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Article ; Online: Indolent T- and NK-Cell Lymphoproliferative Disorders of the Gastrointestinal Tract

Craig R. Soderquist / Govind Bhagat

Hemato, Vol 3, Iss 18, Pp 219-

Current Understanding and Outstanding Questions

2022 Volume 231

Abstract: Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic, and ... ...

Abstract	Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic, and clinical characterization of these disorders have led to increased awareness and a better understanding of disease pathogenesis. However, many questions remain unanswered, including those concerning the cell(s) of origin, inciting immune or environmental factors, and the molecular pathways underlying disease progression and transformation. In this review, we discuss recent findings regarding the immunophenotypic and genomic spectrum of these lymphoproliferative disorders and highlight unresolved issues.
Keywords	indolent ; T-cell ; NK-cell ; lymphoproliferative disorder ; gastrointestinal tract ; genetics ; Medicine ; R
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Research publication trends regarding the extraintestinal manifestations of celiac disease

Kenneth Stier / Suzanne K. Lewis / Govind Bhagat / Peter H.R. Green

Informatics in Medicine Unlocked, Vol 17, Iss , Pp - (2019)

2019

Abstract: Introduction: Celiac disease (CD) is an autoimmune enteropathy triggered by gluten that has a poor diagnosis rate and a range of extraintestinal manifestations (EIMs), which vary in prevalence. Increasing the rate of diagnosis of, and possibly developing ...

Abstract	Introduction: Celiac disease (CD) is an autoimmune enteropathy triggered by gluten that has a poor diagnosis rate and a range of extraintestinal manifestations (EIMs), which vary in prevalence. Increasing the rate of diagnosis of, and possibly developing therapies for, CD relies on our understanding of these EIMs. We therefore tracked trends in research on EIMs of CD from 1960 to 2015, the latest complete year at the time the data were collected. Methods: We selected groups of search terms relating to distinct categories of EIMs of CD, and queried MEDLINE for the number of articles published in each year from 1960 to 2015 that mentioned both CD and any of the terms in each group. Data were normalized to the total number of publications in each year that mentioned either CD or any of those terms. For comparison, we also analyzed inflammatory bowel disease (IBD) for research trends. The resulting time series data were plotted as a five-point moving average and analyzed graphically. Results: Over the analysis time window, the overall normalized publication volume for EIMs was approximately constant for CD, but markedly increased for IBD. Bone manifestations of CD and IBD had simultaneous, comparable peaks in the decade from 2000 to 2010 and decreased since; however, CD had an earlier peak of twice the magnitude in the 1970s. Publication volume regarding central nervous system manifestations varied greatly with multiple peaks for CD, while a peak in IBD occurred in the year 1974, and the trend for IBD has been increasing since the early 1980s. Publication on ataxia has remained low in IBD with marginally increased interest in the past three decades, compared with a rapid increase in publication in the late 1990s for CD. Publication in peripheral nervous system manifestations exhibited bimodal peaks for CD (ca. 1970 and 2008) and a positive trend for IBD. Discussion: The results indicate that there is fluctuating research interest in EIMs of both CD and IBD, with more interest in EIMs of IBD as compared to CD. ...
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	001
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparison of several author indices for gauging academic productivity

Edward J. Ciaccio / Govind Bhagat / Benjamin Lebwohl / Suzanne K. Lewis / Carolina Ciacci / Peter H. Green

Informatics in Medicine Unlocked, Vol 15, Iss , Pp - (2019)

2019

Abstract: Background: Many author indices exist to gauge academic productivity. Several of these indices are calculated based upon an author's scholarly publication record, but the measurement methodology to calculate each index varies considerably, and the ... ...

