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Andreyev H.J.N.,Gastrointestinal Unit | Benton B.E.,Gastrointestinal Unit | Lalji A.,Gastrointestinal Unit | Norton C.,King's College London | And 4 more authors.
The Lancet | Year: 2013

Background Chronic gastrointestinal symptoms after pelvic radiotherapy are common, multifactorial in cause, and affect patients' quality of life. We assessed whether such patients could be helped if a practitioner followed an investigative and management algorithm, and whether outcomes differed by whether a nurse or a gastroenterologist led this algorithm-based care. Methods For this three-arm randomised controlled trial we recruited patients (aged ≥18 years) from clinics in London, UK, with new-onset gastrointestinal symptoms persisting 6 months after pelvic radiotherapy. Using a computergenerated random isation sequence, we randomly allocated patients to one of three groups (1:1:1; stratified by tumour site [urological, gynaecological, or gastrointestinal], and degree of bowel dysfunction [IBDQ-B score <60 vs 60-70]): usual care (a detailed self-help booklet), gastroenterologist-led algorithm-based treatment, or nurse-led algorithm-based treatment. The primary endpoint was change in Inflammatory Bowel Disease Questionnaire-Bowel subset score (IBDQ-B) at 6 months, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00737230. Findings Between Nov 26, 2007, and Dec 12, 2011, we enrolled and randomly allocated 218 patients to treatment: 80 to the nurse group, 70 to the gastroenterologist group, and 68 to the booklet group (figure). Most had a baseline IBDQ-B score indicating moderate-to-severe symptoms. We recorded the following pair-wise mean difference in change in IBDQ-B score between groups: nurse versus booklet 4·12 (95% CI 0·04-8·19; p=0·04), gastroenterologist versus booklet 5·47 (1·14-9·81; p=0·01). Outcomes in the nurse group were not inferior to outcomes in the gastroenterologist group (mean difference 1·36, one sided 95% CI -1·48). Interpretation Patients given targeted intervention following a detailed clinical algorithm had better improvements in radiotherapy-induced gastrointestinal symptoms than did patients given usual care. Our findings suggest that, for most patients, this algorithm-based care can be given by a trained nurse.


News Article | December 5, 2016
Site: www.eurekalert.org

Researchers from Massachusetts General Hospital (MGH) and the University of California, Riverside, have shown for the first time that RNA interference (RNAi) - an antiviral mechanism known to be used by plants and lower organisms - is active in the response of human cells to some important viruses. In their report receiving advance online publication in Nature Microbiology, the investigators document both the production of RNAi molecules in human cells infected with the influenza A virus and the suppression of RNAi defense by a viral protein known to block the process in a common animal model. "Viruses are the most abundant infectious agents and are a constant threat to human health," says Kate Jeffrey, PhD, of the Gastrointestinal Unit in the MGH Department of Medicine, co-corresponding author of the paper. "Vaccines are somewhat effective but can have limited use when viruses like influenza rapidly mutate from year to year. Identifying therapeutic targets within patients that could help them fight off an infection is a critical strategy for combating the spread of common, often-dangerous viruses." First described in the 1990s - a discovery that led to the 2006 Nobel Prize - RNAi is a process by which organisms suppress the expression of target genes through the action of small RNA segments that bind to corresponding gene sequences. Not only is RNAi used to regulate gene expression within an organism, it also can combat viral infection by silencing the activity of viral genes required for the pathogen's replication. Whether or not RNAi contributes to antiviral defense in mammals has been uncertain. The only previous demonstration - by researchers led by Shou-Wei Ding, PhD, a professor of Plant Pathology and Microbiology at UC Riverside and co-corresponding author of the current study - was done in embryonic stem cells and in newborn mice. Ding has been studying antiviral RNAi for more than two decades and also was the first to describe the action of the influenza virus protein NS1 in blocking RNAi in fruit flies. His team collaborated with investigators from Jeffrey's laboratory to investigate whether or not an RNAi response is induced in human and mouse cells infected with the influenza virus, one of many important viruses using RNA as its genetic material. Their experiments verified that influenza-A-infected mature human cells do generate the small RNA segments used in RNAi but that virally-produced NS1 blocks the processing of those molecules into the complexes that bind to and silence their target genes. If cells were infected with an influenza A mutant lacking NS1, they proceeded to produce large number of the molecular complexes required for RNAi, which include a protein called Argonaute that slices through the target gene. Experiments in cells with an inactivated form of Argonaute - which contributes only to the antiviral and not the gene regulation activity of RNAi - confirmed that they were observing an antiviral RNAi response. The observation that a viral protein called VP35, which is used by the Ebola and Marburg viruses to suppress RNAi, suggests that RNAi may also be active against those dangerous pathogens and other viruses that utilized RNA as their genetic code or in their replication cycle. "We now need to assess more directly the role of antiviral RNAi in human infectious diseases caused by RNA viruses - which include Ebola, West Nile and Zika along with influenza - and how harnessing or boosting the antiviral RNAi response could be used to reduce the severity of these infections," says Jeffrey, who is an assistant professor of Medicine at Harvard Medical School. "Bringing the expertise of Dr. Ding's team, which specializes in the RNAi biology of lower organisms, together with my group that specializes in mammalian immunology was a perfect match." The teams will continue to work together to investigate some of these questions. The co-lead authors of the Nature Microbiology paper are Yang Li, Jinfeng Lu and Shu-Wei Dong, University of California, Riverside; and Megha Basavappa, Massachusetts General Hospital. Additional co-authors are Alexander Cronkite, John Prior, Hans-Christian Reinecker and Sihem Cheloufi, MGH; Yanhong Han, Wan-Xiang Li and Fedor Karginov, UC Riverside; and Paul Hertzog, Hudson Institute of Medical Research, Victoria, Australia. Support for the study includes National Institutes of Health grants R01 AI107087, R01 AI52447 and R56 AI110579. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."


