significantly elevated during the acute phase compared to the resolution/chronic phase. Moreover, cardiac-associated miR-208b levels during the subacute phase correlated with systolic left ventricular function recovery as measured during the resolution/chronic phase. The findings of our study demonstrate an association between cardiac damage and the inflammatory response and the expression of miR-208a and miR-21 during the pathological progression of myocarditis. We also found that miR-208b levels exhibit a prognostic significance for left ventricular functional recovery.

Comparison of breast cancer metastasis models reveals a possible mechanism of tumor aggressiveness.

Abstract: In breast cancer patients, the lungs are among the first sites of cancer metastasis, and in nearly one quarter of metastatic patients, the exclusive first event. Two common mouse models mimic breast cancer lung colonization and distal metastasis: an orthotopic model and intravenous (IV) cell injections. Gene expression analysis of pulmonary lesions from these two methods demonstrated high inter-model resemblance. However, microRNA (miRNA) expression profiles were not compared. In this study, we compared the overall miRNA expression profiles (miRNome) of the orthotopic and IV breast cancer metastasis models and identified significant miRNome changes between the two models. Overexpression of the most significant candidate, miR-96 or downregulation of its validated gene-target, ABCE1 reduced cancer cells 2D/3D cell movement and proliferation in vitro, and abated tumor growth and metastasis formation in vivo. Human data analysis further strengthened miR-96/ABCE1 role in breast cancer tumor aggression. Taken together, our results indicate that IV- and orthotopic models differ by their miRNome. Specifically in our study, breast cancer aggressiveness was dictated by miR-96 regulating ABCE1. Overall, miRNome analysis of various metastatic cancer models may lead to the identification of candidate genes critical to metastasis development.

Seasonal Genetic Drift of Human Influenza A Virus Quasispecies Revealed by Deep Sequencing.

Abstract: After a pandemic wave in 2009 following their introduction in the human population, the H1N1pdm09 viruses replaced the previously circulating, pre-pandemic H1N1 virus and, along with H3N2 viruses, are now responsible for the seasonal influenza type A epidemics. So far, the evolutionary potential of influenza viruses has been mainly documented by consensus sequencing data. However, like other RNA viruses, influenza A viruses exist as a population of diverse, albeit related, viruses, or quasispecies. Interest in this quasispecies nature has increased with the development of next generation sequencing (NGS) technologies that allow a more in-depth study of the genetic variability. NGS deep sequencing methodologies were applied to determine the whole genome genetic heterogeneity of the three categories of influenza A viruses that circulated in humans between 2007 and 2012 in France, directly from clinical respiratory specimens. Mutation frequencies and single nucleotide polymorphisms were used for comparisons to address the level of natural intrinsic heterogeneity of influenza A viruses. Clear differences in single nucleotide polymorphism profiles between seasons for a given subtype also revealed the constant genetic drift that human influenza A virus quasispecies undergo.

Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates

Abstract: Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

Abstract: Objective To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

Analysis of microRNAs in familial Mediterranean fever

Abstract: Objectives Although Familial Mediterranean fever (FMF) is categorized as autosomal recessive, frequent exceptions to this model exist and therefore we aimed to search epigenetic modifications in this disease. Methods Ten M694V homozygous FMF patients (the most severe phenotype) were recruited for this study. Patients with inflammatory flare were excluded. Total RNA was extracted from peripheral blood, and microRNA expression profiled using NanoString nCounter technology. These patients were compared to 10 healthy age- and sex-matched controls. Results Seven hundred nighty-eight mature human miRNAs were probed, 103 of which had expression levels above the negative control probes. Seven miRNAs showed significant differences in expression in samples from FMF patients compared to healthy controls: four miRNAs were upregulated (miR-144-3p, miR-21-5p, miR-4454, and miR-451a), and three were downregulated (miR-107, let-7d-5p, and miR-148b-3p). Conclusion In this pilot study, we identified epigenetic modifications in clinically quiescent FMF patients. More studies are required for exploration of their contribution to FMF pathogenesis and their potential role as clinical biomarkers.

SMYD1 is the underlying gene for the AnWj-negative blood group phenotype.

Abstract: BACKGROUND AnWj is a high-incidence blood group antigen associated with three clinical disorders: lymphoid malignancies, immunologic disorders, and autoimmune hemolytic anemia. The aim of this study was to determine the genetic basis of an inherited AnWj-negative phenotype. METHODS We identified a consanguineous family with two AnWj-negative siblings and 4 additional AnWj-negative individuals without known familial relationship to the index family. We performed exome sequencing in search for rare homozygous variants shared by the two AnWj-negative siblings of the index family and searched for these variants in the four non-related AnWj-negative individuals. RESULTS Exome sequencing revealed seven candidate genes that showed complete segregation in the index family and for which the two AnWj-negative siblings were homozygous. However, the four additional non-related AnWj-negative subjects were homozygous for only one of these variants, rs114851602 (R320Q) in the SMYD1 gene. Considering the frequency of the minor allele, the chance of randomly finding 4 consecutive such individuals is 2.56 × 10-18 . CONCLUSION We present genetic and statistical evidence that the R320Q substitution in SMYD1 underlies an inherited form of the AnWj-negative blood group phenotype. The mechanism by which the mutation leads to this phenotype remains to be determined.

