Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-27 (of 27 Records) |
Query Trace: Dominique Y[original query] |
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Prevention of zoonotic spillover: From relying on response to reducing the risk at source
Wanda M , Thomas CM , Wiku BA , Salama A , Casey BB , Pépé B , Salome AB , Natalia C , Natalia CB , Dominique FC , Abhishek C , Janice RCZ , Andrew AC , Osman D , Nitish D , Baptiste D , Elmoubasher F , George FG , David TSH , Margaret K , Marion PGK , Catherine M , John SM , Serge M , Vyacheslav S , Zhou L , Giraudoux P . PLoS Pathog 2023 19 (10) e1011504 |
Global phylogeography and evolutionary history of Shigella dysenteriae type 1.
Njamkepo E , Fawal N , Tran-Dien A , Hawkey J , Strockbine N , Jenkins C , Talukder KA , Bercion R , Kuleshov K , Kolínská R , Russell JE , Kaftyreva L , Accou-Demartin M , Karas A , Vandenberg O , Mather AE , Mason CJ , Page AJ , Ramamurthy T , Bizet C , Gamian A , Carle I , Sow AG , Bouchier C , Wester AL , Lejay-Collin M , Fonkoua MC , Le Hello S , Blaser MJ , Jernberg C , Ruckly C , Mérens A , Page AL , Aslett M , Roggentin P , Fruth A , Denamur E , Venkatesan M , Bercovier H , Bodhidatta L , Chiou CS , Clermont D , Colonna B , Egorova S , Pazhani GP , Ezernitchi AV , Guigon G , Harris SR , Izumiya H , Korzeniowska-Kowal A , Lutyńska A , Gouali M , Grimont F , Langendorf C , Marejková M , Peterson LA , Perez-Perez G , Ngandjio A , Podkolzin A , Souche E , Makarova M , Shipulin GA , Ye C , Žemličková H , Herpay M , Grimont PA , Parkhill J , Sansonetti P , Holt KE , Brisse S , Thomson NR , Weill FX . Nat Microbiol 2016 1 16027 Together with plague, smallpox and typhus, epidemics of dysentery have been a major scourge of human populations for centuries(1). A previous genomic study concluded that Shigella dysenteriae type 1 (Sd1), the epidemic dysentery bacillus, emerged and spread worldwide after the First World War, with no clear pattern of transmission(2). This is not consistent with the massive cyclic dysentery epidemics reported in Europe during the eighteenth and nineteenth centuries(1,3,4) and the first isolation of Sd1 in Japan in 1897(5). Here, we report a whole-genome analysis of 331 Sd1 isolates from around the world, collected between 1915 and 2011, providing us with unprecedented insight into the historical spread of this pathogen. We show here that Sd1 has existed since at least the eighteenth century and that it swept the globe at the end of the nineteenth century, diversifying into distinct lineages associated with the First World War, Second World War and various conflicts or natural disasters across Africa, Asia and Central America. We also provide a unique historical perspective on the evolution of antibiotic resistance over a 100-year period, beginning decades before the antibiotic era, and identify a prevalent multiple antibiotic-resistant lineage in South Asia that was transmitted in several waves to Africa, where it caused severe outbreaks of disease. |
Health Care-Associated Infections Studies Project: An American Journal of Infection Control and National Healthcare Safety Network Data Quality Collaboration.
Watkins J , Gross C , Godfrey-Johnson D , Allen-Bridson K , Hebden JN , Wright MO . Am J Infect Control 2021 49 (8) 1075-1077 This case study is part of a series centered on the Centers for Disease Control and Prevention/National Healthcare Safety Network (NHSN) healthcare-associated infection (HAI) surveillance definitions. This specific case study focuses on the application of the Pneumonia (PNEU), Ventilator-associated event (VAE), and Bloodstream infections (BSI) surveillance definitions to a patient with COVID-19. The intent of the case study series is to foster standardized application of the NHSN HAI surveillance definitions among Infection Preventionists (IPs) and encourage accurate determination of HAI events. |
Molecular diagnostic assays for the detection of common bacterial meningitis pathogens: A narrative review.
Diallo K , Feteh VF , Ibe L , Antonio M , Caugant DA , du Plessis M , Deghmane AE , Feavers IM , Fernandez K , Fox LM , Rodrigues CMC , Ronveaux O , Taha MK , Wang X , Brueggemann AB , Maiden MCJ , Harrison OB . EBioMedicine 2021 65 103274 Bacterial meningitis is a major global cause of morbidity and mortality. Rapid identification of the aetiological agent of meningitis is essential for clinical and public health management and disease prevention given the wide range of pathogens that cause the clinical syndrome and the availability of vaccines that protect against some, but not all, of these. Since microbiological culture is complex, slow, and often impacted by prior antimicrobial treatment of the patient, molecular diagnostic assays have been developed for bacterial detection. Distinguishing between meningitis caused by Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and Streptococcus agalactiae and identifying their polysaccharide capsules is especially important. Here, we review methods used in the identification of these bacteria, providing an up-to-date account of available assays, allowing clinicians and diagnostic laboratories to make informed decisions about which assays to use. |
The Global Meningitis Genome Partnership.
