CAFET Algorithm Reveals Wnt/PCP Signature in Lung Squamous Cell Carcinoma

We analyzed the gene expression patterns of 138 Non-Small Cell Lung Cancer (NSCLC) samples and developed a new algorithm called Coverage Analysis with Fisher’s Exact Test (CAFET) to identify molecular pathways that are differentially activated in squamous cell carcinoma (SCC) and adenocarcinoma (AC) subtypes. Analysis of the lung cancer samples demonstrated hierarchical clustering according to the histological subtype and revealed a strong enrichment for the Wnt signaling pathway components in the cluster consisting predominantly of SCC samples. The specific gene expression pattern observed correlated with enhanced activation of the Wnt Planar Cell Polarity (PCP) pathway and inhibition of the canonical Wnt signaling branch. Further real time RT-PCR follow-up with additional primary tumor samples and lung cancer cell lines confirmed enrichment of Wnt/PCP pathway associated genes in the SCC subtype. Dysregulation of the canonical Wnt pathway, characterized by increased levels of β-catenin and epigenetic silencing of negative regulators, has been reported in adenocarcinoma of the lung. Our results suggest that SCC and AC utilize different branches of the Wnt pathway during oncogenesis

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Zumbido e intolerância a sons : evidência e experiência de um grupo brasileiro

Introdução Zumbido e intolerância a sons são queixas frequentes e subjetivas que podem ter impacto na qualidade de vida do paciente. Objetivo Apresentar uma revisão dos principais pontos, inclusive conceitos, fisiopatologia, diagnóstico e abordagem do paciente com zumbido e sensibilidade a sons. Método Revisão da literatura com levantamento bibliográfico na base de dados da LILACS, SciELO, Pubmed e MEDLINE. Foram selecionados artigos e capítulos de livros sobre zumbido e sensibilidade a sons. Os diversos tópicos foram discutidos por um grupo de profissionais brasileiros e as conclusões, descritas. Resultado A prevalência de zumbido tem aumentado ao longo dos anos, muitas vezes associado a perda auditiva, fatores metabólicos e erros alimentares. A avaliação médica deve ser feita minuciosamente no sentido de orientar a solicitação de exames subsidiários. Os tratamentos disponíveis atualmente variam de medicamentos ao uso de sons com características específicas e técnicas de meditação, com resultados variáveis. Conclusão Foi apresentada uma revisão sobre os temas que permitindo ao leitor uma visão ampla da abordagem dos pacientes com zumbido e sensibilidade auditiva baseada em evidências científicas e experiência nacional.Introduction Tinnitus and sound intolerance are frequent and subjective complaints that may have an impact on a patient's quality of life. Objective To present a review of the salient points including concepts, pathophysiology, diagnosis and approach of the patient with tinnitus and sensitivity to sounds. Methods Literature review with bibliographic survey in LILACS, SciELO, Pubmed and MEDLINE database. Articles and book chapters on tinnitus and sound sensitivity were selected. The several topics were discussed by a group of Brazilian professionals and the conclusions were described. Results The prevalence of tinnitus has increased over the years, often associated with hearing loss, metabolic factors and inadequate diet. Medical evaluation should be performed carefully to guide the request of subsidiary exams. Currently available treatments range from medications to the use of sounds with specific characteristics and meditation techniques, with variable results. Conclusion A review on tinnitus and auditory sensitivity was presented, allowing the reader a broad view of the approach to these patients, based on scientific evidence and national experience

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Peer reviewe

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Omvårdnad av personer med diabetes i hemsjukvård

Syftet med denna studie var att undersöka hur sjuksköterskor upplever omvårdnaden och den assisterade egenvården av personer med diabetes inskrivna inom hemsjukvården. I studien har elva sjuksköterskor anställda inom kommunal och privat hemsjukvård intervjuats. En kvalitativ innehållsanalys har använts för att analysera intervjutexterna. Analysen har resulterat i två teman och sex kategorier. Temat: ''Sjuksköterskans känsla av otillräcklighet'' bestod av tre kategorier;''Att uppleva brist på kunskap/utbildning'', ''att uppleva brist på stöd'',''att uppleva brist på riktlinjer och rutiner''. Temat: ''Sjuksköterskans upplevelse av känsla av otrygghet hos personer med diabetes''; ''Att sakna kontinuerlig vårdkontakt'', att sakna kunskap om sjukdomen'','' att behöva assisterad egenvård''. Resultatet visade att de intervjuade sjuksköterskorna upplevde diabetes som en komplex sjukdom med stort omvårdnadsbehov. De uppgav att de behövde mer kunskaper om sjukdomen, de kände sig otillräckliga. Vidare upplevde de intervjuade sjuksköterskorna att personerna med diabetes inte kände sig trygga, de saknade den kontinuerliga kontakten med diabetessjuksköterska som de tidigare haft när hemsjukvården sköttes av landstingen