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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
Scott Martin, Abhilash I Chiramel, Marie Luisa Schmidt, Yu-Chi Chen, Nadia Whitt, Ari Watt, Eric C Dunham, Kyle Shifflett, Shelby Traeger, Anne Leske, Eugen Buehler, Cynthia Martellaro, Janine Brandt, Lisa Wendt, Andreas Müller, Stephanie Peitsch, Sonja M Best, Jürgen Stech, Stefan Finke, Angela Römer-Oberdörfer, Allison Groseth, Heinz Feldmann, Thomas Hoenen
BACKGROUND: The 2014-2016 Ebola virus (EBOV) outbreak in West Africa highlighted the need for improved therapeutic options against this virus. Approaches targeting host factors/pathways essential for the virus are advantageous because they can potentially target a wide range of viruses, including newly emerging ones and because the development of resistance is less likely than when targeting the virus directly. However, systematic approaches for screening host factors important for EBOV have been hampered by the necessity to work with this virus at biosafety level 4 (BSL4)...
August 7, 2018: Genome Medicine
Lidia Mateo, Oriol Guitart-Pla, Miquel Duran-Frigola, Patrick Aloy
BACKGROUND: The widespread incorporation of next-generation sequencing into clinical oncology has yielded an unprecedented amount of molecular data from thousands of patients. A main current challenge is to find out reliable ways to extrapolate results from one group of patients to another and to bring rationale to individual cases in the light of what is known from the cohorts. RESULTS: We present OncoGenomic Landscapes, a framework to analyze and display thousands of cancer genomic profiles in a 2D space...
August 3, 2018: Genome Medicine
Yan Y Lam, Chenhong Zhang, Liping Zhao
We provide a conceptual framework to establish a causal link between diet, gut microbiota, and health. Identifying the key strains that mediate microbe-host interactions and understanding the mechanisms involved and the ecology of these strains are critical to translating gut microbiome research into clinical applications and to advancing a new concept of "microbiome nutrition".
August 1, 2018: Genome Medicine
Petar Scepanovic, Cécile Alanio, Christian Hammer, Flavia Hodel, Jacob Bergstedt, Etienne Patin, Christian W Thorball, Nimisha Chaturvedi, Bruno Charbit, Laurent Abel, Lluis Quintana-Murci, Darragh Duffy, Matthew L Albert, Jacques Fellay
BACKGROUND: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines...
July 27, 2018: Genome Medicine
Sohini Sengupta, Sam Q Sun, Kuan-Lin Huang, Clara Oh, Matthew H Bailey, Rajees Varghese, Matthew A Wyczalkowski, Jie Ning, Piyush Tripathi, Joshua F McMichael, Kimberly J Johnson, Cyriac Kandoth, John Welch, Cynthia Ma, Michael C Wendl, Samuel H Payne, David Fenyö, Reid R Townsend, John F Dipersio, Feng Chen, Li Ding
BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO...
July 27, 2018: Genome Medicine
Jinzhou Yuan, Hanna Mendes Levitin, Veronique Frattini, Erin C Bush, Deborah M Boyett, Jorge Samanamud, Michele Ceccarelli, Athanassios Dovas, George Zanazzi, Peter Canoll, Jeffrey N Bruce, Anna Lasorella, Antonio Iavarone, Peter A Sims
BACKGROUND: Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). METHODS: We sampled the cellular milieu of HGGs by profiling dissociated human surgical specimens with a high-density microwell system for massively parallel single-cell RNA-Seq. We analyzed the resulting profiles to identify subpopulations of both HGG and microenvironmental cells and applied graph-based methods to infer structural features of the malignantly transformed populations...
July 24, 2018: Genome Medicine
Na Zhu, Carrie L Welch, Jiayao Wang, Philip M Allen, Claudia Gonzaga-Jauregui, Lijiang Ma, Alejandra K King, Usha Krishnan, Erika B Rosenzweig, D Dunbar Ivy, Eric D Austin, Rizwan Hamid, Michael W Pauciulo, Katie A Lutz, William C Nichols, Jeffrey G Reid, John D Overton, Aris Baras, Frederick E Dewey, Yufeng Shen, Wendy K Chung
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD. METHODS: To identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients...
July 20, 2018: Genome Medicine
Sabrina Grasse, Matthias Lienhard, Steffen Frese, Martin Kerick, Anne Steinbach, Christina Grimm, Michelle Hussong, Jana Rolff, Michael Becker, Felix Dreher, Uwe Schirmer, Stefan Boerno, Anna Ramisch, Gunda Leschber, Bernd Timmermann, Christian Grohé, Heike Lüders, Martin Vingron, Iduna Fichtner, Sebastian Klein, Margarete Odenthal, Reinhard Büttner, Hans Lehrach, Holger Sültmann, Ralf Herwig, Michal R Schweiger
BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed. METHODS: Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies...
July 20, 2018: Genome Medicine
Vinay K Kartha, Khalid A Alamoud, Khikmet Sadykov, Bach-Cuc Nguyen, Fabrice Laroche, Hui Feng, Jina Lee, Sara I Pai, Xaralabos Varelas, Ann Marie Egloff, Jennifer E Snyder-Cappione, Anna C Belkina, Manish V Bais, Stefano Monti, Maria A Kukuruzinska
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments...
July 20, 2018: Genome Medicine
Lin Zhou, Fangqing Zhao
Unraveling functional noncoding variants associated with complex diseases is still a great challenge. We present a novel algorithm, Prioritization And Functional Assessment (PAFA), that prioritizes and assesses the functionality of genetic variants by introducing population differentiation measures and recalibrating training variants. Comprehensive evaluations demonstrate that PAFA exhibits much higher sensitivity and specificity in prioritizing noncoding risk variants than existing methods. PAFA achieves improved performance in distinguishing both common and rare recurrent variants from non-recurrent variants by integrating multiple annotations and metrics...
July 11, 2018: Genome Medicine
Annie N Cowell, Hugo O Valdivia, Danett K Bishop, Elizabeth A Winzeler
BACKGROUND: Plasmodium vivax poses a significant challenge to malaria elimination due to its ability to cause relapsed infections from reactivation of dormant liver parasites called hypnozoites. We analyzed 69 P. vivax whole genome sequences obtained from subjects residing in three different villages along the Peruvian Amazon. This included 23 paired P. vivax samples from subjects who experienced recurrent P. vivax parasitemia following observed treatment with chloroquine and primaquine...
July 4, 2018: Genome Medicine
Vítor Borges, Miguel Pinheiro, Pedro Pechirra, Raquel Guiomar, João Paulo Gomes
BACKGROUND: A new era of flu surveillance has already started based on the genetic characterization and exploration of influenza virus evolution at whole-genome scale. Although this has been prioritized by national and international health authorities, the demanded technological transition to whole-genome sequencing (WGS)-based flu surveillance has been particularly delayed by the lack of bioinformatics infrastructures and/or expertise to deal with primary next-generation sequencing (NGS) data...
June 29, 2018: Genome Medicine
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