PurposeAutosomal recessive non-syndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity with reported mutations in 58 different genes. This study was designed to detect deafness causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%) and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.
During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the cell's UPR-mediated response to misfolded proteins. Here, we
Heterocyclic amines (HCAs) are primarily produced during high temperature meat cooking. These compounds have been intensively investigated as mutagens and carcinogens. However, converging data suggest that HCAs may also be neurotoxic and potentially relevant to neurodegenerative diseases such as Parkinson's disease (PD). The identification of new potential etiological factors is important because most PD cases are sporadic. Our group previously showed that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was selectively neurotoxic to dopaminergic neurons. However, PhIP is one of many HCAs, a class of compounds that exhibits wide structural variability. The goal of this study was to determine the neurotoxicity of the most prevalent and best studied HCAs from three subclasses: aminoimidazoaazarenes (AIA), α-carbolines, and β-carbolines. Using E17 rat primary midbrain cultures, we tested dopaminergic and non-dopaminergic neurotoxicity elicited by the following compounds: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), PhIP, 1-methyl-9H-pyrido[3,4-b]indole (harmane), 9H-pyrido[3,4-b]indole (norharmane) and 2-amino-9H-pyrido[2,3-b]indole (AαC) at concentrations ranging from 100 nM-5 μM. All tested HCAs were selectively neurotoxic, though the dose required to elicit selective loss of dopaminergic neurons or decreases in dopaminergic neurite length was compound specific. Non-dopaminergic neurons were unaffected at all tested doses. The sensitivity (determined by threshold dose required to elicit selective neurotoxicity) appears to be unrelated to published mutagenic potency. Both AIA and α/β-carbolines produced oxidative damage, which was magnified in dopaminergic neurons vs. non-dopaminergic neurons as further evidence of selective neurotoxicity. These studies are expected to prompt clinical and mechanistic studies on the potential role of HCA exposure in PD.
COVID-19 pandemic is the more challenging public health emergency of the century, producing the collapse of health systems and unprecedented levels of morbidity and mortality around the world, especially in low resource settings. Patients with chronic diseases are the most affected, not only due to the high susceptibility to SARS-CoV-2 infection but also due to the decrease in opportunities for timely care. In this dark landscape, telemedicine, before limited to very specific scenarios, has become one of our main tools to manage cancer patients, particularly in Latin America where COVID-19 has had a strong impact on the public health. Telemedicine can provide rapid access to specialized cancer care in a scenario complicated, reducing the exposure of patients and healthcare personnel to the SARS-CoV-2. In this review, we would like to share our experience and our workflow using telemedicine at Oncosalud-AUNA, a private clinic in Peru.
PURPOSE Helicobacter pylori (HP) and Epstein Barr virus (EBV) infections induce chronic gastritis (CG) and are accepted carcinogenics of gastric cancer (GC). Our objective for this study was to determine the prevalence of these agents and clinicopathological features of GC and CG associated with the infection. PATIENTS AND METHODS A single-center cohort of 375 Peruvian patients with GC and 165 control subjects with CG were analyzed. Evaluation of HP and EBV genes was performed through quantitative polymerase chain reaction. RESULTS Prevalence of HP was 62.9% in the whole population and 60.8% in the GC subset. The cagA gene was detected in 79.9%; vacAs1 and vacAm1 alleles in 41.6% and 60.7%, respectively; and concurrent expression of vacAs1 and vacAm1 in 30.4% of infected patients in the whole series. The prevalence of EBV was 14.1% in the whole population and was higher in GC ( P < .001). Coinfection of HP and EBV was found in 7.8% and was also higher in GC in univariate ( P < .001) and multivariate ( P = .011) analyses. Infection rates of HP and EBV were not associated with a geographic location in the whole series. Few clinicopathological features have been associated with infectious status. CONCLUSION Prevalence of HP infection and virulent strains are high in the Peruvian population. Infection by EBV was more frequent in patients with GC.
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