Comprehensive Integration of Genome-wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter Pylori-induced Gastric Disease PDF Download
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Author: Mohamed Tarek Badr
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Abstract: Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection
Author: Mohamed Tarek Badr
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Abstract: Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection
Author: Shruti Marwaha
Publisher:
ISBN:
Category :
Languages : en
Pages : 134
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Book Description
Gastric cancer is the fifth most common malignancy in the world and third the leading cause of cancer-related mortality worldwide, with five-year survival rate of only 20-29%. In order to develop better drugs, diagnostics and preventive measures for gastric cancer, it is critical to understand the underlying molecular biology of the disease and factors that increase the risk for the disease. Helicobacter pylori-induced chronic gastritis is a major risk factor associated with gastric cancer development. We analyzed publically available gene expression data from patients with gastric cancer and patients with H. pylori mediated gastritis, to identify genes and pathways that play an important role in the two diseases. We further integrated the identified disease signature with Broad Institute's Connectivity Map to identify and prioritize drugs that can potentially reverse the molecular signature of gastric cancer cells and that of gastric tumors resistant to Cisplatin-Flurouracil (CF) chemotherapy. Our analysis identified vorinostat, trichostatin A and thiostrepton as potential therapeutic compounds for gastric cancer treatment. We identified genes and pathways that are differentially expressed (57 up-regulated and 86 down-regulated) in both gastric cancer and H. pylori mediated atrophic gastritis. The topmost pathways enriched for these genes include - cell-cell adhesion/communication, tight junctions, leukocyte transendothelial migration, gastric acid secretion, potassium ion transport and creatine pathways. Analysis of CF resistant and sensitive tumors suggests the role of metabolic and statin pathways towards resistance to the chemotherapy. We also developed a mathematical model of a sub-network comprising of sonic hedgehog (SHH), pro-inflammatory cytokines and anti-inflammatory cytokines, which play a critical role in H. pylori mediated gastritis. We integrated qPCR results, mathematical modeling technique and microarray data from H. pylori infected mice to explore the temporal behavior of the cytokine-SHH sub-network. Our mathematical model suggests that NF?B, SHH and the cytokines engage in a feedback loop which can result in damped oscillations. The model helps to bring out emergent properties of the network and generate testable hypotheses. Future experiments capturing cytokines and SHH profile over time can reveal more insights about the relationship between the different genes, their regulation and improve our current understanding of the dynamics and sequence of the events in the system.
Author: Bruna Maria Roesler
Publisher: BoD – Books on Demand
ISBN: 183881146X
Category : Science
Languages : en
Pages : 136
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Book Description
Helicobacter pylori is an universally distributed bacterium which affects more than half of the world population. H. pylori infection causes persistent inflammation with different clinical outcomes in humans, including chronic gastritis, peptic ulcer disease and gastric cancer. The infection has also been associated with several extradigestive disorders. In this book there is a comprehensive overview of contributors on H. pylori infection in diverse areas, including virulence factors of H. pylori and their importance for the clinical outcome of the diseases, discussions about the principal therapeutic regimens of bacterium eradication, also considering the antimicrobial resistance. H. pylori is clearly a very interesting bacteria and great studies and discussions about all its aspects are welcome to the medical and scientific communities.