Rodgers E , Bentley SD , Borrow R , Bratcher HB , Brisse S , Brueggemann AB , Caugant DA , Findlow J , Fox L , Glennie L , Harrison LH , Harrison OB , Heyderman RS , van Rensburg MJ , Jolley KA , Kwambana-Adams B , Ladhani S , LaForce M , Levin M , Lucidarme J , MacAlasdair N , Maclennan J , Maiden MCJ , Maynard-Smith L , Muzzi A , Oster P , Rodrigues CMC , Serino ORL , Smith V , van der Ende A , Vazquez J , Wang X , Yezli S , Stuart JM . J Infect 2020 81 (4) 510-520 Genomic surveillance of bacterial meningitis pathogens is essential for effective disease control globally, enabling identification of emerging and expanding strains and consequent public health interventions. While there has been a rise in the use of whole genome sequencing, this has been driven predominately by a subset of countries with adequate capacity and resources. Global capacity to participate in surveillance needs to be expanded, particularly in low and middle-income countries with high disease burdens. In light of this, the WHO-led collaboration, Defeating Meningitis by 2030 Global Roadmap, has called for the establishment of a Global Meningitis Genome Partnership that links resources for: N. meningitidis (Nm), S. pneumoniae (Sp), H. influenzae (Hi) and S. agalactiae (Sa) to improve worldwide co-ordination of strain identification and tracking. Existing platforms containing relevant genomes include: PubMLST: Nm (31,622), Sp (15,132), Hi (1,935), Sa (9,026); The Wellcome Sanger Institute: Nm (13,711), Sp (>24,000), Sa (6,200), Hi (1738); and BMGAP: Nm (8,785), Hi (2,030). A steering group is being established to coordinate the initiative and encourage high-quality data curation. Next steps include: developing guidelines on open-access sharing of genomic data; defining a core set of metadata; and facilitating development of user-friendly interfaces that represent publicly available data. |
International Society of Cardiovascular Infectious Diseases Guidelines for the Diagnosis, Treatment and Prevention of Disseminated Mycobacterium chimaera Infection Following Cardiac Surgery with Cardiopulmonary Bypass.
Hasse B , Hannan M , Keller PM , Maurer FP , Sommerstein R , Mertz D , Wagner D , Fernandez-Hidalgo N , Nomura J , Manfrin V , Bettex D , Conte AH , Durante-Mangoni E , Hing-Cheung Tang T , Stuart RL , Lundgren J , Gordon S , Jarashow MC , Schreiber PW , Niemann S , Kohl TA , Daley C , Stewardson AJ , Whitener CJ , Perkins K , Plachouras D , Lamagni T , Chand M , Freiberger T , Zweifel S , Sander P , Schulthess B , Scriven J , Sax H , van Ingen J , Mestres CA , Diekema D , Brown-Elliott BA , Wallace RJJr , Baddour LM , Miro JM , Hoen B . J Hosp Infect 2019 104 (2) 214-235 Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects. |
Phylogenetic relationships and regional spread of meningococcal strains in the meningitis belt, 2011-2016.
Topaz N , Caugant DA , Taha MK , Brynildsrud OB , Debech N , Hong E , Deghmane AE , Ouedraogo R , Ousmane S , Gamougame K , Njanpop-Lafourcade BM , Diarra S , Fox LM , Wang X . EBioMedicine 2019 41 488-496 BACKGROUND: Historically, the major cause of meningococcal epidemics in the meningitis belt of sub-Saharan Africa has been Neisseria meningitidis serogroup A (NmA), but the incidence has been substantially reduced since the introduction of a serogroup A conjugate vaccine starting in 2010. We performed whole-genome sequencing on isolates collected post-2010 to assess their phylogenetic relationships and inter-country transmission. METHODS: A total of 716 invasive meningococcal isolates collected between 2011 and 2016 from 11 meningitis belt countries were whole-genome sequenced for molecular characterization by the three WHO Collaborating Centers for Meningitis. FINDINGS: We identified three previously-reported clonal complexes (CC): CC11 (n=434), CC181 (n=62) and CC5 (n=90) primarily associated with NmW, NmX, and NmA, respectively, and an emerging CC10217 (n=126) associated with NmC. CC11 expanded throughout the meningitis belt independent of the 2000 Hajj outbreak strain, with isolates from Central African countries forming a distinct sub-lineage within this expansion. Two major sub-lineages were identified for CC181 isolates, one mainly expanding in West African countries and the other found in Chad. CC10217 isolates from the large outbreaks in Nigeria and Niger were more closely related than those from the few cases in Mali and Burkina Faso. INTERPRETATIONS: Whole-genome based phylogenies revealed geographically distinct strain circulation as well as inter-country transmission events. Our results stress the importance of continued meningococcal molecular surveillance in the region, as well as the development of an affordable vaccine targeting these strains. FUND: Meningitis Research Foundation; CDC's Office of Advanced Molecular Detection; GAVI, the Vaccine Alliance. |
Genetic Meningococcal Antigen Typing System (gMATS): A genotyping tool that predicts 4CMenB strain coverage worldwide.
