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Genome Medicine

Serena Manara, Edoardo Pasolli, Daniela Dolce, Novella Ravenni, Silvia Campana, Federica Armanini, Francesco Asnicar, Alessio Mengoni, Luisa Galli, Carlotta Montagnani, Elisabetta Venturini, Omar Rota-Stabelli, Guido Grandi, Giovanni Taccetti, Nicola Segata
BACKGROUND: Staphylococcus aureus is an opportunistic pathogen and a leading cause of nosocomial infections. It can acquire resistance to all the antibiotics that entered the clinics to date, and the World Health Organization defined it as a high-priority pathogen for research and development of new antibiotics. A deeper understanding of the genetic variability of S. aureus in clinical settings would lead to a better comprehension of its pathogenic potential and improved strategies to contrast its virulence and resistance...
November 13, 2018: Genome Medicine
S Y Cindy Yang, Stephanie Lheureux, Katherine Karakasis, Julia V Burnier, Jeffery P Bruce, Derek L Clouthier, Arnavaz Danesh, Rene Quevedo, Mark Dowar, Youstina Hanna, Tiantian Li, Lin Lu, Wei Xu, Blaise A Clarke, Pamela S Ohashi, Patricia A Shaw, Trevor J Pugh, Amit M Oza
BACKGROUND: Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses...
October 31, 2018: Genome Medicine
Vanessa L Hale, Patricio Jeraldo, Jun Chen, Michael Mundy, Janet Yao, Sambhawa Priya, Gary Keeney, Kelly Lyke, Jason Ridlon, Bryan A White, Amy J French, Stephen N Thibodeau, Christian Diener, Osbaldo Resendis-Antonio, Jaime Gransee, Tumpa Dutta, Xuan-Mai Petterson, Jaeyun Sung, Ran Blekhman, Lisa Boardman, David Larson, Heidi Nelson, Nicholas Chia
BACKGROUND: Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would be enhanced by better accounting for tumor subtype, microbial community interactions, metabolism, and ecology. METHODS: We collected paired colon tumor and normal-adjacent tissue and mucosa samples from 83 individuals who underwent partial or total colectomies for CRC...
October 31, 2018: Genome Medicine
Samantha L Bucktrout, Jeffrey A Bluestone, Fred Ramsdell
For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cancer immunotherapies. Pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease. We discuss the basic principles of the immune response, how these are co-opted in chronic infection and malignancy, and how these can be harnessed to treat disease...
October 31, 2018: Genome Medicine
Alexander Khoruts
The modern techniques of microbiome science can be applied to the development and evaluation of all microbiota-directed products, including probiotics and fecal microbiota transplantation.
October 30, 2018: Genome Medicine
Margaret M C Lam, Kelly L Wyres, Louise M Judd, Ryan R Wick, Adam Jenney, Sylvain Brisse, Kathryn E Holt
BACKGROUND: Klebsiella pneumoniae is a recognised agent of multidrug-resistant (MDR) healthcare-associated infections; however, individual strains vary in their virulence potential due to the presence of mobile accessory genes. In particular, gene clusters encoding the biosynthesis of siderophores aerobactin (iuc) and salmochelin (iro) are associated with invasive disease and are common amongst hypervirulent K. pneumoniae clones that cause severe community-associated infections such as liver abscess and pneumonia...
October 29, 2018: Genome Medicine
Jhuma Pramanik, Xi Chen, Gozde Kar, Johan Henriksson, Tomás Gomes, Jong-Eun Park, Kedar Natarajan, Kerstin B Meyer, Zhichao Miao, Andrew N J McKenzie, Bidesh Mahata, Sarah A Teichmann
BACKGROUND: The IRE1a-XBP1 pathway is a conserved adaptive mediator of the unfolded protein response. The pathway is indispensable for the development of secretory cells by facilitating protein folding and enhancing secretory capacity. In the immune system, it is known to function in dendritic cells, plasma cells, and eosinophil development and differentiation, while its role in T helper cell is unexplored. Here, we investigated the role of the IRE1a-XBP1 pathway in regulating activation and differentiation of type-2 T helper cell (Th2), a major T helper cell type involved in allergy, asthma, helminth infection, pregnancy, and tumor immunosuppression...
October 24, 2018: Genome Medicine
Qian Zhang, Riccardo E Marioni, Matthew R Robinson, Jon Higham, Duncan Sproul, Naomi R Wray, Ian J Deary, Allan F McRae, Peter M Visscher
BACKGROUND: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals. METHODS: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2-4 time points (N = 2894) in 954 individuals (67-90 years). RESULTS: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis...
October 22, 2018: Genome Medicine
Lisa E Wagar, Robert M DiFazio, Mark M Davis
There are fundamental differences between humans and the animals we typically use to study the immune system. We have learned much from genetically manipulated and inbred animal models, but instances in which these findings have been successfully translated to human immunity have been rare. Embracing the genetic and environmental diversity of humans can tell us about the fundamental biology of immune cell types and the elasticity of the immune system. Although people are much more immunologically diverse than conventionally housed animal models, tools and technologies are now available that permit high-throughput analysis of human samples, including both blood and tissues, which will give us deep insights into human immunity in health and disease...
