Inhibition of CXCR2 Plays a Pivotal Role in Re-Sensitizing Ovarian Cancer to Cisplatin Treatment

cDNA microarray data conducted by our group revealed overexpression of CXCL2 and CXCL8 in ovarian cancer (OC) microenvironment. Herein, we have proven that the chemokine receptor, CXCR2, is a pivotal molecule in re-sensitizing OC to cisplatin, and its inhibition decreases cell proliferation, viability, tumor size in cisplatinresistant cells, as well as reversed the overexpression of mesenchymal epithelium transition markers. Altogether, our study indicates a central effect of CXCR2 in preventing tumor progression, due to acquisition of cisplatin chemoresistant phenotype by tumor cells, and patients’ high lethality rate. We found that the overexpression of CXCR2 by OC cells is persistent and anomalously confined to the cellular nuclei, thus pointing to an urge in developing highly lipophilic molecules that promptly permeate cells, bind to and inhibit nuclear CXCR2 to fight OC, instead of relying on the high-cost genetic engineered cells.acknowledge financial support from CAPES, FAPES and CNPq, as well as the Biotechnology Program/ RENORBIO from the Federal University of Espirito Santo, Espirito Santo, Brazil; Institute of Pathology and Molecular Immunology (IPATIMUP) and the Institute of Innovation and Health Research (I3s), Porto, Portugal

Transcultural adaptation and validation of the Conditions of Work Effectiveness - Questionnaire-II instrument

OBJECTIVE: This study aims at translating and validating the content of the instrument Conditions of Work Effectiveness - Questionnaire-II (CWEQ-II), developed by Laschinger, Finegan, Shamian and Wilk, modified from the original CWEQ for the Brazilian culture. METHOD: the methodological procedure consisted of the stages of translation of the instrument into the Portuguese language; back-translation; semantic, idiomatic and cultural equivalence and tests of the final version. The instrument in the Portuguese version was applied to a group of 40 nurses in two hospitals. RESULTS: the data resulted in a Cronbach's Alpha of 0.86 for the first hospital and 0.88 for the second one. The results of the factorial analysis are considered sufficiently satisfactory. CONCLUSION: It is to conclude that the instrument can be used in Brazil

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Accuracy versus precision in boosted top tagging with the ATLAS detector

Abstract The identification of top quark decays where the top quark has a large momentum transverse to the beam axis, known as top tagging, is a crucial component in many measurements of Standard Model processes and searches for beyond the Standard Model physics at the Large Hadron Collider. Machine learning techniques have improved the performance of top tagging algorithms, but the size of the systematic uncertainties for all proposed algorithms has not been systematically studied. This paper presents the performance of several machine learning based top tagging algorithms on a dataset constructed from simulated proton-proton collision events measured with the ATLAS detector at √ s = 13 TeV. The systematic uncertainties associated with these algorithms are estimated through an approximate procedure that is not meant to be used in a physics analysis, but is appropriate for the level of precision required for this study. The most performant algorithms are found to have the largest uncertainties, motivating the development of methods to reduce these uncertainties without compromising performance. To enable such efforts in the wider scientific community, the datasets used in this paper are made publicly available.</jats:p