Punctate palmoplantar keratoderma: an unusual mutation causing an unusual phenotype

Abstract: Palmoplantar keratodermas (PPKs, OMIM #144200) refers to a large phenotypically and genetically heterogeneous group of keratinization disorders characterized by marked hyperkeratosis on the surface of palms and soles. Punctate PPK (PPKP) features multiple hyperkeratotic papules that develop in early adolescence or later and are irregularly distributed on the palms and soles. The disease is clinically classified into three autosomal dominant subtypes: PPKP1 (OMIM #148600, 614936) characterized by multiple tiny punctate keratoses and caused by mutations in the AAGAB or COL14A1 genes; PPKP2 (OMIM #175860) which features tiny hyperkeratotic spinous papules and PPKP3 or acrokeratoelastoidosis (AKE, OMIM # 101850) which manifests with small hyperkeratotic papules located over the peripheral margins of the palms and soles and is typically associated with degeneration of elastic fibers on histology. The molecular etiology of PPKP2 and AKE remains unknown. This article is protected by copyright. All rights reserved.

The ABC of reporting statistical analyses in the BJD: Always Be Clear

Abstract: The BJD editorial team now includes five associate editors who review the methodological reporting of articles submitted to the BJD; it is of utmost importance that methods and results are described in sufficient detail by authors. The BJD author guidelines, editorials on reporting and reporting guidelines all contribute to achieving this goal. Here we would like to highlight a few general and study-specific issues.

Abstract 5397: ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal cancer

Abstract: There is urgent need for prognostic markers to stratify intermediate-stage colorectal cancer (CRC) patients for the benefit of adjuvant therapy. Tumor heterogeneity is a major obstacle in stratification attempts as rare cancer cell populations may display stem cell properties and allow generation of therapy resistance. Tumor stroma, on the other hand, is less susceptible to genetic alterations than cancer cells, providing signals that are more reproducible across patient samples. Exosome encapsulated microRNAs (exomiRs) are particularly amenable to biomarker development because they circulate, closely resemble the tissue of origin and are inherently stable. We sought to identify a stromal exomiR signature in colorectal cancer with biomarker potential. Paired primary tumor-associated and normal fibroblasts were extracted from human colonic tissue. Exosomes were isolated by differential ultracentrifugation, validated according to International Society for Extracellular Vesicles recommendations, and profiled for over 800 microRNAs (miRNAs) by NanoString. Data preprocessing and normalization was conducted prior to differential expression analysis. Candidate miRNAs were validated by qPCR. Pathway and network analyses were conducted using miRPath and Ingenuity Pathway Analysis. Forty one exomiRs were differentially present in tumor-associated and normal fibroblasts. Of these, 21 were more abundant in tumor-associated fibroblasts. Thirty-six KEGG pathways were found to be regulated by this exomiR signature, such as “PI3K-Akt” and “colorectal cancer.” A potential target of these exomiRs is PHLPP2, which encodes a phosphatase acting on AKT. In keeping with this, exposure to fibroblast exosomes increased AKT phosphorylation and that of its direct target Bad, in CRC cells, potentially due to a decrease in PHLPP2 protein abundance. Consequently, these cells were protected from drug-induced apoptosis. For the first time, stromal exomiRs have been profiled in colorectal cancer. Tumor-associated and normal stroma can be distinguished by a specific exomiR signature, which is potentially functionally important. Further mechanistic characterization is now required to identify the clinical significance of stromal exomiRs. Citation Format: Rahul Bhome, Rebecca Goh, Nir Pillar, Noam Shomron, Emre Sayan, Alex Mirnezami. ExomiRs can distinguish tumor-associated from normal stroma: Potential biomarkers in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5397.

Augmented-Genomics: Protecting Privacy for Clinical Genomics with Inferential Interfaces

Abstract: Recent advances in genetic technology enable large-scale genome sequencing, creating new avenues for research and clinical care. At the same time, these advances raise growing concerns about data protection and privacy. In this demonstration, we present Augmented-Genomics, a system that puts the individuals in control over their genetic information. To envision user-controllable privacy in the hospital, and in other complex clinical situations, we demonstrate several techniques accessible through a mobile application. The system infers the risk of exposing certain parts of the genome and provide a simple interface for users to set their desired level of exposure. Patients and caregivers (such as doctors) exchange visual keys that are used to decrypt genomic data while indirectly fostering discussion and negotiation over the patient's privacy. After the patient provides the permission, the caregiver can access information about essential genes and mutations through a mobile interface or through an augmented reality glasses.