News Article | November 4, 2016
Site: www.sciencedaily.com

A study led by investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and two academic medical centers in the Netherlands has begun to elucidate how differences in the gut microbiome -- the microbial population of the gastrointestinal tract -- affect the immune response in healthy individuals. The study is one of three related papers published in this week's issue of Cell, the other two looking at genetic and environmental influences, as part of the Human Functional Genomics Project (HFGP). "The underlying premise of the HFGP is that the immune system is a perfect target for studying human variation and the intersection of genes and the environment," says Ramnik Xavier, MD, PhD, chief of the MGH Gastrointestinal Unit, an institute member at the Broad and a principal investigator of the HFGP. "We know that some people are more susceptible to infections than others; some develop autoimmune diseases while most don't. In these studies we wanted to see how genes affect the immune system, how environmental factors affect susceptibility and in this investigation, whether and how the gut microbiome influences the immune system's response to various pathogens." The microbiome study -- led by Xavier and Mihai Netea, MD, PhD, of Radboud University Medical Center in the Netherlands -- analyzed blood and stool samples from 500 healthy Western European HFGP participants to look for individual variations in immune responses to pathogens, represented by production of molecules called cytokines; variations in the gut microbiome, and how those two factors relate to each other. Immune cells from individual participants were exposed to three bacterial stimulants -- the commensal microbe B. fragilis, the common pathogen S. aureus, and a toxin produced by E. coli -- and two forms of the Candida fungus. Their response was reflected in the production of cytokines, proteins through which immune cells exert many of their effects. Looking at possible relationships between immune responses and the microbiome in individual participants, the investigators found clear patterns by which both the population of the microbiome and its function, reflected in the production of proteins called metabolites, interact with the immune response. Some of those interactions depended on the particular pathogen, some on the cytokines, and some on both. Among the team's observations was how, depending on the specific pathogenic stimulus, breakdown of the amino acid tryptophan into the metabolite tryptophol can inhibit production of the cytokine TNF-alpha. They also identified an effect of palmitoleic acid -- a fatty acid found in several dietary oils and known to suppress some immune activities -- on production of the cytokine gamma interferon, although the precise mechanism is yet to be discovered. The Isselbacher Professor of Medicine in Gastroenterology at Harvard Medical School and a member of the MGH Center for Computational and Integrative Biology, Xavier says, "We still don't have all the components, but the overall picture suggests that variations in the gut microbiome change production of the metabolites that go on to educate or influence immune cells, leading to differential outcomes when immune cells are exposed to various infections." The accompanying studies, on which he is a co-author, found similar influences on immune response by environmental factors -- including the season of the year as well as participants' age and gender -- and most powerfully, by genetic differences. Among the next steps, Xavier notes, will be conducting similar studies in individuals with specific diseases and in participants from other parts of the world. "By understanding how all of these complex mechanisms -- genetics, microbiome and environment -- drive variations in the immune response, we may be able to identify factors responsible for individual patients' susceptibilities and better target therapies," he says.


