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Biomedical subjects

Govind Bhagat

Publications and source records attributed to Govind Bhagat.

At least 19 recordsLinked to original sources
PubMed2026

An inflammatory bowel disease-linked lncRNA suppresses transcription factor T-BET expression in T cells to limit intestinal inflammation.

Among the tens of thousands of annotated long noncoding RNAs (lncRNAs) in the human genome, only a small fraction have been functionally characterized. Here, we show that a well-established inflammatory bowel disease (IBD) risk locus encoded a conserved lncRNA, lnc15 (2310015A10Rik/ENSMUSG00000097729), whose structure was destabilized by risk-associated variants, leading to its degradation. Deletion of lnc15 in mice resulted in molecular features of inflammation under steady-state conditions and conferred heightened susceptibility to experimental colitis. Lnc15 was abundantly expressed in T cells, with highest expression in regulatory T (Treg) cells. Mechanistically, lnc15 suppressed the transcription factor T-BET by recruiting the CCR4-NOT RNA degradation complex to Tbx21 mRNA. Our study identifies that lnc15 simultaneously enhances Treg cell suppressive function and impairs conventional T cell pathogenicity in the context of intestinal inflammation. Collectively, these findings identify lnc15 as a functional lncRNA that links noncoding genetic variation to immune regulation and prevention of mucosal inflammation. VIDEO ABSTRACT.

RNA, Long Noncoding↗
PubMed2007

Pediatric ALK+ anaplastic large cell lymphoma with t(3;8)(q26.2;q24) translocation and c-myc rearrangement terminating in a leukemic phase.

Pediatric ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is usually associated with a favorable prognosis. ALK+ ALCL associated with a leukemic phase is uncommon, but has been associated with an aggressive clinical course and unfavorable prognosis. Overexpression of c-myc has been shown to be a consistent finding in ALK+, but not ALK-negative ALCL (ALK- ALCL), and the c-myc gene is considered a downstream target of deregulated ALK signaling. We describe a pediatric ALK+ ALCL with a leukemic phase at relapse. Similar to other rare cases described in the literature, it followed an aggressive clinical course despite multiple regimens of chemotherapy and bone marrow transplantation. Lymphoma cells showed aberrant ALK expression and c-myc overexpression. In addition to the characteristic t(2;5)(p23;q35) translocation, a t(3;8)(q26.2;q24) translocation was also present, and c-myc gene rearrangement was confirmed by FISH analysis. The findings in this case demonstrate the association of peripheral blood leukemic involvement and aggressive clinical course, and suggest that other factors, such as c-myc rearrangement, may be responsible for the aggressive clinical behavior in ALK+ ALCL.

Anaplastic Lymphoma Kinase↗
PubMed2007

Hepatitis C-associated granulomas after liver transplantation: morphologic spectrum and clinical implications.

Liver granulomas have been described in biopsy specimens from people with de novo chronic hepatitis C virus (HCV) infection and in allograft biopsy specimens from recipients of transplants for HCV-related liver disease. The latter have not been well studied, and there are no data regarding the prevalence, morphologic spectrum, and clinical significance of HCV-associated granulomas after liver transplantation. We observed granulomas in allograft liver biopsy specimens of 4 (8%) of 53 recipients of transplants for HCV-related end-stage liver disease during a 3-year period. Initial appearance of granulomas ranged from 4 to 41 weeks after transplantation. Lobular and portal nonnecrotizing, epithelioid granulomas and lobular microgranulomas were observed, with the latter predominating. Serum transaminase and alkaline phosphatase levels were significantly higher in patients with granulomas than in age- and sex-matched control subjects, but histologic disease activity, cellular rejection scores, HCV genotypes, viral titers, and retransplantation rate owing to recurrent disease were not significantly different. Our study suggests that a granulomatous response to HCV infection occurs in a subset of patients after transplantation; however, this histologic finding does not portend a worse clinical outcome.

Adult↗
PubMed2006

Cytogenetic analysis of B-cell posttransplant lymphoproliferations validates the World Health Organization classification and suggests inclusion of florid follicular hyperplasia as a precursor lesion.

Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)-like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein-Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM-like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD.

Adolescent↗
PubMed2006

Intrachromosomal rearrangement of chromosome 3q27: an under recognized mechanism of BCL6 translocation in B-cell non-Hodgkin lymphoma.

Balanced reciprocal translocations involving chromosomal region 3q27, which led to identification of the BCL6 protooncogene, are one of the most common recurrent chromosomal abnormalities reported in B-cell non-Hodgkin lymphomas (B-NHL). Cloning of the breakpoints of these translocations has facilitated the identification of a number of BCL6 partners including immunoglobulin genes and more than 20 non-immunoglobulin genes on almost all human chromosomes. Fusion of BCL6 with these genes leads to deregulated BCL6 expression because of substitution of its promoter with that of the translocation partner. Despite the promiscuous nature of BCL6 translocations, intrachromosomal rearrangements of the BCL6 gene have not been well recognized. In the present study, we present evidence for intrachromosomal rearrangements, because of interstitial deletions and inversions, involving region 3q27 as an overlooked mechanism of BCL6 deregulation. These rearrangements accounted for 3/20 (15%) of all BCL6 translocations occurring in B-NHL, including follicular lymphomas, diffuse large B-cell lymphomas, and marginal zone B-cell lymphomas, diagnosed at our institute. In addition to confirming previously described partner loci on chromosome 3, we also identified a novel BCL6 partner locus (3p24) that to our knowledge has not been reported previously. Our data should help facilitate the identification of new BCL6 partner genes, which may enhance our understanding of the clinical and biological role of BCL6 in B-NHL pathogenesis.

Adult↗
PubMed2006

Reprogramming of CTLs into natural killer-like cells in celiac disease.

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.

Base Sequence↗
PubMed2006

Celiac disease in African-Americans.

Celiac disease is generally under diagnosed in the United States and it is unclear whether the disease is encountered in ethnic minorities. Our purpose is to describe a case series of African-American patients with celiac disease. Nine (1.3%) African-American patients with celiac disease were identified from a prospectively generated database of 700 patients with biopsy proven celiac disease and seen between 1981 and 2004. Females predominated, with seven, compared to two males. Diarrhea was the presentation in only two patients, while three presented with iron deficiency anemia. One third had at least one autoimmune disease. Compliance with a gluten-free diet, the only medical therapy of this disease, was poor. Only four patients adhered strictly to the diet. Celiac disease occurs in African-Americans and may well be underdiagnosed. Special attention needs to be given to methods that encourage adherence to the diet in minority groups.

Adult↗
PubMed2006

Adult-onset nemaline myopathy and monoclonal gammopathy.

A 45-year-old man with severe proximal muscle weakness had findings diagnostic of adult-onset nemaline myopathy. He also had a monoclonal gammopathy. This is the fifth report of adult-onset nemaline myopathy in a patient with monoclonal gammopathy, suggesting that the occurrence of these entities may be more than a chance association. Myocyte-bound immunoglobulin or light chains were not detected and immunotherapy was not effective in this patient. Other causes of adult-onset nemaline myopathy were ruled out, including the most common mutations of sarcomeric thin filament genes.

Bone Marrow↗
PubMed2006

Increased risk of papillary thyroid cancer in celiac disease.

Patients with celiac disease have an increased rate of malignancies that are not limited to lymphomas. Thyroid carcinoma has not previously been associated with celiac disease. However, among a cohort of patients with celiac disease, we identified an increased risk of papillary carcinoma of the thyroid, standard morbidity ratio of 22.52 (95% confidence interval 14.90-34.04; P < .001), compared to United States national surveillance data. These patients were on a gluten-free diet. Only 1 had Hashimoto's thyroiditis, suggesting that mechanisms apart from autoimmune thyroiditis contribute to the increased risk of carcinoma of the thyroid in celiac disease.

Adult↗
PubMed2006

Development of hairy cell leukemia in a patient after cardiac transplantation.

