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Genome Medicine

Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Eric Q Konnick, Colin C Pritchard
Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Correct assessment of a genetic variant relies on the clinical context and knowledge of the underlying biology. We outline four scenarios encountered in genetic testing where careful consideration of the origin of genetic variation is required for variant interpretation.
October 5, 2016: Genome Medicine
Ewan M Harrison, Catherine Ludden, Hayley J Brodrick, Beth Blane, Gráinne Brennan, Dearbháile Morris, Francesc Coll, Sandra Reuter, Nicholas M Brown, Mark A Holmes, Brian O'Connell, Julian Parkhill, M Estee Török, Martin Cormican, Sharon J Peacock
BACKGROUND: Long-term care facilities (LTCF) are potential reservoirs for methicillin-resistant Staphylococcus aureus (MRSA), control of which may reduce MRSA transmission and infection elsewhere in the healthcare system. Whole-genome sequencing (WGS) has been used successfully to understand MRSA epidemiology and transmission in hospitals and has the potential to identify transmission between these and LTCF. METHODS: Two prospective observational studies of MRSA carriage were conducted in LTCF in England and Ireland...
October 3, 2016: Genome Medicine
Jun Chen, Yoshitaka Toyomasu, Yujiro Hayashi, David R Linden, Joseph H Szurszewski, Heidi Nelson, Gianrico Farrugia, Purna C Kashyap, Nicholas Chia, Tamas Ordog
BACKGROUND: Nutritional interventions often fail to prevent growth failure in childhood and adolescent malnutrition and the mechanisms remain unclear. Recent studies revealed altered microbiota in malnourished children and anorexia nervosa. To facilitate mechanistic studies under physiologically relevant conditions, we established a mouse model of growth failure following chronic dietary restriction and examined microbiota in relation to age, diet, body weight, and anabolic treatment...
October 3, 2016: Genome Medicine
Carlota Rubio-Perez, Jordi Deu-Pons, David Tamborero, Nuria Lopez-Bigas, Abel Gonzalez-Perez
BACKGROUND: Profiling the somatic mutations of genes which may inform about tumor evolution, prognostics and treatment is becoming a standard tool in clinical oncology. Commercially available cancer gene panels rely on manually gathered cancer-related genes, in a "one-size-fits-many" solution. The design of new panels requires laborious search of literature and cancer genomics resources, with their performance on cohorts of patients difficult to estimate. RESULTS: We present OncoPaD, to our knowledge the first tool aimed at the rational design of cancer gene panels...
October 3, 2016: Genome Medicine
Marc-Emmanuel Dumas, Céline Domange, Sophie Calderari, Andrea Rodríguez Martínez, Rafael Ayala, Steven P Wilder, Nicolas Suárez-Zamorano, Stephan C Collins, Robert H Wallis, Quan Gu, Yulan Wang, Christophe Hue, Georg W Otto, Karène Argoud, Vincent Navratil, Steve C Mitchell, John C Lindon, Elaine Holmes, Jean-Baptiste Cazier, Jeremy K Nicholson, Dominique Gauguier
BACKGROUND: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus occurs through complex organ-specific cellular mechanisms and networks contributing to impaired insulin secretion and insulin resistance. Genome-wide gene expression profiling systems can dissect the genetic contributions to metabolome and transcriptome regulations. The integrative analysis of multiple gene expression traits and metabolic phenotypes (i.e., metabotypes) together with their underlying genetic regulation remains a challenge...
September 30, 2016: Genome Medicine
W Jiang, C Johnson, N Simecek, M R López-Álvarez, D Di, J Trowsdale, J A Traherne
Killer cell immunoglobulin-like receptors (KIRs), expressed on natural killer cells and T cells, have considerable biomedical relevance playing significant roles in immunity, pregnancy and transplantation. The KIR locus is one of the most complex and polymorphic regions of the human genome. Extensive sequence homology and copy number variation makes KIRs technically laborious and expensive to type. To aid the investigation of KIRs in human disease we developed a high-throughput, multiplex real-time polymerase chain reaction method to determine gene copy number for each KIR locus...
September 29, 2016: Genome Medicine
Nuno Rodrigues Faria, Ester C Sabino, Marcio R T Nunes, Luiz Carlos Junior Alcantara, Nicholas J Loman, Oliver G Pybus
The World Health Organization has declared Zika virus an international public health emergency. Knowledge of Zika virus genomic epidemiology is currently limited due to challenges in obtaining and processing samples for sequencing. The ZiBRA project is a United Kingdom-Brazil collaboration that aims to improve this situation using new sequencing technologies.
September 29, 2016: Genome Medicine
Anna Maria Seekatz, Anna Maria Rao, Kavitha Santhosh, Vincent Bensan Young
BACKGROUND: Recurrent Clostridium difficile infection (CDI) remains problematic, with up to 30 % of individuals diagnosed with primary CDI experiencing at least one episode of recurrence. The success of microbial-based therapeutics, such as fecal microbiota transplantation, for the treatment of recurrent CDI underscores the importance of restoring the microbiota. However, few studies have looked at the microbial factors that contribute to the development of recurrent disease. Here we compare microbial changes over time in patients with or without recurrence to identify microbial signatures associated with the development of recurrence...
April 27, 2016: Genome Medicine
Amy Langdon, Nathan Crook, Gautam Dantas
The widespread use of antibiotics in the past 80 years has saved millions of human lives, facilitated technological progress and killed incalculable numbers of microbes, both pathogenic and commensal. Human-associated microbes perform an array of important functions, and we are now just beginning to understand the ways in which antibiotics have reshaped their ecology and the functional consequences of these changes. Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food...