News Article | November 3, 2016
Site: www.eurekalert.org

A study led by investigators at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and two academic medical centers in the Netherlands has begun to elucidate how differences in the gut microbiome - the microbial population of the gastrointestinal tract - affect the immune response in healthy individuals. The study is one of three related papers published in this week's issue of Cell, the other two looking at genetic and environmental influences, as part of the Human Functional Genomics Project (HFGP). "The underlying premise of the HFGP is that the immune system is a perfect target for studying human variation and the intersection of genes and the environment," says Ramnik Xavier, MD, PhD, chief of the MGH Gastrointestinal Unit, an institute member at the Broad and a principal investigator of the HFGP. "We know that some people are more susceptible to infections than others; some develop autoimmune diseases while most don't. In these studies we wanted to see how genes affect the immune system, how environmental factors affect susceptibility and in this investigation, whether and how the gut microbiome influences the immune system's response to various pathogens." The microbiome study - led by Xavier and Mihai Netea, MD, PhD, of Radboud University Medical Center in the Netherlands - analyzed blood and stool samples from 500 healthy Western European HFGP participants to look for individual variations in immune responses to pathogens, represented by production of molecules called cytokines; variations in the gut microbiome, and how those two factors relate to each other. Immune cells from individual participants were exposed to three bacterial stimulants - the commensal microbe B. fragilis, the common pathogen S. aureus, and a toxin produced by E. coli - and two forms of the Candida fungus. Their response was reflected in the production of cytokines, proteins through which immune cells exert many of their effects. Looking at possible relationships between immune responses and the microbiome in individual participants, the investigators found clear patterns by which both the population of the microbiome and its function, reflected in the production of proteins called metabolites, interact with the immune response. Some of those interactions depended on the particular pathogen, some on the cytokines, and some on both. Among the team's observations was how, depending on the specific pathogenic stimulus, breakdown of the amino acid tryptophan into the metabolite tryptophol can inhibit production of the cytokine TNF-alpha. They also identified an effect of palmitoleic acid - a fatty acid found in several dietary oils and known to suppress some immune activities - on production of the cytokine gamma interferon, although the precise mechanism is yet to be discovered. The Isselbacher Professor of Medicine in Gastroenterology at Harvard Medical School and a member of the MGH Center for Computational and Integrative Biology, Xavier says, "We still don't have all the components, but the overall picture suggests that variations in the gut microbiome change production of the metabolites that go on to educate or influence immune cells, leading to differential outcomes when immune cells are exposed to various infections." The accompanying studies, on which he is a co-author, found similar influences on immune response by environmental factors - including the season of the year as well as participants' age and gender - and most powerfully, by genetic differences. Among the next steps, Xavier notes, will be conducting similar studies in individuals with specific diseases and in participants from other parts of the world. "By understanding how all of these complex mechanisms - genetics, microbiome and environment - drive variations in the immune response, we may be able to identify factors responsible for individual patients' susceptibilities and better target therapies," he says. Melanie Schirmer, PhD, of the Broad Institute is lead author of the Cell paper. Additional co-authors are Hera Vlamakis, Eric Franzosa, and Curtis Huttenhower, Broad Institute; Sanne Smeekens Martin Jaeger, Marije Oosting, Trees Jansen, Liesbeth Jacobs and Leo Joosten, Radboud University Medical Center; and Marc Jan Bonder, Alexander Kurilshikov, Jingyuan Fu, Alexandra Zhernakova, and Cisca Wijmenga, University Medical Center, Groningen, the Netherlands. Support for the study includes National Institutes of Health grants U54DK102557 and R01DK092405, Juvenile Diabetes Research Foundation grant 17-2011-529, Crohn's and Colitis Foundation of America grant 20144126, and support from the Helmsley Charitable Trust Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."