Muzzi A , Brozzi A , Serino L , Bodini M , Abad R , Caugant D , Comanducci M , Lemos AP , Gorla MC , Krizova P , Mikula C , Mulhall R , Nissen M , Nohynek H , Simoes MJ , Skoczynska A , Stefanelli P , Taha MK , Toropainen M , Tzanakaki G , Vadivelu-Pechai K , Watson P , Vazquez JA , Rajam G , Rappuoli R , Borrow R , Medini D . Vaccine 2019 37 (7) 991-1000 BACKGROUND: The Meningococcal Antigen Typing System (MATS) was developed to identify meningococcus group B strains with a high likelihood of being covered by the 4CMenB vaccine, but is limited by the requirement for viable isolates from culture-confirmed cases. We examined if antigen genotyping could complement MATS in predicting strain coverage by the 4CMenB vaccine. METHODS: From a panel of 3912 MATS-typed invasive meningococcal disease isolates collected in England and Wales in 2007-2008, 2014-2015 and 2015-2016, and in 16 other countries in 2000-2015, 3481 isolates were also characterized by antigen genotyping. Individual associations between antigen genotypes and MATS coverage for each 4CMenB component were used to define a genetic MATS (gMATS). gMATS estimates were compared with England and Wales human complement serum bactericidal assay (hSBA) data and vaccine effectiveness (VE) data from England. RESULTS: Overall, 81% of the strain panel had genetically predictable MATS coverage, with 92% accuracy and highly concordant results across national panels (Lin's accuracy coefficient, 0.98; root-mean-square deviation, 6%). England and Wales strain coverage estimates were 72-73% by genotyping (66-73% by MATS), underestimating hSBA values after four vaccine doses (88%) and VE after two doses (83%). The gMATS predicted strain coverage in other countries was 58-88%. CONCLUSIONS: gMATS can replace MATS in predicting 4CMenB strain coverage in four out of five cases, without requiring a cultivable isolate, and is open to further improvement. Both methods underestimated VE in England. Strain coverage predictions in other countries matched or exceeded England and Wales estimates. |
Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067.
Figueroa DB , Tillotson J , Li M , Piwowar-Manning E , Hendrix CW , Holtz TH , Bokoch K , Bekker LG , van Griensven F , Mannheimer S , Hughes JP , Grant RM , Bumpus NN . PLoS One 2018 13 (4) e0195764 Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a >/=30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation. |
Revisiting the taxonomy of the genus Elizabethkingia using whole-genome sequencing, optical mapping, and MALDI-TOF, along with proposal of three novel Elizabethkingia species: Elizabethkingia bruuniana sp. nov., Elizabethkingia ursingii sp. nov., and Elizabethkingia occulta sp. nov.
Nicholson AC , Gulvik CA , Whitney AM , Humrighouse BW , Graziano J , Emery B , Bell M , Loparev V , Juieng P , Gartin J , Bizet C , Clermont D , Criscuolo A , Brisse S , McQuiston JR . Antonie Van Leeuwenhoek 2017 111 (1) 55-72 The genus Elizabethkingia is genetically heterogeneous, and the phenotypic similarities between recognized species pose challenges in correct identification of clinically derived isolates. In addition to the type species Elizabethkingia meningoseptica, and more recently proposed Elizabethkingia miricola, Elizabethkingia anophelis and Elizabethkingia endophytica, four genomospecies have long been recognized. By comparing historic DNA-DNA hybridization results with whole genome sequences, optical maps, and MALDI-TOF mass spectra on a large and diverse set of strains, we propose a comprehensive taxonomic revision of this genus. Genomospecies 1 and 2 contain the type strains E. anophelis and E. miricola, respectively. Genomospecies 3 and 4 are herein proposed as novel species named as Elizabethkingia bruuniana sp. nov. (type strain, G0146T = DSM 2975T = CCUG 69503T = CIP 111191T) and Elizabethkingia ursingii sp. nov. (type strain, G4122T = DSM 2974T = CCUG 69496T = CIP 111192T), respectively. Finally, the new species Elizabethkingia occulta sp. nov. (type strain G4070T = DSM 2976T = CCUG 69505T = CIP 111193T), is proposed. |
Evolutionary dynamics and genomic features of the Elizabethkingia anophelis 2015 to 2016 Wisconsin outbreak strain.
Perrin A , Larsonneur E , Nicholson AC , Edwards DJ , Gundlach KM , Whitney AM , Gulvik CA , Bell ME , Rendueles O , Cury J , Hugon P , Clermont D , Enouf V , Loparev V , Juieng P , Monson T , Warshauer D , Elbadawi LI , Walters MS , Crist MB , Noble-Wang J , Borlaug G , Rocha EPC , Criscuolo A , Touchon M , Davis JP , Holt KE , McQuiston JR , Brisse S . Nat Commun 2017 8 15483 An atypically large outbreak of Elizabethkingia anophelis infections occurred in Wisconsin. Here we show that it was caused by a single strain with thirteen characteristic genomic regions. Strikingly, the outbreak isolates show an accelerated evolutionary rate and an atypical mutational spectrum. Six phylogenetic sub-clusters with distinctive temporal and geographic dynamics are revealed, and their last common ancestor existed approximately one year before the first recognized human infection. Unlike other E. anophelis, the outbreak strain had a disrupted DNA repair mutY gene caused by insertion of an integrative and conjugative element. This genomic change probably contributed to the high evolutionary rate of the outbreak strain and may have increased its adaptability, as many mutations in protein-coding genes occurred during the outbreak. This unique discovery of an outbreak caused by a naturally occurring mutator bacterial pathogen provides a dramatic example of the potential impact of pathogen evolutionary dynamics on infectious disease epidemiology. |
Genotypic analysis of Tropheryma whipplei from patients with Whipple disease in the Americas.
