Paralog Studies Augment Gene Discovery: DDX and DHX Genes

PubMedID: 31256877Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders. © 2019 American Society of Human GeneticsNational Heart, Lung, and Blood Institute Aicardi Syndrome Foundation: 2T32NS043124-16 National Institute on Drug Abuse National Institute of Diabetes and Digestive and Kidney Diseases: K12 DK083014 National Heart, Lung, and Blood Institute Fondazione Telethon National Institute of Neurological Disorders and Stroke: U54-HG003273 GSP15001 Deutsche Forschungsgemeinschaft California Department of Fish and Game: LE 4223/1 National Human Genome Research Institute National Institutes of Health: K08 HG008986, DK088767 National Cancer Institute R01 NS058529, R35 NS105078 National Institute of Mental Health National Institute of Neurological Disorders and StrokeThis work was supported in part by grants UM1 HG006542 (J.R.L) and UM1 HG006493 (M.B.) from the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) to the Baylor Hopkins Center for Mendelian Genomics and the University of Washington Center for Mendelian Genomics, R01 NS058529 and R35 NS105078 (J.R.L.) from the National Institute of Neurological Disorders and Stroke (NINDS), U54-HG003273 (R.A.G.) from NHGRI , and Telethon Undiagnosed Diseases Program (TUDP) GSP15001 (N.B.-P.) from the Telethon Foundation , and also by the Aicardi Syndrome Foundation. I.P. was supported by 2T32NS043124-16 through the National Institutes of Health . J.E.P. was supported by NHGRI K08 HG008986 . F.H. was supported by the National Institutes of Health ( DK088767 ). M.R.B. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K12 DK083014 . D.L was supported by the Werner Otto Stiftung and the German Research Foundation ( DFG; LE 4223/1 ). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , and by the National Cancer Institute , NHGRI , NHLBI , the National Institute on Drug Abuse , the National Institute of Mental Health , and NINDS . The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/29/18. The authors would like to thank Hans-Jurgen Kreienkamp for the help in identifying helicase core motifs and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about

Nuclear factor-κB predicts outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy.

NF-κB expression has been shown to be responsible for resistance to antineoplastic agents.The aim of our study was to investigate the importance of NF-κB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.We retrospectively analysed the immunoreactivity for NF-κB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006.Seventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-κB was performed both in biopsies and in primary tumour samples. NF-κB was considered positive when at least 1\% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-κB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed. Moreover, median time to progression was significantly shorter in the NF-κB-positive subgroup of patients.Globally, our findings seem to suggest that NF-κB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-κB system in their mechanism of action in NF-κB-positive patients

Nuclear factor-κB predicts outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy.

NF-κB expression has been shown to be responsible for resistance to antineoplastic agents.The aim of our study was to investigate the importance of NF-κB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.We retrospectively analysed the immunoreactivity for NF-κB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006.Seventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-κB was performed both in biopsies and in primary tumour samples. NF-κB was considered positive when at least 1\% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-κB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed. Moreover, median time to progression was significantly shorter in the NF-κB-positive subgroup of patients.Globally, our findings seem to suggest that NF-κB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-κB system in their mechanism of action in NF-κB-positive patients

Antibiotic use in low and middle-income countries and the challenges of antimicrobial resistance in surgery

Antimicrobial resistance (AMR) is a phenomenon resulting from the natural evolution of microbes. Nonetheless, human activities accelerate the pace at which microorganisms develop and spread resistance. AMR is a complex and multidimensional problem, threatening not only human and animal health, but also regional, national, and global security, and the economy. Inappropriate use of antibiotics, and poor infection prevention and control strategies are contributing to the emergence and dissemination of AMR. All healthcare providers play an important role in preventing the occurrence and spread of AMR. The organization of healthcare systems, availability of diagnostic testing and appropriate antibiotics, infection prevention and control practices, along with prescribing practices (such as over-the-counter availability of antibiotics) differs markedly between high-income countries and low and middle-income countries (LMICs). These differences may affect the implementation of antibiotic prescribing practices in these settings. The strategy to reduce the global burden of AMR includes, among other aspects, an in-depth modification of the use of existing and future antibiotics in all aspects of medical practice. The Global Alliance for Infections in Surgery has instituted an interdisciplinary working group including healthcare professionals from different countries with different backgrounds to assess the need for implementing education and increasing awareness about correct antibiotic prescribing practices across the surgical pathways. This article discusses aspects specific to LMICs, where pre-existing factors make surgeons’ compliance with best practices even more important

Perioperative anemia and blood transfusions as prognostic factors in patients undergoing resection for non-small cell lung cancers

We hypothesised that anemia could represent an important prognostic factor and perioperative blood transfusions do not reduce the risk of relapse. In order to explore this topic, we assessed the correlation of preoperative anemia and blood transfusions with survival in patients with resected non-small cell lung cancer (NSCLC). Patients who underwent radical surgery for NSCLC at the Department of Thoracic Surgery of University Politecnica delle Marche from January 1996 through December 2001, were included in our study. Four hundred and thirty-nine patients were eligible for our analysis. Survival appeared worse in patients with haemoglobin (Hb) 10g/dl (p=0.012). Stratifying patients in three groups on their Hb level (group 1: Hb = 12g/dl), we observed a worse prognosis in patients with lower Hb levels, too (p=0.0325) and also in the transfused population (p=0.046). At multivariate analysis, only the age of patients, pathological stage and Hb levels resulted indicators of prognosis. Our results suggested that anemia could represent an important prognostic factor in resected NSCLC and correction of anemia in the perioperative setting does not reduce the risk of relapse. (c) 2005 Elsevier Ireland Ltd. All rights reserved