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Jonathan Glickman

Publications and source records attributed to Jonathan Glickman.

At least 19 recordsLinked to original sources
PubMed2006

SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms.

T cell activation through the T cell receptor (TCR) is subsequently modified by secondary signals that are either stimulatory or inhibitory. We show that CEACAM1 adhesion molecule isoforms containing a long cytoplasmic domain inhibited multiple T cell functions as a consequence of TCR ligation. Overexpression of CEACAM1 resulted in decreased proliferation, allogeneic reactivity, and cytokine production in vitro and delayed type hypersensitivity and inflammatory bowel disease in mouse models in vivo. Conditioned deletion of CEACAM1 in T cells caused increased TCR-CD3 complex signaling. This T cell regulation was dependent upon the presence of immunoreceptor tyrosine-based inhibition motifs (ITIM) within the cytoplasmic domain of CEACAM1 and the Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP1) in the T cell. Thus, CEACAM1 overexpression or deletion in T cells resulted in T cell inhibition or activation, respectively, revealing a role for CEACAM1 as a class of inhibitory receptors potentially amenable to therapeutic manipulation.

Adoptive Transfer↗
PubMed2006

Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review.

Digestive tract involvement in Langerhans cell histiocytosis is exceedingly rare. We report a case of Langerhans cell histiocytosis in an otherwise thriving neonate presenting with hematochezia, anemia, and rash. We also review the few cases of Langerhans cell histiocytosis with gastrointestinal involvement reported in the English-language medical literature. Although gastrointestinal involvement can range in severity from mild to life-threatening, its presence may be indicative of multisystemic disease, and aggressive treatment should be considered.

Female↗
PubMed2006

Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo.

Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction. The binding of pVHL to HIFalpha requires that HIFalpha be hydroxylated on one of two prolyl residues. We introduced HIF1alpha and HIF2alpha variants that cannot be hydroxylated on these sites into the ubiquitously expressed ROSA26 locus along with a Lox-stop-Lox cassette that renders their expression Cre-dependent. Expression of the HIF2alpha variant in the skin and liver induced changes that were highly similar to those seen when pVHL is lost in these organs. Dual expression of the HIF1alpha and HIF2alpha variants in liver, however, more closely phenocopied the changes seen after pVHL inactivation than did the HIF2alpha variant alone. Moreover, gene expression profiling confirmed that the genes regulated by HIF1alpha and HIF2alpha in the liver are overlapping but non-identical. Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes.

Animals↗
PubMed2006

Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice.

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer.

Animals↗
PubMed2006

Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression.

Hepatocellular carcinoma is among the most common and lethal cancers in humans. Hepatocellular carcinoma is commonly associated with physical or functional inactivation of the p53 tumor suppressor, high levels of chromosomal instability, and disease conditions causing chronic cycles of hepatocyte death and regeneration. Mounting evidence has implicated regeneration-induced telomere erosion as a potential mechanism fueling genome instability. In mouse models of hepatocellular carcinoma, telomere dysfunction has been shown to enhance initiation of hepatic neoplasias yet constrain full malignant progression of these neoplasms possibly due to activation of a p53-dependent checkpoint and/or intolerable levels of genomic instability. Here, in a hepatocellular carcinoma-prone model brought about through toxin-induced hepatocyte injury and regeneration, we sought to determine the cooperative interactions of germ line p53 mutation and telomere dysfunction [produced by telomerase reverse transcriptase (mTERT) gene knockout]. In the setting of intact telomeres, p53 mutation had no effect on hepatocarcinogenesis, whereas in the setting of telomere dysfunction, p53 mutation enabled advanced hepatocellular carcinoma disease. Notably, there was no evidence of deletion or mutation of the wild-type p53 allele in the late generation mTert(-/-)p53(+/-) mice, suggesting that reduced levels of p53 potently enable hepatocellular carcinoma progression in the setting of telomere dysfunction. Thus, this study supports a model that, in the face of chronic liver damage, attenuated p53 function and telomere-induced chromosomal instability play critical and cooperative roles in the progression of hepatocellular carcinoma.

Alleles↗
PubMed2004

Absence of clinical GVHD and the in vivo induction of regulatory T cells after transplantation of facilitating cells.

Graft-versus-host disease (GVHD) and failure of engraftment limit clinical bone marrow transplantation (BMT) to patients with closely matched donors. Engraftment failure of purified allogeneic hematopoietic stem cells (HSCs) has been decreased in various BMT models by including donor BM-derived CD8(+)/alphabetagammadeltaTCR(-) facilitating cells (FCs) or CD8(+)/alphabetaTCR(+) T cells in the BM inoculum. To aggressively investigate the GVHD potential of these donor CD8(+) populations, a purified cell model of lethal GVHD was established in a murine semiallogeneic parent --> F(1) combination. Lethally irradiated recipients were reconstituted with purified donor HSCs alone or in combination with splenic T cells (T(SP)), BM-derived T cells (T(BM)), or the FC population. In marked contrast to the lethal GVHD present in recipients of HSCs plus T(SP) or CD8(+) T(BM), recipients of donor HSC+FC inocula did not exhibit significant clinical or histologic evidence of GVHD. Instead, HSC+FC recipients were characterized by increased splenocyte expression of transforming growth factor-beta (TGF-beta) and the induction of the regulatory T-cell genes CTLA4, GITR, and FoxP3. These findings suggest that the FCs, which express a unique FCp33-TCRbeta heterodimer in place of alphabetaTCR, permits HSC alloengraftment and prevents GVHD through the novel approach of regulatory T-cell induction in vivo.

Animals↗
PubMed2004

CD1d function is regulated by microsomal triglyceride transfer protein.

CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.