Post-transplant lymphoproliferative disorders (PTLDs) are well-recognized complications of bone marrow and solid organ transplantation, comprising a heterogenous group of lymphoproliferations with a spectrum of morphologic, phenotypic and molecular features. Although PTLDs are usually Epstein-Barr virus-driven B-cell lymphoproliferations, T/natural killer-cell lymphoproliferations, multiple myeloma, and Hodgkin's lymphoma are also recognized as part of the PTLD spectrum. Hairy cell leukemia, a low-grade B-cell lymphoproliferation, has not been recognized as part of the PTLD spectrum. We report the first case of hairy cell leukemia occurring after cardiac transplantation. It is unclear whether this case, similar to other cases of low-grade B-cell lymphoproliferations reported after transplantation, is related to immunosuppression and therefore part of the spectrum of PTLDs, or merely represents coincidental event occurring in an immunocompromised patient.

Antineoplastic Agents↗
PubMed2006

Perioperative immunomodulation with Flt3 kinase ligand or a whole tumor cell vaccine is associated with a reduction in lung metastasis formation after laparotomy in mice.

INTRODUCTION: Laparotomy has been associated with temporary postoperative immunosuppression and accelerated tumor growth in experimental models. In a previous murine study, a whole cell vaccine plus the adjuvant monophosphoryl-lipid A was shown to be effective in decreasing the number of lung metastases that develop after laparotomy. This study was conducted to assess the impact of the adjuvant fetal liver tyrosine kinase 3 (Flt3) ligand on perioperative tumor growth when used alone or with a tumor cell vaccine. METHODS: An intravenous tumor cell injection lung metastases model was used. Sixty female A/J mice were divided into six equal groups designated (1) anesthesia control (AC), (2) AC with Flt3 ligand (ACFlt3), (3) sham laparotomy (OP), (4) OP with Flt3 ligand (OPFlt3), (5) OP with vaccine (OPVac), and (6) OP with Flt3 ligand and vaccine (OPFlt3Vac). Groups 2, 4, and 6 received daily intraperitoneal injections of Flt3 ligand (10 microg/dose with carrier) for 5 days before and 5 days after surgery. Groups 1 and 3 received similar injections of saline on the same schedule. Groups 5 and 6 were vaccinated with irradiated whole Ta3Ha tumor cells intraperitoneally three times before and twice after surgery. Immediately after surgery, all mice were injected with 10(5) Ta3Ha tumor cells via a tail vein. After 14 days, the mice were sacrificed and their lungs and tracheas were excised en bloc. Specimens were stained and counterstained with India ink and Fekete solution, and surface metastases were counted by a blinded observer. Differences between study groups were determined by analysis of variance. The peritumoral inflammatory cell infiltrate of some Flt3 and control specimens was also assessed. RESULTS: Regarding laparotomy, Flt3 ligand (mean, 1.22 metastases), whole cell vaccine (1.12 metastases), and the combination of these two agents (0.1 metastases) were each effective in significantly decreasing the number of surface lung metastases compared with surgery alone (9.88 metastases, P < .05 for all comparisons). There were no differences between the various treatment groups in regards to number of metastases. Only the combination of Flt3 and the vaccine significantly lowered the incidence of tumors (number of mice with > or =1 tumors). Histologic analysis revealed that the Flt3-treated mice demonstrated increased numbers of antigen-presenting cells surrounding the tumors compared with controls. CONCLUSIONS: Perioperative treatment with either Flt3 ligand or a whole cell tumor vaccine significantly reduced the number of lung metastases after laparotomy. The combination of the Flt3 ligand and the vaccine also decreased the incidence of metastases and was the most effective treatment. Further studies regarding perioperative immune modulation in the setting of cancer appear warranted.

Adenocarcinoma↗
PubMed2006

Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling.

