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

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

Particularities and Universalities of the Emergence of Inductive Generalization

21 páginaInductive generalization is the primary way by which human beings arrive at the construction of knowledge. Usually, it is assumed that it operates in a linear manner—each new feature becomes “piled up” in the inductive accumulation of evidence. We question this view, and otherwise claim that inductive generalization is essentially a non-linear dynamic process that fits the theoretical premises of the Dynamic Systems Theory. In our study, we explore the ability that young infants have when making inductive generalizations -previous studies show the existence of this capacity not earlier than at the age of 14 months. These studies have been cross-sectional in nature, but they do not offer an answer to the question of emergence of cognitive capabilities, therefore, a short-term longitudinal study is needed. Based on 3 case studies carried out longitudinally in infants ranging from 9 to 14 months, we demonstrate how the process of inductive generalization occurs from a conceptualization of nonlinear dynamic systems. We use Min – Max and State Space techniques, which allow us to show how the infant uses diverse pathways of actions with everyday objects to facilitate inductive generalization. The identified paths are not the same, they present differential and common moments that confirm the dynamic nature of development, and provide empirical evidence on the emergence of non-linear, non-sequential or inductive generalization