Rollin DC , Paddock CD , Pritt BS , Cunningham SA , Denison AM . J Clin Pathol 2017 70 (10) 891-895 Tropheryma whipplei, the agent of Whipple disease, causes a rare bacterial disease that may be fatal if not treated. The classical form of the disease includes diarrhoea, weight loss, arthritis, endocarditis and neurological manifestations. Genotyping studies done in Europe, Africa and Asia showed high genetic diversity with no correlation between genotypes and clinical features, but contributed to a better understanding of the epidemiology of the disease. More than 70 genotypes have been described. No similar assessment of T. whipplei in the USA and the Caribbean has been performed. In this study, we describe genetic analysis of DNA from histopathological samples obtained from 30 patients from the Americas with Whipple disease and compare the genotypes with those previously identified. Complete genotypes were obtained from 18 patients (60%). Only 4 genotypes were previously described, and 14 were newly reported, confirming the diversity of T. whipplei strains. |
Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.
Rhee SY , Varghese V , Holmes SP , Van Zyl GU , Steegen K , Boyd MA , Cooper DA , Nsanzimana S , Saravanan S , Charpentier C , de Oliveira T , Etiebet MA , Garcia F , Goedhals D , Gomes P , Gunthard HF , Hamers RL , Hoffmann CJ , Hunt G , Jiamsakul A , Kaleebu P , Kanki P , Kantor R , Kerschberger B , Marconi VC , D'Amour Ndahimana J , Ndembi N , Ngo-Giang-Huong N , Rokx C , Santoro MM , Schapiro JM , Schmidt D , Seu L , Sigaloff KC , Sirivichayakul S , Skhosana L , Sunpath H , Tang M , Yang C , Carmona S , Gupta RK , Shafer RW . EBioMedicine 2017 18 225-235 Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naive individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen. |
Multi-center evaluation of one commercial and 12 in-house real-time PCR assays for detection of Mycoplasma pneumoniae.
Dumke R , Benitez AJ , Chalker V , Gullsby K , Henrich B , Hidalgo-Grass C , Hoogenboezem T , Kese D , Loens K , Maaskant J , Michael-Gayego A , Moses AE , Nir-Paz R , Pas SD , Pereyre S , Petersen RF , Rosenblatt M , van Rossum AM , Uldum SA , Unger WW , Ursi D , Winchell JM , Bebear C . Diagn Microbiol Infect Dis 2017 88 (2) 111-114 Detection of Mycoplasma pneumoniae by real-time PCR is not yet standardized across laboratories. We have implemented a standardization protocol to compare the performance of thirteen commercial and in-house approaches. Despite differences on threshold values of samples, all assays were able to detect at least 20M. pneumoniae genomes per reaction. |
Whole-Genome Characterization of Epidemic Neisseria meningitidis Serogroup C and Resurgence of Serogroup W, Niger, 2015.
Kretz CB , Retchless AC , Sidikou F , Issaka B , Ousmane S , Schwartz S , Tate AH , Pana A , Njanpop-Lafourcade BM , Nzeyimana I , Nse RO , Deghmane AE , Hong E , Brynildsrud OB , Novak RT , Meyer SA , Oukem-Boyer OO , Ronveaux O , Caugant DA , Taha MK , Wang X . Emerg Infect Dis 2016 22 (10) 1762-8 In 2015, Niger reported the largest epidemic of Neisseria meningitidis serogroup C (NmC) meningitis in sub-Saharan Africa. The NmC epidemic coincided with serogroup W (NmW) cases during the epidemic season, resulting in a total of 9,367 meningococcal cases through June 2015. To clarify the phylogenetic association, genetic evolution, and antibiotic determinants of the meningococcal strains in Niger, we sequenced the genomes of 102 isolates from this epidemic, comprising 81 NmC and 21 NmW isolates. The genomes of 82 isolates were completed, and all 102 were included in the analysis. All NmC isolates had sequence type 10217, which caused the outbreaks in Nigeria during 2013-2014 and for which a clonal complex has not yet been defined. The NmC isolates from Niger were substantially different from other NmC isolates collected globally. All NmW isolates belonged to clonal complex 11 and were closely related to the isolates causing recent outbreaks in Africa. |
Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.
Healey KR , Zhao Y , Perez WB , Lockhart SR , Sobel JD , Farmakiotis D , Kontoyiannis DP , Sanglard D , Taj-Aldeen SJ , Alexander BD , Jimenez-Ortigosa C , Shor E , Perlin DS . Nat Commun 2016 7 11128 The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata. We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy. |
Malignant Transformation of Hymenolepis nana in a Human Host.