Wedlake L.,Royal Marsden NHS Foundation Trust | Wedlake L.,King's College London | Slack N.,King's College London | Andreyev H.J.N.,Gastrointestinal Unit | Whelan K.,King's College London
Inflammatory Bowel Diseases | Year: 2014

Background: Dietary fiber may favorably influence fermentation, gastrointestinal inflammation, and disease progression in Crohn's disease, ulcerative colitis (UC), and pouchitis and offer an attractive therapeutic addition to pharmacological treatment. This systematic review appraised data from randomized controlled trials of fiber in the management of inflammatory bowel disease. Methods: The review followed Cochrane and PRISMA recommendations. Seven electronic databases were searched along with hand searching and contacting experts. Inclusion criteria were randomized controlled trials of the effects of fiber on clinical endpoints (primarily disease activity for treatment or maintenance) or physiological outcomes in patients with inflammatory bowel disease. Results: In total, 23 randomized controlled trials fulfilled the inclusion criteria (UC, 10; Crohn's disease, 12; and pouchitis, 1) recruiting 1296 patients. In UC, 3/10 studies reported fiber supplementation to benefit disease outcomes. In Crohn's disease, 0/12 studies and in pouchitis 1/1 study reported a benefit on disease activity. Despite this, a number of studies reported favorable intragroup effects on physiological outcomes including fecal butyrate, fecal calprotectin, inflammatory cytokines, microbiota, and gastrointestinal symptom indices. Meta-analysis was not possible. Conclusions: There is limited weak evidence for the efficacy of fiber in improving disease outcomes in UC and pouchitis. The potential antiinflammatory role of fiber is intriguing and merits further investigation in adequately powered clinical trials. Excluding overt gastrointestinal obstruction, there was no evidence that fiber intake should be restricted in patients with inflammatory bowel disease. Copyright © 2014 Crohn's & Colitis Foundation of America, Inc.


Gupta N.K.,Gastrointestinal Unit | Masia R.,Massachusetts General Hospital
American Journal of Surgical Pathology | Year: 2013

Cord colitis syndrome (CCS) is a recently described diarrheal illness of uncertain pathogenesis that affects recipients of umbilical cord blood transplant and is associated with negative cultures. CCS exhibits a peculiar histopathologic appearance, as it commonly manifests as granulomatous inflammation involving the upper and lower gastrointestinal tract, with features of chronicity in the colon. Importantly, the treatment for CCS differs from that for acute graft-versus-host disease, which is commonly in the clinical differential diagnosis: CCS responds to antibiotic treatment, whereas acute graft-versus-host disease responds to immunosuppression. We describe here the case of a 36-year-old woman with a history of acute myeloid leukemia who developed refractory diarrhea after cord blood transplant. Endoscopic biopsies of the stomach and colon revealed granulomatous inflammation, consisting of scattered ill-defined aggregates of epithelioid histiocytes, with associated mild neutrophilic inflammation and mildly increased epithelial cell apoptosis. In the colon, the granulomatous inflammation was associated with surface epithelial injury (including surface erosions) and contained occasional multinucleated epithelioid giant cells. Paneth cell metaplasia was present in the distal colon, but crypt architecture was preserved, and there was no basal lymphoplasmacytosis. Special stains and immunohistochemical stains for infectious organisms were negative. A diagnosis of CCS was made, and the patient promptly responded to treatment with ciprofloxacin and metronidazole. We present this case to raise awareness among pathologists of this newly described entity, in order to facilitate its timely diagnosis and treatment. © 2013 Lippincott Williams and Wilkins.