Abstract	Background: Many author indices exist to gauge academic productivity. Several of these indices are calculated based upon an author's scholarly publication record, but the measurement methodology to calculate each index varies considerably, and the precise function being used, as well as the end result, is often complex and difficult to assess. Method: Two straightforward methods to weigh author productivity from the publication and citation record were evaluated as possible means for providing a clearer assessment of scholarly activity. The author characteristic index (termed c-index) assigns author rank for each publication based upon author position. The characteristic prime (c') -index normalizes author rank from author position, so that the total weight per publication is unity. The top 10 scholars with keyword 'celiac disease' in the Google Scholar database were then assessed using these metrics. Rankings according to total number of publications, h-index, and c- and c'-indices were compared, then tabulated along with total papers included for assessment, and mean values per paper for author position, number of authors, citations, and year of publication. Results: The order of the top ten authors with keyword 'celiac disease' varied substantially depending upon whether the h-index, c-index, or c'-index was used as a gauge. The characteristic indices assign credit to authors according to their position in an author list. The affiliated metrics provided a more complete picture of scholarly activity. Conclusions: Academic achievement by scholars, based upon quantitative publication characteristics, has recently become of interest for evaluating job candidates, for determining work performance, and for bestowing awards and honors. The characteristic indices as described herein are readily calculated and interpreted, and may improve the assessment of scholarly activity. Keywords: Author index, Author rank, Celiac disease, c-index, h-index
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	001
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Trends in gluten research and its relationship to autoimmune and allergic diseases

Edward J. Ciaccio / Govind Bhagat / Suzanne K. Lewis / Peter H. Green

Informatics in Medicine Unlocked, Vol 3, Iss , Pp 7-

2016 Volume 14

Abstract: Introduction: Gluten is a protein found in certain grains, and causes an autoimmune response in celiac disease patients. Although the subject of considerable research, gluten research foci and future directions are largely unknown. Methods: The MEDLINE ... ...

Abstract	Introduction: Gluten is a protein found in certain grains, and causes an autoimmune response in celiac disease patients. Although the subject of considerable research, gluten research foci and future directions are largely unknown. Methods: The MEDLINE search tool was used to evaluate research trends. For perspective, yearly publications on gluten and other celiac disease reactive proteins were compared to food allergy proteins research. Then the relationship of gluten publications to affiliated keywords was determined. The affiliated keywords belonged to one of several groups: grains, vitamins and minerals, interaction, autoimmunity, genetics, or enzymes. The yearly number of publications in the peer-reviewed medical literature was determined for each relationship from years 1960â2013. The relationships were graphed, and linear regression analysis was used to determine the rate of change in publications per year, and the coefficient of determination. Results: Among celiac disease reactive proteins (gluten, gliadin, and glutenin) and selected food allergy proteins (ovalbumin, lysozyme, ovomucoid, and Ara h), gluten showed the greatest rate of increase in published medical research (+20.01 studies/year since 1996, r2=0.97). Additionally, there were sharp increases in the rate of gluten research publications per year in association with keywords âautoimmunityâ (+7.69 studies/year since 1997), âwheatâ (+6.08 studies/year since 1999), and âtransglutaminaseâ enzyme (+5.05 studies/year since 1995). The longest running moderate trend was research on âglutenâ and âantibodiesâ (+2.50 studies/year, r2=0.92 since 1971). Conclusions: Research on gluten as a reactive protein is of rapidly growing interest in the medical literature. MEDLINE is helpful to determine foci and future directions. Keywords: Celiac disease, Gluten, Gliadin, Medline, Transglutaminase
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	001
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice

Veronica S. Gil / Govind Bhagat / Louise Howell / Jiyuan Zhang / Chae H. Kim / Sven Stengel / Francisco Vega / Arthur Zelent / Kevin Petrie

Disease Models & Mechanisms, Vol 9, Iss 12, Pp 1483-

2016 Volume 1495

Abstract: Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary ...

Abstract	Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.
Keywords	HDAC9 ; Lymphoma ; Transgenic mouse ; Medicine ; R ; Pathology ; RB1-214
Subject code	570
Language	English
Publishing date	2016-12-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Implementation of a polling protocol for predicting celiac disease in videocapsule analysis

Edward J Ciaccio / Christina A Tennyson / Govind Bhagat / Suzanne K Lewis / Peter H Green

World Journal of Gastrointestinal Endoscopy, Vol 5, Iss 7, Pp 313-

2013 Volume 322

Abstract: AIM: To investigate the presence of small intestinal villous atrophy in celiac disease patients from quantitative analysis of videocapsule image sequences. METHODS: Nine celiac patient data with biopsy-proven villous atrophy and seven control patient ... ...