September 28, 2018: Genome Medicine
Elizabeth A Normand, Alicia Braxton, Salma Nassef, Patricia A Ward, Francesco Vetrini, Weimin He, Vipulkumar Patel, Chunjing Qu, Lauren E Westerfield, Samantha Stover, Avinash V Dharmadhikari, Donna M Muzny, Richard A Gibbs, Hongzheng Dai, Linyan Meng, Xia Wang, Rui Xiao, Pengfei Liu, Weimin Bi, Fan Xia, Magdalena Walkiewicz, Ignatia B Van den Veyver, Christine M Eng, Yaping Yang
BACKGROUND: Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting. METHODS: We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive "fetal exomes" performed in a clinical diagnostic laboratory between March 2012 and November 2017...
September 28, 2018: Genome Medicine
Erik L Clarke, A Jesse Connell, Emmanuelle Six, Nadia A Kadry, Arwa A Abbas, Young Hwang, John K Everett, Casey E Hofstaedter, Rebecca Marsh, Myriam Armant, Judith Kelsen, Luigi D Notarangelo, Ronald G Collman, Salima Hacein-Bey-Abina, Donald B Kohn, Marina Cavazzana, Alain Fischer, David A Williams, Sung-Yun Pai, Frederic D Bushman
BACKGROUND: Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. METHODS: Here we interrogate T cell reconstitution using four forms of high throughput analysis...
September 28, 2018: Genome Medicine
Julia Simundza
No abstract text is available yet for this article.
September 26, 2018: Genome Medicine
Cherry S Leung, Kevin Y Yang, Xisheng Li, Vicken W Chan, Manching Ku, Herman Waldmann, Shohei Hori, Jason C H Tsang, Yuk Ming Dennis Lo, Kathy O Lui
BACKGROUND: We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and costimulation blockade. However, the exact mechanisms of acquired immune tolerance in this model have remained unclear. METHODS: We utilize the NOD.Foxp3hCD2 reporter mouse line and an ablative anti-hCD2 antibody to ask if CD4+ FOXP3+ regulatory T cells (Treg) are required for coreceptor and costimulation blockade-induced immune tolerance...
September 20, 2018: Genome Medicine
Alexandra R Buckley, Trey Ideker, Hannah Carter, Olivier Harismendy, Nicholas J Schork
BACKGROUND: Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). METHODS: We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes...
September 14, 2018: Genome Medicine
Amy P Webster, Darren Plant, Simone Ecker, Flore Zufferey, Jordana T Bell, Andrew Feber, Dirk S Paul, Stephan Beck, Anne Barton, Frances M K Williams, Jane Worthington
BACKGROUND: Rheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease-discordant monozygotic twin pairs...
September 4, 2018: Genome Medicine
Romain Guérillot, Lucy Li, Sarah Baines, Brian Howden, Mark B Schultz, Torsten Seemann, Ian Monk, Sacha J Pidot, Wei Gao, Stefano Giulieri, Anders Gonçalves da Silva, Anthony D'Agata, Takehiro Tomita, Anton Y Peleg, Timothy P Stinear, Benjamin P Howden
Mutation acquisition is a major mechanism of bacterial antibiotic resistance that remains insufficiently characterised. Here we present RM-seq, a new amplicon-based deep sequencing workflow based on a molecular barcoding technique adapted from Low Error Amplicon sequencing (LEA-seq). RM-seq allows detection and functional assessment of mutational resistance at high throughput from mixed bacterial populations. The sensitive detection of very low-frequency resistant sub-populations permits characterisation of antibiotic-linked mutational repertoires in vitro and detection of rare resistant populations during infections...
August 31, 2018: Genome Medicine
Mikhail V Pogorelyy, Alla D Fedorova, James E McLaren, Kristin Ladell, Dmitri V Bagaev, Alexey V Eliseev, Artem I Mikelov, Anna E Koneva, Ivan V Zvyagin, David A Price, Dmitry M Chudakov, Mikhail Shugay
BACKGROUND: Adaptive immune responses to newly encountered pathogens depend on the mobilization of antigen-specific clonotypes from a vastly diverse pool of naive T cells. Using recent advances in immune repertoire sequencing technologies, models of the immune receptor rearrangement process, and a database of annotated T cell receptor (TCR) sequences with known specificities, we explored the baseline frequencies of T cells specific for defined human leukocyte antigen (HLA) class I-restricted epitopes in healthy individuals...
August 25, 2018: Genome Medicine
Stefano G Giulieri, Sarah L Baines, Romain Guerillot, Torsten Seemann, Anders Gonçalves da Silva, Mark Schultz, Ruth C Massey, Natasha E Holmes, Timothy P Stinear, Benjamin P Howden
BACKGROUND: Large-scale genomic studies of within-host diversity in Staphylococcus aureus bacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in management of SAB. However, available comparative genomic studies of sequential SAB isolates have tended to focus on selected cases of unusually prolonged bacteraemia, where secondary antimicrobial resistance has developed. METHODS: To understand bacterial genetic diversity during SAB more broadly, we applied whole genome sequencing to a large collection of sequential isolates obtained from patients with persistent or relapsing bacteraemia...
August 23, 2018: Genome Medicine
Michela Traglia, Lisa A Croen, Karen L Jones, Luke S Heuer, Robert Yolken, Martin Kharrazi, Gerald N DeLorenze, Paul Ashwood, Judy Van de Water, Lauren A Weiss
BACKGROUND: The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS: This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype...
August 22, 2018: Genome Medicine
Anastasia Conti, Raffaella Di Micco
No abstract text is available yet for this article.
August 17, 2018: Genome Medicine
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