BACKGROUND AND OBJECTIVES: In early and polymorphic post-transplant lymphoproliferative disorders (PTLD) Epstein-Barr virus (EBV), through its latency proteins, drives the proliferation of B lymphocytes, a process which in immunocompetent individuals leads to the establishment of latently infected memory B cells. DESIGN AND METHODS: We analyzed 11 cases, which included early and polymorphic PTLD, and 12 controls for latency of EBV infection and their antigenic profile. RESULTS: We identified a minority of terminally differentiated EBER+ IRTA1+ memory B cells and EBER+ CD138+ PRDM1+ plasma cells in these samples. These elements were identified both in PTLD and in tumor-free tonsils from post-transplant patients but not in EBV- control tonsils. The expression of EBV latency proteins is heterogeneous, and is associated with activation of the NF-kB pathway. EBV signaling (through EBNA2, LMP1 and LMP2A) and NF-kB activation correlated with upregulation of target proteins: cMYC, JunB, CCL22, TRAF1 and IRF4. EBV-infected lymphocytes in early and polymorphic PTLDs represent a mixture of latencies II, III and, in at least 1/3 of infected cells, of latency 0. INTERPRETATION AND CONCLUSIONS: EBV infection correlates with NF-kB activation, with EBV-dependent cell signaling, and lastly, with the presence of EBV-infected plasma cells and memory cells.

Adolescent↗
PubMed2005

Alpha-thalassemia major presenting in a term neonate without hydrops.

We describe the clinical and pathologic features of an unusual case of alpha-thalassemia major in a patient who survived to term and lived for 9 days. The neonate was nonhydropic and the clinical picture was dominated by severe hypoxia with pulmonary hypertension. The diagnosis was not suspected until postnatal examination of the blood smear, which prompted the performance of hemoglobin electrophoresis and subsequent molecular confirmation. This case illustrates that alpha-thalassemia major should be in the differential diagnosis of hypoxic neonates even in the absence of hydrops.

Diagnosis, Differential↗
PubMed2005

Fatal CNS vasculopathy in a patient with refractory celiac disease and lymph node cavitation.

Celiac disease is an enteropathy occurring in genetically predisposed individuals due to a dietary intolerance to gluten. Patients with celiac disease may develop a neurological disorder of unknown cause, although autoimmune mechanisms are suspected. We report on a 56-year-old man with celiac disease, who became refractory to a gluten-free diet and died of a rapidly progressive encephalopathy. Magnetic resonance imaging indicated focal lesions of the cerebellum and brainstem, and electrodiagnostic studies suggested an axonal neuropathy. Autopsy revealed a flattened small-bowel mucosa with intraepithelial lymphocytosis, a spectrum of degenerative changes of the intra-abdominal and mediastinal lymph nodes, including cavitary degeneration, and splenomegaly. Histologically, the lymph nodes showed pseudocyst formation and lymphocytic vasculitis with fibrinoid necrosis, and sections of the brain exhibited fibrinoid degeneration of small blood vessels, sparse perivascular lymphocytic infiltrates, and perivascular ischemic lesions. Identical T-cell clones were identified in the duodenum, stomach, lymph nodes, and spleen. This patient had an unusual neurological disorder related to a vasculopathy, probably mediated by a circulating neoplastic clone of activated T cells.

Brain Diseases↗
PubMed2005

T-Cell lymphoblastic lymphoma presenting as bilateral multinodular breast masses: a case report and review of the literature.

Non-Hodgkin lymphoma of T-cell lineage involving the breast is rare. We report on a 41-year-old woman with T-cell lymphoblastic lymphoma who presented with multiple bilateral breast masses. The patient was treated with intensive chemotherapy and mediastinal and whole-brain irradiation. She remains in complete remission 24 months after diagnosis. The clinical, histologic, phenotypic, and cytogenetic features are described, with a review of the literature.

Adult↗
PubMed2005

EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett's esophagus.