Muehlenbachs A , Bhatnagar J , Agudelo CA , Hidron A , Eberhard ML , Mathison BA , Frace MA , Ito A , Metcalfe MG , Rollin DC , Visvesvara GS , Pham CD , Jones TL , Greer PW , Velez Hoyos A , Olson PD , Diazgranados LR , Zaki SR . N Engl J Med 2015 373 (19) 1845-52 Neoplasms occur naturally in invertebrates but are not known to develop in tapeworms. We observed nests of monomorphic, undifferentiated cells in samples from lymph-node and lung biopsies in a man infected with the human immunodeficiency virus (HIV). The morphologic features and invasive behavior of the cells were characteristic of cancer, but their small size suggested a nonhuman origin. A polymerase-chain-reaction (PCR) assay targeting eukaryotes identified Hymenolepis nana DNA. Although the cells were unrecognizable as tapeworm tissue, immunohistochemical staining and probe hybridization labeled the cells in situ. Comparative deep sequencing identified H. nana structural genomic variants that are compatible with mutations described in cancer. Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer. |
A molecular sensor to characterize arenavirus envelope glycoprotein cleavage by subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P).
Oppliger J , da Palma JR , Burri DJ , Bergeron E , Khatib AM , Spiropoulou CF , Pasquato A , Kunz S . J Virol 2015 90 (2) 705-14 Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses only genetic information is available and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears therefore as a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate efficiency and subcellular location of arenavirus GPC processing. In proof-of-concept, our sensor correctly predicts efficient processing of the GPC of the newly emerged pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and non-pathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system to assess processing of putative cleavage sites derived from newly discovered arenavirus GPC by SKI-1/S1P of humans or any other species, based solely on sequence information. IMPORTANCE: Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high m-+ortality in humans. A crucial step in productive infection of arenaviruses in human cells is processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). In order to break the species barrier during zoonotic transmission and to cause severe disease in man, newly emerging arenaviruses must be able to efficiently hijack human SKI-1/S1P. Here we implement a newly developed cell-based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emerged pathogenic Lujo virus by human SKI-1/S1P. Our sensor represents thus a rapid and robust test system to assess if the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information. |
Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data.
Wang Z , Rajaraman P , Melin BS , Chung CC , Zhang W , McKean-Cowdin R , Michaud D , Yeager M , Ahlbom A , Albanes D , Andersson U , Freeman LE , Buring JE , Butler MA , Carreon T , Feychting M , Gapstur SM , Gaziano JM , Giles GG , Hallmans G , Henriksson R , Hoffman-Bolton J , Inskip PD , Kitahara CM , Marchand LL , Linet MS , Li S , Peters U , Purdue MP , Rothman N , Ruder AM , Sesso HD , Severi G , Stampfer M , Stevens VL , Visvanathan K , Wang SS , White E , Zeleniuch-Jacquotte A , Hoover R , Fraumeni JF , Chatterjee N , Hartge P , Chanock SJ . Hum Mutat 2015 36 (7) 684-8 We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10-11 ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximately 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. |
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Wang Z , Zhu B , Zhang M , Parikh H , Jia J , Chung CC , Sampson JN , Hoskins JW , Hutchinson A , Burdette L , Ibrahim A , Hautman C , Raj PS , Abnet CC , Adjei AA , Ahlbom A , Albanes D , Allen NE , Ambrosone CB , Aldrich M , Amiano P , Amos C , Andersson U , Andriole G Jr , Andrulis IL , Arici C , Arslan AA , Austin MA , Baris D , Barkauskas DA , Bassig BA , Beane Freeman LE , Berg CD , Berndt SI , Bertazzi PA , Biritwum RB , Black A , Blot W , Boeing H , Boffetta P , Bolton K , Boutron-Ruault MC , Bracci PM , Brennan P , Brinton LA , Brotzman M , Bueno-de-Mesquita HB , Buring JE , Butler MA , Cai Q , Cancel-Tassin