Sociodemographic and Clinical Characteristics of Psychiatric Re-hospitalizations

Segregated individuals with mental disorders, families without support or guidance concerning disease and treatment, and unprepared professionals are some of the factors that can contribute to re-hospitalizations. This study identifies sociodemographic variables, clinical conditions, diagnoses and treatments in order to identify their relationship with psychiatric re-hospitalizations. This is an exploratory and descriptive study. A form was used to search data in patients&#39; files from 2006 and 2007 in a regional psychiatric facility. A total of 681 re-hospitalizations were identified, the majority due to treatment abandonment. Length of hospitalization was higher for women between 40 and 49 years of age. Positive associations of sociodemographic data with previous hospitalizations were found, such as type of discharge, and physical and mental condition, which is in accordance with the literature. Readmissions are associated with sociodemographic and clinical indicators. These findings can guide care and public policies regarding mental health.Algunos de los factores que pueden contribuir para las reinternaciones psiquiátricas son los trastornos mentales que ocurren en familias sin apoyo u orientación acerca de la enfermedad y tratamientos y, por causa de profesionales mal preparados. El objetivo de este estudio fue identificar las variables sociodemográficos, las condiciones clínicas, los diagnósticos médicos, los tratamientos y su relación con las reinternaciones psiquiátricas. Se trata de un estudio exploratorio y descriptivo, en el cual se utilizó un guía para recolectar datos en los registros médicos de 2006 y 2007, en un hospital psiquiátrico regional. Fueron identificadas 681 reinternaciones, la mayoría por abandono de tratamiento. El tiempo de permanencia en la internación fue mayor para la mujeres que tenían de 40 a 49 años. Se encontró asociaciones positivas de los datos sociodemográficos con internaciones anteriores, tipo de alta, estado físico y mental, los cuales están de acuerdo con otros datos de la literatura. Se concluye que las reinternaciones están asociadas con indicadores sociodemográficos y clínicos; conocimiento que puede ser utilizado en las políticas públicas en salud mental sobre el cuidado.Portadores de transtorno mental discriminados, famílias sem apoio e orientação sobre a doença e tratamentos e profissionais despreparados são alguns dos fatores que podem contribuir para as reinternações. O objetivo deste estudo foi identificar as variáveis sociodemográficas, as condições clínicas, o diagnóstico médico e tratamento, buscando sua relação com as reinternações psiquiátricas. A metodologia usada aqui foi exploratório-descritiva. Utilizou-se roteiro para levantamento dos dados nos prontuários, de 2006 e 2007, num hospital psiquiátrico regional. Foram encontradas 681 reinternações, a maioria por abandono de tratamento. O tempo de permanência na internação é maior nas mulheres de 40 a 49 anos. Este estudo mostrou, também, associações positivas dos dados sociodemográficos com internações anteriores, tipo de alta, estado físico e mental, os quais estão de acordo com outros dados da literatura. Conclui-se que há associações das reinternações com indicadores sociodemográficos e clínicos que podem direcionar o cuidado e políticas públicas na saúde mental

Integration of functional assay data results provides strong evidence for classification of hundreds of <i>BRCA1</i> variants of uncertain significance

PURPOSE: BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. METHODS: We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. RESULTS: Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. CONCLUSION: High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity

Identificação dos distúrbios da linguagem na escola

OBJETIVO: verificar se os educadores infantis são capazes de identificar as crianças com alteração no desenvolvimento de linguagem. MÉTODOS: tratou-se de um estudo observacional transversal comparativo realizado em escolas carentes de educação infantil. A amostra do estudo foi composta por 14 educadores e 91 alunos regularmente matriculados nas instituições de ensino selecionadas, nas faixas etárias de dois a quatro anos e 11 meses. Os educadores responderam um questionário sobre o desenvolvimento das crianças e aplicou-se a avaliação fonoaudiológica em todas elas. Realizou-se análise da concordância entre a avaliação fonoaudiológica e a do educador por meio do coeficiente Kappa e cálculos de sensibilidade e especificidade, considerando a avaliação fonoaudiológica como referência. RESULTADOS: segundo avaliação fonoaudiológica, o desenvolvimento da linguagem das crianças estava comprometido da seguinte forma: 22% possuíam alteração na recepção, 34,1% na emissão, 35,2% nos aspectos cognitivos e 6,6% nos aspectos motores. Identificou-se baixa concordância entre a avaliação fonoaudiológica e do educador. A avaliação do educador teve sensibilidade que variou entre 0,3 e 0,4 e especificidade que variou entre 0,6 e 0,9. CONCLUSÃO: os educadores apresentaram dificuldades em identificar as crianças com riscos para alterações de linguagem