Author: Steffen Backert
Publisher: Springer Nature
ISBN: 3031473310
Category : Medical
Languages : en
Pages : 328
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Book Description
This volume explores in detail the molecular biology, genetics and immunology of the bacterium Helicobacter pylori that causes serious gastric diseases such as gastric cancer. The book provides in-depth insights into the mechanisms of H. pylori-induced pathogenicity, gives an overview of how the bacterium colonizes the human gut, how it manages to persist in the body and which factors play a role in the development of H. pylori-induced gastric cancer. Furthermore, the interaction between the Gram-negative bacterium and the human gut microbiome is explored, and clinical management and treatment strategies to combat gastric cancer are discussed. Helicobacter pylori is an extremely successful pathogen that persistently colonizes the gut of about 50% of the world’s population. H. pylori and its human host share a long co-evolutionary relationship that dates back for at least last 100,000 years and possibly longer. Infection by this bacterium is a high-risk factor for the development of gastric diseases, including gastric cancer. Gastric cancer is associated with high morbidity and mortality and represents the 5th most common malignant tumour and the 4th leading cause of cancer-related death worldwide. H. pylori is the first bacterium that has been classified as a type-I carcinogen by the International Agency for Research on Cancer (IARC). Recent research progress identified crucial bacterial, host and environmental factors which control H. pylori-induced gastric malignancy. New studies also suggest that specific human germline mutations and other genetic aberrations have an important impact on H. pylori-induced pathology. In this volume, all these recently discovered mechanisms are reviewed in the light of gastric cancer development, and H. pylori epidemiology, virulence factors, immune evasion, pathophysiology, cancer signalling and novel therapeutic protocols are presented. This volume is aimed at researchers in the fields of immunology, genetics, microbiology and medicine who are interested in the detailed mechanisms of the pathogenicity of this carcinogenic stomach bacterium.
Author: Hervé Tettelin
Publisher: Springer Nature
ISBN: 3030382818
Category : Science
Languages : en
Pages : 311
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Book Description
This open access book offers the first comprehensive account of the pan-genome concept and its manifold implications. The realization that the genetic repertoire of a biological species always encompasses more than the genome of each individual is one of the earliest examples of big data in biology that opened biology to the unbounded. The study of genetic variation observed within a species challenges existing views and has profound consequences for our understanding of the fundamental mechanisms underpinning bacterial biology and evolution. The underlying rationale extends well beyond the initial prokaryotic focus to all kingdoms of life and evolves into similar concepts for metagenomes, phenomes and epigenomes. The book’s respective chapters address a range of topics, from the serendipitous emergence of the pan-genome concept and its impacts on the fields of microbiology, vaccinology and antimicrobial resistance, to the study of microbial communities, bioinformatic applications and mathematical models that tie in with complex systems and economic theory. Given its scope, the book will appeal to a broad readership interested in population dynamics, evolutionary biology and genomics.
Author: Albert Jeltsch
Publisher: Springer
ISBN: 3319436244
Category : Science
Languages : en
Pages : 537
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Book Description
DNA methyltransferases are important enzymes in a broad range of organisms. Dysfunction of DNA methyltransferases in humans leads to many severe diseases, including cancer. This book focuses on the biochemical properties of these enzymes, describing their structures and mechanisms in bacteria, humans and other species, including plants, and also explains the biological processes of reading of DNA methylation and DNA demethylation. It covers many emerging aspects of the biological roles of DNA methylation functioning as an essential epigenetic mark and describes the role of DNA methylation in diseases. Moreover, the book explains modern technologies, like targeted rewriting of DNA methylation by designed DNA methyltransferases, as well as technological applications of DNA methyltransferases in DNA labelling. Finally, the book summarizes recent methods for the analysis of DNA methylation in human DNA. Overall, this book represents a comprehensive state-of-the-art- work and is a must-have for advanced researchers in the field of DNA methylation and epigenetics.