Shimoyama S.,Gastrointestinal Unit
Hepato-Gastroenterology | Year: 2011

Background/Aims: Statin is the most promising agent in the improvement of blood lipid profiles, and a substantial risk reduction of subsequent cardiovascular events leads to a rapid increase in current prescription rates. However, statin use or a lower total cholesterol has been associated with an increased cancer risk, although some deny such an association. Whether a positive statincancer association exists or not remains a matter of debate because such a causal association, if any, may offset anticipated cardioprotective benefits from statins. So far, no statin-cancer association in gastric cancer has been systematically highlighted in the literature. Methodology: Original studies concerning the effect of statins on gastric cancer incidence were searched in PubMed Central published between 1993 and 2008. A manual search was additionally performed though reference lists in the retrieved manuscripts. Pooled gastric or upper gastrointestinal cancer risk ratio (RR) with 95% confidence interval (CI) was independently calculated by random effects model, provided by the Cochrane Library software Review Manager 5. Results: Six publications were considered finally eligible, three were for gastric cancer risk and three were for upper gastrointestinal cancer risk. Statin use proved no significant increase (RR; 1.37, 95% CI; 0.57-3.25) in gastric cancer risk, nor was there any evidence of increased risk (RR; 1.20, 95% CI; 0.94-1.53) even in upper gastrointestinal cancer. Conclusions: These results suggest that statins had no short-term effect on gastric or upper gastrointestinal cancer incidence. Further investigation of long-term associations between statin use and gastric cancer is warranted. © H.G.E. Update Medical Publishing S.A.


Purpose: Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies. Methods: Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins. Results: In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies. Conclusions: It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia. © 2011 Springer-Verlag.


Ciuffreda D.,Gastrointestinal Unit | Kim A.Y.,Harvard University
Current Opinion in HIV and AIDS | Year: 2011

Purpose of review: The goal of this study is to review key recent findings related to the immunopathogenesis of hepatitis C virus (HCV) infection, especially in regards to T lymphocytes. It aims to complement other reviews in this issue on the roles of host genetics (IL-28B), acute HCV infection (when disease outcome is determined) and other factors that may influence fibrosis progression (microbial translocation). The main focus is on specific immunity and T cells in the context of success and failure to control viral infection. Recent findings: This review focuses on two areas of intense interest in the recent literature: the relationship between the human leukocyte antigen (HLA), class I-restricted T-cell responses and the evolution of the virus and the role of inhibitory markers on T cells in the immunopathogenesis of HCV. When appropriate, we compare findings from studies of HIV-specific immunity. Summary: From examining the virus and the mutational changes associated with T-cell responses and from analyzing the markers on T cells, there have been numerous advances in the understanding of immune evasion mechanisms employed by HCV. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Shimoyama S.,Gastrointestinal Unit
World Journal of Gastroenterology | Year: 2013

Aim: To investigate the association and quantify the relationship between diabetes mellitus (DM) and gastric cancer (GC) by an updated meta-analysis. Methods: The initial PubMed search identified 1233 publications. Studies not reporting GC or those not reporting actual number of GC were excluded. Twelve pertinent studies were retrieved from the PubMed database or from a manual search and considered for the meta-analysis. Pooled risk ratios and 95%CI were estimated by a random-effects model. Subgroup analysis was performed according to gender or geographical regions. Heterogeneity and publication bias were evaluated by I 2 and funnel plot analysis, respectively. Results: DM was significantly associated with GC with a RR of 1.41 (P = 0.006) (95%CI: 1.10-1.81). Subgroup analyses revealed that both sexes showed a significant association with GC, with a greater magnitude of risk in females (RR = 1.90; 95%CI: 1.27-2.85; P = 0.002) than in males (RR = 1.24; 95%CI: 1.08-1.43; P = 0.002). In addition, the link between DM and GC was significant in East Asian DM patients (RR = 1.77; 95%CI: 1.38-2.26; P < 0.00001) but not in Western DM patients (RR = 1.23; 95%CI: 0.90-1.68; P = 0.2). There was no evidence of publication bias, but the results indicated significant heterogeneity. Conclusion: This updated meta-analysis has provided evidence of positive DM-GC associations. The limited information on potentially important clinical confounding factors in each study deserves further investigation. © 2013 Baishideng. All rights reserved.

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