Cellular and Molecular Gastroenterology and Hepatology

Editor picks for Cellular and Molecular Gastroenterology and Hepatology

Factors Associated With Missed and Cancelled Colonoscopy Appointments at Veterans Health Administration Facilities We examined individual and organizational factors associated with missed and cancelled colonoscopy appointments in Veteran Health Administration facilities.
Jan. 21, 2016

Proton Pump Inhibitors, Irritable Bowel Syndrome, and Small Intestinal Bacterial Overgrowth: Coincidence or Newton's Third Law Revisited?
Dec. 1, 2014

Spontaneous Control of Primary Hepatitis C Virus Infection and Immunity Against Persistent Reinfection
Oct. 27, 2014

Endoscopist-Directed Administration of Propofol: A Worldwide Safety Experience
Oct. 22, 2014

Activation of ?-Catenin and Yap1 in Human Hepatoblastoma and Induction of Hepatocarcinogenesis in Mice
Sept. 5, 2014

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  • Bacterial Encroachment in Metabolic Syndrome: TooMuchTogetherness?

    As our understanding of the intestinal microbiotas structure, function, regulation, and wide-ranging influence on human health grows, several important roadblocks to therapeutic targeting remain. First is the descriptive nature of most studies to date, which in many cases have documented steady-state phenotypes without investigating causeeffect relationships. Substantive progress is underway in this direction, with a number of investigators beginning to mechanistically address causal relationships using mouse models and direct manipulation or transfer of microbial populations.
  • The microbiome activates CD4 T-cell-mediated immunity to compensate for increased intestinal permeability

    Despite common perceptions, studies of human subjects and experimental animals show that intestinal barrier loss is insufficient to induce disease in healthy individuals. Here, we define a compensatory immune response that prevents pathogen invasion in mice with chronic barrier loss.
  • Do animal models of acute pancreatitis reproduce human disease?

    Multiple animal models of clinical pancreatitis have been developed, however, limitations with respect to the pathobiology of human disease, makes it difficult to assess the validity of animal models. Though the growing availability of human pancreatic acinar cells are likely to provide information on early pancreatitis events that can be meaningfully compared to animal models, the relevance of animals to later events may be more difficult to obtain.
  • Maintaining a Vibrant and Productive Laboratory as a Senior Investigator

    This issues columnist for Paths and Places is Dr James Boyer, the Ensign Professor of Medicine at Yale, former president of the American Association for the Study of Liver Diseases, as well as the International Association for the Study of the Liver, and a senior investigator who runs a vigorous and impactful research program funded by a grant currently in its 40th year. We asked Dr Boyer to discuss his decision to maintain a research program (as opposed to switching his focus to teaching or administration) at this stage of his career.
  • Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic Tumorigenesis

    Transforming growth factor beta (TGF) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGF activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterodimeric receptors. Previous studies investigating TGF-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive.
  • Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma

    Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolicgene alterations that repeatedly occur in liver cancer arelargely unknown. We aimed to identify metabolic genesthat are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC).
  • Clocking the Pace of Organoid Research

    Organoids are 3-dimensional structures that reflect some of the complex features of a native tissue, making them organ like.1,2 Organoids have seen a rapid growth in popularity and are becoming a mainstay in gastrointestinal research, owing in part to the ability of organoids to recapitulate some physiological functions of the tissue from which they are derived. For example, intestinal organoids possess the full complement of epithelial cell types and, unlike most other invitro systems, provide the cellular heterogeneity of the native intestine.
  • A Twist in the Tale of a Pig Model of Short-Bowel Syndrome

    Short-bowel syndrome (SBS) occurs after a long surgical resection of small intestine. This results in malabsorption of nutrients, especially lipids, and is associated with the development of liver disease. It is particularly serious in infants. The contributions of altered lipid metabolism, bile acid physiology, dysbiosis, and supplemental enteral or parenteral nutrition to the development of this pathology remain unclear, and a piglet model has provided useful evidence due to various similarities with humans.
  • Of Mice and Men and Metaplasia