Abstract	AIM: To investigate the presence of small intestinal villous atrophy in celiac disease patients from quantitative analysis of videocapsule image sequences. METHODS: Nine celiac patient data with biopsy-proven villous atrophy and seven control patient data lacking villous atrophy were used for analysis. Celiacs had biopsy-proven disease with scores of Marsh II-IIIC except in the case of one hemophiliac patient. At four small intestinal levels (duodenal bulb, distal duodenum, jejunum, and ileum), video clips of length 200 frames (100 s) were analyzed. Twenty-four measurements were used for image characterization. These measurements were determined by quantitatively processing the videocapsule images via techniques for texture analysis, motility estimation, volumetric reconstruction using shape-from-shading principles, and image transformation. Each automated measurement method, or automaton, was polled as to whether or not villous atrophy was present in the small intestine, indicating celiac disease. Each automaton’s vote was determined based upon an optimized parameter threshold level, with the threshold levels being determined from prior data. A prediction of villous atrophy was made if it received the majority of votes (≥ 13), while no prediction was made for tie votes (12-12). Thus each set of images was classified as being from either a celiac disease patient or from a control patient. RESULTS: Separated by intestinal level, the overall sensitivity of automata polling for predicting villous atrophy and hence celiac disease was 83.9%, while the specificity was 92.9%, and the overall accuracy of automata-based polling was 88.1%. The method of image transformation yielded the highest sensitivity at 93.8%, while the method of texture analysis using subbands had the highest specificity at 76.0%. Similar results of prediction were observed at all four small intestinal locations, but there were more tie votes at location 4 (ileum). Incorrect prediction which reduced sensitivity occurred for two celiac patients with Marsh type II pattern, which is characterized by crypt hyperplasia, but normal villous architecture. Pooled from all levels, there was a mean of 14.31 ± 3.28 automaton votes for celiac vs 9.67 ± 3.31 automaton votes for control when celiac patient data was analyzed (P < 0.001). Pooled from all levels, there was a mean of 9.71 ± 2.8128 automaton votes for celiac vs 14.32 ± 2.7931 automaton votes for control when control patient data was analyzed (P < 0.001). CONCLUSION: Automata-based polling may be useful to indicate presence of mucosal atrophy, indicative of celiac disease, across the entire small bowel, though this must be confirmed in a larger patient set. Since the method is quantitative and automated, it can potentially eliminate observer bias and enable the detection of subtle abnormality in patients lacking a clear diagnosis. Our paradigm was found to be more efficacious at proximal small intestinal locations, which may suggest a greater presence and severity of villous atrophy at proximal as compared with distal locations.
Keywords	Automata ; Celiac disease ; Small intestine ; Videocapsule ; Villous atrophy ; Diseases of the digestive system. Gastroenterology ; RC799-869 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Gastroenterology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Surgery ; RD1-811 ; DOAJ:Surgery
Subject code	610
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Baishideng Publishing Group Co., Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MYC protein expression in primary diffuse large B-cell lymphoma of the central nervous system.

Kamraan Z Gill / Fabio Iwamoto / Ashleigh Allen / Daniela Hoehn / Vundavalli V Murty / Bachir Alobeid / Govind Bhagat

PLoS ONE, Vol 9, Iss 12, p e

2014 Volume 114398

Abstract: Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare, aggressive subtype of DLBCL, the biology of which is poorly understood. Recent studies have suggested a prognostic role of MYC protein expression in systemic DLBCL, ...