G , Canzian F , Cao G , Caporaso NE , Carrato A , Carreon T , Carta A , Chang GC , Chang IS , Chang-Claude J , Che X , Chen CJ , Chen CY , Chen CH , Chen C , Chen KY , Chen YM , Chokkalingam AP , Chu LW , Clavel-Chapelon F , Colditz GA , Colt JS , Conti D , Cook MB , Cortessis VK , Crawford ED , Cussenot O , Davis FG , De Vivo I , Deng X , Ding T , Dinney CP , Di Stefano AL , Diver WR , Duell EJ , Elena JW , Fan JH , Feigelson HS , Feychting M , Figueroa JD , Flanagan AM , Fraumeni JF Jr , Freedman ND , Fridley BL , Fuchs CS , Gago-Dominguez M , Gallinger S , Gao YT , Gapstur SM , Garcia-Closas M , Garcia-Closas R , Gastier-Foster JM , Gaziano JM , Gerhard DS , Giffen CA , Giles GG , Gillanders EM , Giovannucci EL , Goggins M , Gokgoz N , Goldstein AM , Gonzalez C , Gorlick R , Greene MH , Gross M , Grossman HB , Grubb R 3rd , Gu J , Guan P , Haiman CA , Hallmans G , Hankinson SE , Harris CC , Hartge P , Hattinger C , Hayes RB , He Q , Helman L , Henderson BE , Henriksson R , Hoffman-Bolton J , Hohensee C , Holly EA , Hong YC , Hoover RN , Hosgood HD 3rd , Hsiao CF , Hsing AW , Hsiung CA , Hu N , Hu W , Hu Z , Huang MS , Hunter DJ , Inskip PD , Ito H , Jacobs EJ , Jacobs KB , Jenab M , Ji BT , Johansen C , Johansson M , Johnson A , Kaaks R , Kamat AM , Kamineni A , Karagas M , Khanna C , Khaw KT , Kim C , Kim IS , Kim YH , Kim YC , Kim YT , Kang CH , Jung YJ , Kitahara CM , Klein AP , Klein R , Kogevinas M , Koh WP , Kohno T , Kolonel LN , Kooperberg C , Kratz CP , Krogh V , Kunitoh H , Kurtz RC , Kurucu N , Lan Q , Lathrop M , Lau CC , Lecanda F , Lee KM , Lee MP , Le Marchand L , Lerner SP , Li D , Liao LM , Lim WY , Lin D , Lin J , Lindstrom S , Linet MS , Lissowska J , Liu J , Ljungberg B , Lloreta J , Lu D , Ma J , Malats N , Mannisto S , Marina N , Mastrangelo G , Matsuo K , McGlynn KA , McKean-Cowdin R , McNeill LH , McWilliams RR , Melin BS , Meltzer PS , Mensah JE , Miao X , Michaud DS , Mondul AM , Moore LE , Muir K , Niwa S , Olson SH , Orr N , Panico S , Park JY , Patel AV , Patino-Garcia A , Pavanello S , Peeters PH , Peplonska B , Peters U , Petersen GM , Picci P , Pike MC , Porru S , Prescott J , Pu X , Purdue MP , Qiao YL , Rajaraman P , Riboli E , Risch HA , Rodabough RJ , Rothman N , Ruder AM , Ryu JS , Sanson M , Schned A , Schumacher FR , Schwartz AG , Schwartz KL , Schwenn M , Scotlandi K , Seow A , Serra C , Serra M , Sesso HD , Severi G , Shen H , Shen M , Shete S , Shiraishi K , Shu XO , Siddiq A , Sierrasesumaga L , Sierri S , Sihoe AD , Silverman DT , Simon M , Southey MC , Spector L , Spitz M , Stampfer M , Stattin P , Stern MC , Stevens VL , Stolzenberg-Solomon RZ , Stram DO , Strom SS , Su WC , Sund M , Sung SW , Swerdlow A , Tan W , Tanaka H , Tang W , Tang ZZ , Tardon A , Tay E , Taylor PR , Tettey Y , Thomas DM , Tirabosco R , Tjonneland A , Tobias GS , Toro JR , Travis RC , Trichopoulos D , Troisi R , Truelove A , Tsai YH , Tucker MA , Tumino R , Van Den Berg D , Van Den Eeden SK , Vermeulen R , Vineis P , Visvanathan K , Vogel U , Wang C , Wang C , Wang J , Wang SS , Weiderpass E , Weinstein SJ , Wentzensen N , Wheeler W , White E , Wiencke JK , Wolk A , Wolpin BM , Wong MP , Wrensch M , Wu C , Wu T , Wu X , Wu YL , Wunder JS , Xiang YB , Xu J , Yang HP , Yang PC , Yatabe Y , Ye Y , Yeboah ED , Yin Z , Ying C , Yu CJ , Yu K , Yuan JM , Zanetti KA , Zeleniuch-Jacquotte A , Zheng W , Zhou B , Mirabello L , Savage SA , Kraft P , Chanock SJ , Yeager M , Landi MT , Shi J , Chatterjee N , Amundadottir LT . Hum Mol Genet 2014 23 (24) 6616-33 Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. |
Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences.
Nasser W , Beres SB , Olsen RJ , Dean MA , Rice KA , Long SW , Kristinsson KG , Gottfredsson M , Vuopio J , Raisanen K , Caugant DA , Steinbakk M , Low DE , McGeer A , Darenberg J , Henriques-Normark B , Van Beneden CA , Hoffmann S , Musser JM . Proc Natl Acad Sci U S A 2014 111 (17) E1768-76 We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD(+)-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide. |
Localization of pandemic 2009 H1N1 influenza A virus RNA in lung and lymph nodes of fatal influenza cases by in situ hybridization: new insights on virus replication and pathogenesis.