April 13, 2016: Genome Medicine
Andrew E Jaffe, Joel E Kleinman
Several recent studies have investigated either genetic or epigenetic variation in schizophrenia. A recent study presents comprehensive analyses of blood samples to better characterize the combined role of genetic and epigenetic variation in schizophrenia. While the paper identifies significant associations with schizophrenia risk and diagnosis, the potential relevance to the brain in schizophrenia is questionable.
2016: Genome Medicine
Julianne M O'Daniel, Jonathan S Berg
For genomic medicine research to be fully translated into clinical care, it is critical for researchers to engage stakeholders who ultimately regulate the use of genomic technologies and therapeutics within healthcare practice. Herein, we describe an example of how this might work.
2016: Genome Medicine
Nils Grabole, Jitao David Zhang, Stefan Aigner, Nadine Ruderisch, Veronica Costa, Felix C Weber, Michel Theron, Nikolaos Berntenis, Olivia Spleiss, Martin Ebeling, Gene W Yeo, Ravi Jagasia, Anna Kiialainen
BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumor growths in multiple organs and neurological symptoms induced by mTOR hyperfunction. Because the molecular pathology is highly complex and the etiology poorly understood, we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology and suggest new targets for treatment. METHODS: We investigate the disease phenotype of TSC by neural differentiation of a human stem cell model that had been deleted for TSC2 by genome editing...
2016: Genome Medicine
Jose P Silva, Guerline Lambert, Derek van Booven, Claes Wahlestedt
BACKGROUND: Epidemiological and animal studies have reported that prenatal nicotine exposure (PNE) leads to obesity and type-2 diabetes in offspring. Central leptin-melanocortin signaling via hypothalamic arcuate proopiomelanocortin (POMC) neurons is crucial for the regulation of energy and glucose balance. Furthermore, hypothalamic POMC neurons were recently found to mediate the anorectic effects of nicotine through activation of acetylcholine receptors. Here, we hypothesized that PNE impairs leptin-melanocortinergic regulation of energy balance in first-generation offspring by altering expression of long non-coding RNAs (lncRNAs) putatively regulating development and/or function of hypothalamic POMC neurons...
2016: Genome Medicine
Sebastian Kirchner, B Joanne Power, Andrew P Waters
Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection...
2016: Genome Medicine
Thuy Doan, Michael R Wilson, Emily D Crawford, Eric D Chow, Lillian M Khan, Kristeene A Knopp, Brian D O'Donovan, Dongxiang Xia, Jill K Hacker, Jay M Stewart, John A Gonzales, Nisha R Acharya, Joseph L DeRisi
BACKGROUND: Ocular infections remain a major cause of blindness and morbidity worldwide. While prognosis is dependent on the timing and accuracy of diagnosis, the etiology remains elusive in ~50 % of presumed infectious uveitis cases. The objective of this study is to determine if unbiased metagenomic deep sequencing (MDS) can accurately detect pathogens in intraocular fluid samples of patients with uveitis. METHODS: This is a proof-of-concept study, in which intraocular fluid samples were obtained from five subjects with known diagnoses, and one subject with bilateral chronic uveitis without a known etiology...
2016: Genome Medicine
Andrew E Teschendorff, Shijie C Zheng, Andy Feber, Zhen Yang, Stephan Beck, Martin Widschwendter
BACKGROUND: Hypermethylation of transcription factor promoters bivalently marked in stem cells is a cancer hallmark. However, the biological significance of this observation for carcinogenesis is unclear given that most of these transcription factors are not expressed in any given normal tissue. METHODS: We analysed the dynamics of gene expression between human embryonic stem cells, fetal and adult normal tissue, as well as six different matching cancer types. In addition, we performed an integrative multi-omic analysis of matched DNA methylation, copy number, mutational and transcriptomic data for these six cancer types...
2016: Genome Medicine
Hao Hu, Hilary Coon, Man Li, Mark Yandell, Chad D Huff
BACKGROUND: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes. RESULTS: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level...
2016: Genome Medicine
Peter Humburg, Narelle Maugeri, Wanseon Lee, Bert Mohr, Julian C Knight
BACKGROUND: The heat shock transcriptional response is essential to effective cellular function under stress. This is a highly heritable trait but the nature and extent of inter-individual variation in heat shock response remains unresolved. METHODS: We determined global transcription profiles of the heat shock response for a panel of lymphoblastoid cell lines established from 60 founder individuals in the Yoruba HapMap population. We explore the observed differentially expressed gene sets following heat shock, establishing functional annotations, underlying networks and nodal genes involving heat shock factor 1 recruitment...
2016: Genome Medicine
Jordi Serra-Musach, Francesca Mateo, Eva Capdevila-Busquets, Gorka Ruiz de Garibay, Xiaohu Zhang, Raj Guha, Craig J Thomas, Judit Grueso, Alberto Villanueva, Samira Jaeger, Holger Heyn, Miguel Vizoso, Hector Pérez, Alex Cordero, Eva Gonzalez-Suarez, Manel Esteller, Gema Moreno-Bueno, Andreas Tjärnberg, Conxi Lázaro, Violeta Serra, Joaquín Arribas, Mikael Benson, Mika Gustafsson, Marc Ferrer, Patrick Aloy, Miquel Àngel Pujana
BACKGROUND: Cancer patients often show no or only modest benefit from a given therapy. This major problem in oncology is generally attributed to the lack of specific predictive biomarkers, yet a global measure of cancer cell activity may support a comprehensive mechanistic understanding of therapy efficacy. We reasoned that network analysis of omic data could help to achieve this goal. METHODS: A measure of "cancer network activity" (CNA) was implemented based on a previously defined network feature of communicability...
2016: Genome Medicine
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