Author: William B. Coleman
Publisher: Academic Press
ISBN: 0128027878
Category : Medical
Languages : en
Pages : 805
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Book Description
As the molecular basis of human disease becomes better characterized, and the implications for understanding the molecular basis of disease becomes realized through improved diagnostics and treatment, Molecular Pathology, Second Edition stands out as the most comprehensive textbook where molecular mechanisms represent the focus. It is uniquely concerned with the molecular basis of major human diseases and disease processes, presented in the context of traditional pathology, with implications for translational molecular medicine. The Second Edition of Molecular Pathology has been thoroughly updated to reflect seven years of exponential changes in the fields of genetics, molecular, and cell biology which molecular pathology translates in the practice of molecular medicine. The textbook is intended to serve as a multi-use textbook that would be appropriate as a classroom teaching tool for biomedical graduate students, medical students, allied health students, and others (such as advanced undergraduates). Further, this textbook will be valuable for pathology residents and other postdoctoral fellows that desire to advance their understanding of molecular mechanisms of disease beyond what they learned in medical/graduate school. In addition, this textbook is useful as a reference book for practicing basic scientists and physician scientists that perform disease-related basic science and translational research, who require a ready information resource on the molecular basis of various human diseases and disease states. Explores the principles and practice of molecular pathology: molecular pathogenesis, molecular mechanisms of disease, and how the molecular pathogenesis of disease parallels the evolution of the disease Explains the practice of “molecular medicine and the translational aspects of molecular pathology Teaches from the perspective of “integrative systems biology Enhanced digital version included with purchase
Author: Paul A. Schulte
Publisher: Academic Press
ISBN: 0323138578
Category : Medical
Languages : en
Pages : 609
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Book Description
This book will serve as a primer for both laboratory and field scientists who are shaping the emerging field of molecular epidemiology. Molecular epidemiology utilizes the same paradigm as traditional epidemiology but uses biological markers to identify exposure, disease or susceptibility. Schulte and Perera present the epidemiologic methods pertinent to biological markers. The book is also designed to enumerate the considerations necessary for valid field research and provide a resource on the salient and subtle features of biological indicators.
Author: Mousumi Debnath
Publisher: Springer Science & Business Media
ISBN: 9048132614
Category : Medical
Languages : en
Pages : 527
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Book Description
A rapid development in diverse areas of molecular biology and genetic engineering resulted in emergence of variety of tools. These tools are not only applicable to basic researches being carried out world over, but also exploited for precise detection of abnormal conditions in plants, animals and human body. Although a basic researcher is well versed with few techniques used by him/her in the laboratory, they may not be well acquainted with methodologies, which can be used to work out some of their own research problems. The picture is more blurred when the molecular diagnostic tools are to be used by physicians, scientists and technicians working in diagnostic laboratories in hospitals, industry and academic institutions. Since many of them are not trained in basics of these methods, they come across several gray areas in understanding of these tools. The accurate application of molecular diagnostic tools demands in depth understanding of the methodology for precise detection of the abnormal condition of living body. To meet the requirements of a good book on molecular diagnostics of students, physicians, scientists working in agricultural, veterinary, medical and pharmaceutical sciences, it needs to expose the reader lucidly to: Give basic science behind commonly used tools in diagnostics Expose the readers to detailed applications of these tools and Make them aware the availability of such diagnostic tools The book will attract additional audience of pathologists, medical microbiologists, pharmaceutical sciences, agricultural scientists and veterinary doctors if the following topics are incorporated at appropriate places in Unit II or separately as a part of Unit-III in the book. Molecular diagnosis of diseases in agricultural crops Molecular diagnosis of veterinary diseases. Molecular epidemiology, which helps to differentiate various epidemic strains and sources of disease outbreaks. Even in different units of the same hospital, the infections could be by different strains of the same species and the information becomes valuable for infection control strategies. Drug resistance is a growing problem for bacterial, fungal and parasitic microbes and the molecular biology tools can help to detect the drug resistance genes without the cultivation and in vitro sensitivity testing. Molecular diagnostics offers faster help in the selection of the proper antibiotic for the treatment of tuberculosis, which is a major problem of the in the developing world. The conventional culture and drug sensitivity testing of tuberculosis bacilli is laborious and time consuming, whereas molecular diagnosis offers rapid drug resistant gene detection even from direct clinical samples. The same approach for HIV, malaria and many more diseases needs to be considered. Molecular diagnostics in the detection of diseases during foetal life is an upcoming area in the foetal medicine in case of genetic abnormalities and infectious like TORCH complex etc. The book will be equally useful to students, scientists and professionals working in the field of molecular diagnostics.
Author: Emanuel Lebenthal
Publisher: Raven Press (ID)
ISBN:
Category : Medical
Languages : en
Pages : 854
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Book Description