BACKGROUND: Accurate staging of high-grade dysplasia and of early cancer in Barrett's esophagus is important in the selection of patients for endoscopic therapy. METHODS: Patients with Barrett's esophagus and biopsy specimen proven high-grade dysplasia and adenocarcinoma in focal nodular lesions or in endoscopically unapparent flat lesions in short-segment Barrett's esophagus were initially staged with EUS. In patients with disease limited to the mucosa on EUS, cap-assisted EMR was performed. The depth of tumor invasion on EMR specimens was classified in a similar manner to squamous-cell cancer of the esophagus: m1 (epithelial layer, dysplasia), m2 (lamina propria invasion), m3 (muscularis mucosae invasion), sm (submucosal invasion). RESULTS: EUS was performed in 48 consecutive patients (27 with focal nodular lesions and 21 with microscopic lesions), and submucosal invasion was diagnosed in 8 (confirmed in 7/8 at surgery). EMR was carried out in the remaining 40 patients without significant complications. In the 25 patients with high-grade dysplasia on prior biopsy specimens, EMR confirmed m1 disease in 19; whereas in 6 (24%), invasive adenocarcinoma was detected (to m2 in 4; to m3 in 2). In the 15 patients with invasive cancer on prior biopsy specimens and staged as intramucosal cancer on EUS, intramucosal carcinoma was confirmed in 9 (m2 in 3; m3 in 6); whereas, in 6 patients (40%), submucosal invasion was found. Overall, EUS provided accurate staging in 41/48 patients (85%) with one patient overstaged and 6 patients understaged compared with pathologic staging obtained by surgery or EMR. Of the 34 patients with m1 to m3 staging after EMR, 29 were treated endoscopically and had no evidence of cancer after a mean follow-up of 22.9 months(standard deviation 9.2 months). CONCLUSIONS: EMR provides pathologic staging information that, in addition, may be helpful after EUS if a stage-determined approach is used in the management of high-grade dysplasia and of early cancer in Barrett's esophagus. EMR may be particularly useful for staging of focal nodules or in short-segment Barrett's esophagus with microscopic lesions when endoscopic therapy is an option.

Adenocarcinoma↗
PubMed2005

Duodenal intraepithelial lymphocytosis with normal villous architecture: common occurrence in H. pylori gastritis.

We have observed expansions of intraepithelial lymphocytes in duodenal biopsies from patients with Helicobacter pylori gastritis. This study was undertaken to prospectively evaluate, unselected, paired gastric and duodenal biopsies from 50 patients with H. pylori gastritis and a comparison group of 30 patients with other types of gastritis (10 autoimmune and 20 reactive) to: (1) quantify duodenal intraepithelial lymphocytes, determine their distribution patterns, epithelial location, and phenotype, and (2) correlate the intraepithelial lymphocyte elevations with various features of gastric and duodenal pathology. Intraepithelial lymphocytes were analyzed with antibodies including CD3, CD8, and TIA-1. A stain for H. pylori was performed on all gastric and duodenal biopsies. Duodenal intraepithelial lymphocytes from patients with H. pylori gastritis (using CD3) ranged from 3 to 42 lymphocytes/100 epithelial cells (mean 18.5) compared to 3 to 18 lymphocytes/100 epithelial cells (mean 6.6) in the comparison group. Intraepithelial lymphocyte elevations were seen in 44% of the duodenal biopsies from patients with H. pylori gastritis (using CD3). Significant differences in the intraepithelial lymphocyte counts between patients with H. pylori gastritis and the comparison group were seen for all three T-cell antigens (P<0.001 for CD3 and CD8 and P<0.002 for TIA-1). Duodenal intraepithelial lymphocytes in the H. pylori+ cases had a latent cytotoxic phenotype, H. pylori was not visualized in any of the duodenal biopsies from patients with H. pylori gastritis, and no patient had clinical evidence of celiac disease. Our study highlights frequent duodenal intraepithelial lymphocytosis in individuals with H. pylori gastritis and the lymphocyte distribution patterns (and numbers) overlapped with those described for celiac disease patients. H. pylori gastritis must be considered as a possible explanation for duodenal intraepithelial lymphocytosis with normal villous architecture, especially when lymphocytosis is patchy, intraepithelial lymphocytes display a 'latent' cytotoxic phenotype, and the clinical findings and serologic profile does not fit celiac disease.

Adolescent↗