Bhatnagar J , Jones T , Blau DM , Shieh WJ , Paddock CD , Drew C , Denison AM , Rollin DC , Patel M , Zaki SR . J Clin Virol 2012 56 (3) 232-7 BACKGROUND: Pandemic 2009 H1N1 influenza A (pH1N1) virus has caused substantial morbidity and mortality globally and continues to circulate. Although pH1N1 viral antigens have been demonstrated in various human tissues by immunohistochemistry (IHC), cellular localization of pH1N1 RNA in these tissues has largely remained uninvestigated. OBJECTIVES: To examine the distribution of pH1N1 RNA in tissues of fatal cases in order to understand the virus tissue tropism, replication and disease pathogenesis. STUDY DESIGN: Formalin-fixed, paraffin embedded autopsy tissues from 21 patients with confirmed pH1N1 infection were analyzed by influenza A IHC and by in situ hybridization (ISH) using DIG-labeled sense (detects viral RNA) and antisense probes (detects positive-stranded mRNA and cRNA) targeting the nucleoprotein gene of pH1N1 virus. RESULTS: pH1N1 RNA was localized by ISH in 57% of cases while viral antigens were detected by IHC in 76%. However, in cases with a short duration of illness (1-3 days), more cases (69%) were positive by ISH than IHC (62%). Strong ISH staining was detected by antisense probes in the alveolar pneumocytes of the lungs, mucous glands and in lymph nodes. IHC staining of viral antigens was demonstrated in the lung pneumocytes and mucous glands, but no immunostaining was detected in any of the lymph nodes examined. CONCLUSIONS: This study demonstrates cellular localization of positive-stranded pH1N1 RNA in the lungs, mucous glands and lymph nodes that suggests viral replication in these tissues. The novel ISH assay can be a useful adjunct for the detection of pH1N1 virus in tissues and for pathogenesis studies. |
Genome-wide association study of glioma and meta-analysis.
Rajaraman P , Melin BS , Wang Z , McKean-Cowdin R , Michaud DS , Wang SS , Bondy M , Houlston R , Jenkins RB , Wrensch M , Yeager M , Ahlbom A , Albanes D , Andersson U , Freeman LE , Buring JE , Butler MA , Braganza M , Carreon T , Feychting M , Fleming SJ , Gapstur SM , Gaziano JM , Giles GG , Hallmans G , Henriksson R , Hoffman-Bolton J , Inskip PD , Johansen C , Kitahara CM , Lathrop M , Liu C , Le Marchand L , Linet MS , Lonn S , Peters U , Purdue MP , Rothman N , Ruder AM , Sanson M , Sesso HD , Severi G , Shu XO , Simon M , Stampfer M , Stevens VL , Visvanathan K , White E , Wolk A , Zeleniuch-Jacquotte A , Zheng W , Decker P , Enciso-Mora V , Fridley B , Gao YT , Kosel M , Lachance DH , Lau C , Rice T , Swerdlow A , Wiemels JL , Wiencke JK , Shete S , Xiang YB , Xiao Y , Hoover RN , Fraumeni JF Jr , Chatterjee N , Hartge P , Chanock SJ . Hum Genet 2012 131 (12) 1877-88 Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk. |
Association between adult height, genetic susceptibility and risk of glioma.
Kitahara CM , Wang SS , Melin BS , Wang Z , Braganza M , Inskip PD , Albanes D , Andersson U , Beane Freeman LE , Buring JE , Carreon T , Feychting M , Gapstur SM , Gaziano JM , Giles GG , Hallmans G , Hankinson SE , Henriksson R , Hsing AW , Johansen C , Linet MS , McKean-Cowdin R , Michaud DS , Peters U , Purdue MP , Rothman N , Ruder AM , Sesso HD , Severi G , Shu XO , Stevens VL , Visvanathan K , Waters MA , White E , Wolk A , Zeleniuch-Jacquotte A , Zheng W , Hoover R , Fraumeni JF Jr , Chatterjee N , Yeager M , Chanock SJ , Hartge P , Rajaraman P . Int J Epidemiol 2012 41 (4) 1075-1085 BACKGROUND: Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. METHODS: We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. RESULTS: Among men, we found a positive association between height and glioma risk (≥190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. CONCLUSION: An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease. |
Detectable clonal mosaicism and its relationship to aging and cancer.
Jacobs KB , Yeager M , Zhou W , Wacholder S , Wang Z , Rodriguez-Santiago B , Hutchinson A , Deng X , Liu C , Horner MJ , Cullen M , Epstein CG , Burdett L , Dean MC , Chatterjee N , Sampson J , Chung CC , Kovaks J , Gapstur SM , Stevens VL , Teras LT , Gaudet MM , Albanes D , Weinstein SJ , Virtamo J , Taylor PR , Freedman ND , Abnet CC , Goldstein AM , Hu N , Yu K , Yuan JM , Liao L , Ding T , Qiao YL , Gao YT , Koh WP , Xiang YB , Tang ZZ , Fan JH , Aldrich MC , Amos C , Blot WJ , Bock CH , Gillanders EM , Harris CC , Haiman CA , Henderson BE , Kolonel LN , Le Marchand L , McNeill LH , Rybicki BA , Schwartz AG , Signorello LB , Spitz MR , Wiencke JK , Wrensch M , Wu X , Zanetti KA , Ziegler RG , Figueroa JD , Garcia-Closas M , Malats N , Marenne G , Prokunina-Olsson L , Baris D , Schwenn M , Johnson A , Landi MT , Goldin L , Consonni D , Bertazzi PA , Rotunno M , Rajaraman P , Andersson U , Freeman LE , Berg CD , Buring JE , Butler MA , Carreon T , Feychting M , Ahlbom A , Gaziano JM , Giles GG , Hallmans G , Hankinson SE , Hartge P , Henriksson R , Inskip PD , Johansen C , Landgren A , McKean-Cowdin R , Michaud DS , Melin BS , Peters U , Ruder AM , Sesso HD , Severi G , Shu XO , Visvanathan K , White E , Wolk A , Zeleniuch-Jacquotte A , Zheng W , Silverman DT , Kogevinas