    Metaplasia, the process in which one type of adult tissue replaces another, is a consequence of chronic tissue injury.1 In the esophagus, gastroesophageal reflux disease (GERD) is the condition that chronically injures the squamous epithelium and causes its replacement by the intestinal-type, columnar epithelium of Barretts esophagus.2 The cell of origin for this columnar metaplasia remains unknown, but a number of candidates have been proposed. For example, GERD might cause mature esophageal squamous cells to change into columnar cells (transdifferentiation) or stimulate immature esophageal progenitor cells (in the squamous epithelium or in the ducts of esophageal submucosal glands) to differentiate abnormally into columnar cells (transcommitment).
  • Epigenetics and Liver Fibrosis

    Liver fibrosis arises because prolonged injury combined with excessive scar deposition within hepatic parenchyma arising from overactive wound healing response mediated by activated myofibroblasts. Fibrosis is the common end point for any type of chronic liver injury including alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cholestatic liver diseases. Although genetic influences are important, it is epigenetic mechanisms that have been shown to orchestrate many aspects of fibrogenesis in the liver.
  • Barretts Stem Cells as a Unique and TargetableEntity

    Although metaplasias have always attracted because of their strangeness, it is now clear they represent precursors for some of the most intractable human cancers. Despite this notoriety, they remain curiously understudied, and even their origins have been the subject of acrimonious debate stretching back to Virchow in the 19th century. Barretts esophagus, with its high incidence, easy endoscopic access, and strong link to esophageal adenocarcinoma, would seem an ideal opportunity to address the origin problem.
  • Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor

    Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp3+ regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon.
  • The Circadian Clock Gene BMAL1 Coordinates IntestinalRegeneration

    The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied.
  • Columnar Metaplasia in Three Types of Surgical Mouse Models of Esophageal Reflux

    Esophageal adenocarcinoma develops in the setting of gastroesophageal reflux and columnar metaplasia in distal esophagus. Columnar metaplasia arising in gastroesophageal reflux models has developed in rat; however, gastroesophageal reflux models in mice have not been well-characterized.
  • Mend Your Fences

    The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohns disease. For a long time, research into the pathophysiology of IBD has been focused on immune cellmediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cellintrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells.
  • Metaplasia in the Stomach Arises From Gastric Chief Cells

    The development of intestinal-type gastric cancer is preceded by loss of parietal cells (oxyntic atrophy) and the induction of metaplastic cell lineages in the gastric mucosa. For example, mouse models have shown that spasmolytic polypeptide-expressing metaplasia can develop following oxyntic atrophy through transdifferentiation of zymogen-secreting chief cells. Evolution of spasmolytic polypeptide-expressing metaplasia from chief cells occurs via a coordinated dismantling of their secretory apparatus and reprogramming of their transcriptome.
  • Regulation of Gastric Carcinogenesis by InflammatoryCytokines

    Chronic inflammation caused by infection with Helicobacter pylori and autoimmune gastritis increases an individuals risk of developing gastric cancer. More than 90% of gastric cancers are adenocarcinomas, which originate from epithelial cells in the chronically inflamed gastric mucosa. However, only a small subset of chronic gastritis patients develops gastric cancer, implying a role for genetic and environmental factors in cancer development. A number of DNA polymorphisms that increase gastric cancer risk have mapped to genes encoding cytokines.
  • Gastrin and Gastric Cancer

    Gastric cancer is the third leading cause of cancer-related mortality worldwide. Despite progress in understanding itsdevelopment, challenges with treatment remain. Gastrin, apeptide hormone, is trophic for normal gastrointestinal epithelium. Gastrin also has been shown to play an important role in the stimulation of growth of several gastrointestinal cancers including gastric cancer. We sought to review theroleof gastrin and its pathway in gastric cancer and itspotential as a therapeutic target in the management ofgastric cancer.
  • Initiation and Maintenance of Gastric Cancer: A Focus on CD44 Variant Isoforms and Cancer Stem Cells