Abstract	Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare, aggressive subtype of DLBCL, the biology of which is poorly understood. Recent studies have suggested a prognostic role of MYC protein expression in systemic DLBCL, but little is known about the frequency and significance of MYC protein expression in CNS DLBCL. Hence, we investigated MYC protein expression profiles of CNS DLBCL and assessed the relationship between MYC expression and a variety of histopathologic, immunophenotypic, genetic, and clinical features. Fifty-nine CNS DLBCL diagnosed at our institution over the past 13 years were evaluated. The majority of cases (80%) showed centroblastic morphology, and 12 (20%) displayed a perivascular pattern of infiltration. According to the Hans criteria, 41 (69%) cases had a non-germinal center B-cell and 18 (31%) had a germinal center B-cell cell-of-origin (COO) phenotype. Mean MYC protein expression was 50% (median: 50%, range: 10-80%). Forty-three cases (73%) showed MYC overexpression (≥ 40%), and 35 (60%) showed MYC/BCL2 coexpression. MYC overexpression was seen in the single case harboring MYC translocation and in the cases showing increased copies of MYC (27%); however, no significant difference in mean MYC expression was seen between groups harboring or lacking MYC aberrations. In our series, age was associated with a significantly increased risk of death, and the perivascular pattern of infiltration was associated with a significantly increased risk of disease progression. Neither MYC expression (with or without BCL2 coexpression) nor other variables, including COO subtype were predictive of clinical outcome. Our findings indicate that the proportion of CNS DLBCL overexpressing MYC is higher compared to systemic DLBCL, and MYC overexpression appears to be independent of genetic MYC abnormalities. Thus, MYC expression and other immunophenotypic markers used for prognostication of systemic DLBCL might not apply to CNS DLBCL due to differences in disease biology.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Indolent small intestinal CD4+ T-cell lymphoma is a distinct entity with unique biologic and clinical features.

Elizabeth Margolskee / Vaidehi Jobanputra / Suzanne K Lewis / Bachir Alobeid / Peter H R Green / Govind Bhagat

PLoS ONE, Vol 8, Iss 7, p e

2013 Volume 68343

Abstract: Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well ... ...

Abstract	Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 570
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs

Catherine Do / Emmanuel L. P. Dumont / Martha Salas / Angelica Castano / Huthayfa Mujahed / Leonel Maldonado / Arunjot Singh / Sonia C. DaSilva-Arnold / Govind Bhagat / Soren Lehman / Angela M. Christiano / Subha Madhavan / Peter L. Nagy / Peter H. R. Green / Rena Feinman / Cornelia Trimble / Nicholas P. Illsley / Karen Marder / Lawrence Honig /

Catherine Monk / Andre Goy / Kar Chow / Samuel Goldlust / George Kaptain / David Siegel / Benjamin Tycko

Genome Biology, Vol 21, Iss 1, Pp 1-

2020 Volume 39

Abstract: Abstract Background Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, ... ...

Abstract	Abstract Background Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. Results We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative “chromatin deserts.” Conclusions ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.
Keywords	Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation

Wang, Richard C / Beth Levine / Govind Bhagat / Guanghua Xiao / Julia Reichelt / Michael White / Yongjie Wei / Zhenyi An / Zhongju Zou

Science. 2012 Nov. 16, v. 338, no. 6109

2012

Abstract: Getting Autophagy to Akt The protein kinase Akt is often activated in human cancers and is thought to promote tumor formation. One way in which it may do so is to inhibit autophagy (a process by which the cell digests its own proteins or organelles, ... ...

Abstract	Getting Autophagy to Akt The protein kinase Akt is often activated in human cancers and is thought to promote tumor formation. One way in which it may do so is to inhibit autophagy (a process by which the cell digests its own proteins or organelles, especially damaged ones). Wang et al. (p. 956, published online 25 October; see the Perspective by Koren and Kimchi) provide a direct molecular mechanism by which Akt regulates autophagy. Beclin, a component of the autophagy machinery, appears to be a direct target of phosphorylation by Akt. Such phosphorylation enhanced interaction of Beclin with intermediate filaments of the cyto skeleton and inhibited autophagy. Expression of a modified Beclin 1 molecule that could not be phosphorylated by Akt inhibited Akt-induced transformation of cells in culture and tumor formation in a mouse model.
Keywords	animal models ; autophagy ; carcinogenesis ; humans ; intermediate filaments ; neoplasms ; organelles ; phosphorylation ; protein kinases ; proteins ; skeleton
Language	English
Dates of publication	2012-1116
Size	p. 956-959.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1225967
Database	NAL-Catalogue (AGRICOLA)

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