M , Gonzalez JR , Villa O , Li D , Duell EJ , Risch HA , Olson SH , Kooperberg C , Wolpin BM , Jiao L , Hassan M , Wheeler W , Arslan AA , Bueno-de-Mesquita HB , Fuchs CS , Gallinger S , Gross MD , Holly EA , Klein AP , LaCroix A , Mandelson MT , Petersen G , Boutron-Ruault MC , Bracci PM , Canzian F , Chang K , Cotterchio M , Giovannucci EL , Goggins M , Hoffman Bolton JA , Jenab M , Khaw KT , Krogh V , Kurtz RC , McWilliams RR , Mendelsohn JB , Rabe KG , Riboli E , Tjønneland A , Tobias GS , Trichopoulos D , Elena JW , Yu H , Amundadottir L , Stolzenberg-Solomon RZ , Kraft P , Schumacher F , Stram D , Savage SA , Mirabello L , Andrulis IL , Wunder JS , Patiño García A , Sierrasesúmaga L , Barkauskas DA , Gorlick RG , Purdue M , Chow WH , Moore LE , Schwartz KL , Davis FG , Hsing AW , Berndt SI , Black A , Wentzensen N , Brinton LA , Lissowska J , Peplonska B , McGlynn KA , Cook MB , Graubard BI , Kratz CP , Greene MH , Erickson RL , Hunter DJ , Thomas G , Hoover RN , Real FX , Fraumeni JF Jr , Caporaso NE , Tucker M , Rothman N , Pérez-Jurado LA , Chanock SJ . Nat Genet 2012 44 (6) 651-8 In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases. |
Characteristics and behaviors of mothers who have a child with fetal alcohol syndrome
Cannon MJ , Dominique Y , O'Leary LA , Sniezek JE , Floyd RL . Neurotoxicol Teratol 2012 34 (1) 90-5 Fetal alcohol syndrome (FAS) is a leading cause of birth defects and developmental disabilities. The objective of this study was to identify the characteristics and behaviors of mothers of children with FAS in the United States using population-based data from the FAS Surveillance Network (FASSNet). FASSNet used a multiple source methodology that identified FAS cases through passive reporting and active review of records from hospitals, specialty clinics, private physicians, early intervention programs, Medicaid, birth certificates and other vital records, birth defects surveillance programs, and hospital discharge data. The surveillance included children born during January 1, 1995 - December 31, 1997. In the four states included in our analysis - Arizona, New York, Alaska, and Colorado - there were 257 confirmed cases and 96 probable cases for a total of 353 FAS cases. Compared to all mothers in the states where surveillance occurred, mothers of children with FAS were significantly more likely to be older, American Indians/Alaska Natives, Black, not Hispanic, unmarried, unemployed, and without prenatal care, to smoke during pregnancy, to have a lower educational level, and to have more live born children. A significant proportion of mothers (9-29%) had another child with suspected alcohol effects. Compared to all US mothers, they were also significantly more likely to be on public assistance, to be on Medicaid at their child's birth, to have received treatment for alcohol abuse, to have confirmed alcoholism, to have used marijuana or cocaine during pregnancy, to have their baby screen positive for alcohol or drugs at birth, to have had an induced abortion, to have had a history of mental illness, to have been involved in binge drinking during pregnancy, and to have drunk heavily (7days/week) during pregnancy. These findings suggest that it is possible to identify women who are at high risk of having a child with FAS and target these women for interventions. |
Diagnosis of influenza from respiratory autopsy tissues: detection of virus by real-time reverse transcription-PCR in 222 cases.
Denison AM , Blau DM , Jost HA , Jones T , Rollin D , Gao R , Liu L , Bhatnagar J , Deleon-Carnes M , Shieh WJ , Paddock CD , Drew C , Adem P , Emery SL , Shu B , Wu KH , Batten B , Greer PW , Smith CS , Bartlett J , Montague JL , Patel M , Xu X , Lindstrom S , Klimov AI , Zaki SR . J Mol Diagn 2011 13 (2) 123-8 The recent influenza pandemic, caused by a novel H1N1 influenza A virus, as well as the seasonal influenza outbreaks caused by varieties of influenza A and B viruses, are responsible for hundreds of thousands of deaths worldwide. Few studies have evaluated the utility of real-time reverse transcription-PCR to detect influenza virus RNA from formalin-fixed, paraffin-embedded tissues obtained at autopsy. In this work, respiratory autopsy tissues from 442 suspect influenza cases were tested by real-time reverse transcription-PCR for seasonal influenza A and B and 2009 pandemic influenza A (H1N1) viruses and the results were compared to those obtained by immunohistochemistry. In total, 222 cases were positive by real-time reverse transcription-PCR, and of 218 real-time, reverse transcription-PCR-positive cases also tested by immunohistochemistry, only 107 were positive. Although formalin-fixed, paraffin-embedded tissues can be used for diagnosis, frozen tissues offer the best chance to make a postmortem diagnosis of influenza because these tissues possess nucleic acids that are less degraded and, as a consequence, provide longer sequence information than that obtained from fixed tissues. We also determined that testing of all available respiratory tissues is critical for optimal detection of influenza virus in postmortem tissues. |
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