    Gastric cancer is the third most common cause of cancer-related death. Although the incidence of gastric cancer in the United States is relatively low, it remains significantly higher in some countries, including Japan and Korea. Interactions between cancer stem cells and the tumor microenvironment can have a substantial impact on tumor characteristics and contribute to heterogeneity. The mechanisms responsible for maintaining malignant cancer stem cells within the tumor microenvironment in human gastric cancer are largely unknown.
  • Self-renewing Monolayer of Primary Colonic or Rectal Epithelial Cells

    Three-dimensional organoid culture has fundamentally changed the invitro study of intestinal biology enabling novel assays; however, its use is limited because of an inaccessible luminal compartment and challenges to data gathering in a three-dimensional hydrogel matrix. Long-lived, self-renewing 2-dimensional (2-D) tissue cultured from primary colon cells has not been accomplished.
  • Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohns DiseaseLike Ileitis: What is the Right Model?

    Crohns disease and ulcerative colitis, together known as inflammatory bowel disease, are debilitating chronic disorders of unknown cause and cure. Our evolving understanding of these pathologies is enhanced greatly by the use of animal models of intestinal inflammation that allow invivo mechanistic studies, preclinical evaluation of new therapies, and investigation into the causative factors that underlie disease pathogenesis. Several animal models, most commonly generated in mice, exist for the study of colitis.
  • Origin of Barretts Epithelium: Esophageal Submucosal Glands

    The origin of the progenitor cell for Barretts esophagus remains a major unsolved mystery. Understanding the source of this progenitor may improve strategies to prevent the development of esophageal adenocarcinoma. Esophageal submucosal glands (ESMGs) and ducts may serve as a potential source of progenitor cells that respond to esophageal injury. Through the use of human histologic and molecular analysis, ESMGs and ducts have been described in physical continuity with areas of columnar esophagus, and shared mutations have been described between ESMG ducts and Barretts esophagus.
  • The Esophageal Squamous Epithelial CellStill a Reasonable Candidate for theBarretts Esophagus Cell ofOrigin?

    Barrett's esophagus is the metaplastic change of the squamous epithelium lining the distal esophagus into an intestinalized columnar epithelium that predisposes to esophageal adenocarcinoma development. The cell that gives rise to Barrett's esophagus has not been identified definitively, although several sources for the Barrett's esophagus cell of origin have been postulated. One possible source is a fully differentiated squamous epithelial cell or a squamous epithelial progenitor or stem cell native to the esophagus that, through molecular reprogramming, either transdifferentiation or transcommitment, could give rise to an intestinalized columnar cell.
  • Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus

    The acquisition of genetic/epigenetic mutations in long-lived gastrointestinal stem cells leads to the development of cancer, as well as precancerous lesions such as metaplasia and dysplasia. In the proximal stomach corpus, this model of progression from stem cells has been supported by studies in mice and human beings, showing abundant proliferation in the isthmus and clonal expansion of mutated cells from the stem cell region. An alternative theory proposes that gastric metaplasia arises from mature differentiated chief cells.
  • Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism butExacerbates Liver Damage in a Piglet Model of Short-BowelSyndrome

    Options for the prevention of short-bowel syndromeassociated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs.
  • Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis

    Bcl-xL, an anti-apoptotic Bcl-2 family protein, is overexpressed in 90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, Bcl-xL expression in pancreatic intraepithelial neoplasias (PanINs) and its significance in PDAC carcinogenesis remain unclear. The aim of this study was to elucidate the significance of Bcl-xL expression in PanINs.
  • A B-Cell Gene Signature Correlates With the Extent of Gluten-Induced Intestinal Injury in Celiac Disease

    Celiac disease (CeD) provides an opportunity to study autoimmunity and the transition in immune cells as dietary gluten induces small intestinal lesions.
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