Abetalipoproteinemia↗
PubMed2004

Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma.

BACKGROUND: Survival after tri-modality therapy with extrapleural pneumonectomy (EPP) and postoperative chemoradiotherapy is longer for patients with epithelial MPM versus mixed or sarcomatoid subtypes, leading some to decline aggressive therapy for patients with nonepithelial histology. However, pathologic diagnosis of malignant pleural mesothelioma (MPM) and subclassification into one of the three histologic subtypes (epithelial, mixed, sarcomatoid) can be challenging. Pleural biopsy has been proposed as the diagnostic gold standard. We investigated the accuracy of open pleural biopsy for diagnosis and subtype identification in MPM. METHODS: Patients with suspected MPM routinely undergo open pleural biopsy to establish diagnosis. Those diagnosed definitively by pleural biopsy or cytology are offered pleurectomy or EPP dependent on stage and cardiorespiratory status. We reviewed medical records for all patients undergoing EPP at our institution, comparing tissue and subtype diagnosis at initial diagnostic biopsy versus definitive resection. RESULTS: Between 1988 and 2000, 305 of 332 consecutive patients undergoing EPP had MPM. One patient diagnosed with MPM at pleural biopsy was misclassified. Subtype analysis at pleural biopsy proved correct in 80% (226/282). Most patients (174/192) with epithelial subtype at final diagnosis were diagnosed correctly at pleural biopsy. However, 44% (45/103) with pathologic diagnosis of nonepithelial subtype at resection were initially misdiagnosed with the epithelial subtype. The sensitivity of pleural biopsy for epithelial MPM was 97% with a specificity of 56%. CONCLUSIONS: Open pleural biopsy is accurate and should be considered the gold standard diagnostic method for MPM. It is less sensitive for determining histologic subclass, particularly with nonepithelial subtypes.

Biopsy↗
PubMed2004

Abnormal distribution and hyperplasia of thyroid C-cells in PTEN-associated tumor syndromes.

INTRODUCTION: Cowden's disease (CD) and Bannayan-Ruvalcaba-Riley syndrome (BRRS) are allelic disorders characterized by multiple hamartomatous overgrowths of the thyroid, breast, skin, and gastrointestinal tract, and an increased risk of developing benign and malignant tumors of the breast and thyroid gland, secondary to germline point mutations in the PTEN gene. In contrast to thyroid epithelial lesions, abnormalities of the C-cells are currently not considered part of the spectrum of manifestations seen in PTEN-associated syndromes. METHODS: The thyroid glands from two patients with overlapping CD/BRRS phenotypes, and with distinct PTEN mutations, were entirely submitted for histopathological examination, calcitonin immunostaining and C-cell mapping. RESULTS: Multiple follicular adenomas and adenomatous nodules were present in the thyroid glands from both patients. A microscopic focus of papillary carcinoma was also present in one gland. C-cell hyperplasia was documented in both cases by calcitonin immunostaining. CONCLUSIONS: PTEN-associated tumor syndromes should be considered in the differential diagnosis of C-cell hyperplasia of the thyroid.

Adenocarcinoma, Follicular↗
PubMed2003

Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.

Telomere maintenance and telomerase reactivation are near universal features of human hepatocellular carcinoma (HCC), yet the shorter telomeres and highly abnormal cytogenetic profiles of HCC suggest that telomere erosion and dysfunction may be operative during the formative stages of tumorigenesis. Previous studies have established that the cancer-enhancing or suppressing impact of telomere dysfunction is highly dependent on several parameters including cell type, tumor stage, and p53 status. Here, to understand better the pathogenetic role of telomere dysfunction in the initiation and progression in human HCC, we have used three mechanistically distinct liver cancer-prone model systems (urokinase plasminogen activator transgenic mice, carbon tetrachloride exposure, and diethylnistrosamine treatment) in the context of successive generations of telomerase-deficient mice null for the telomerase RNA component, mTERC. Across all of the HCC model systems, telomere dysfunction suppressed both the incidence and growth of HCC lesions, a trend that mirrored the level of intratumoral proliferative arrest and apoptosis. On the histological level, telomere dysfunction was associated with a significant increase in the number of early stage neoplastic lesions and a reciprocal decline in the occurrence of high-grade malignancies. These genetic data in the mouse indicate that telomere dysfunction exerts an opposing role in the initiation versus progression of HCC and provide a framework for understanding the intimate link among chronic liver disease, chromosomal instability, and increased HCC in humans.

Animals↗
PubMed2003

Rectal inflammation as first manifestation of graft-vs-host disease: radiologic-pathologic findings.

Graft-vs-host disease (GVHD) is a common, life-threatening complication of bone marrow transplantation that frequently involves the gastrointestinal tract. Since symptoms are typically nonspecific, radiologic examination is often performed to reach a diagnosis. To the best of our knowledge, this is the first reported radiologic description of a case of rectal involvement as the first manifestation of GVHD. The differential diagnosis of segmental rectal wall thickening in a patient following bone marrow transplantation should include GVHD.

Abdominal Pain↗
PubMed2003

Colon cancer-associated DNA mutations: marker selection for the detection of proximal colon cancer.

This study evaluates the potential ability of a specific panel of DNA mutations to identify right-sided colorectal carcinomas (CRCs) that would be missed by a flexible sigmoidoscopy (FS) screening program. This panel could then be applied to stool DNA analysis for noninvasive proximal CRC detection. A series of resected right-sided CRCs from 101 patients who had no left-sided advanced colonic neoplasms distal to the splenic flexure were analyzed. Tumor DNA was isolated from microdissected tumor sections. Deletions in the BAT-26 locus, a marker of microsatellite instability, and mutations at 19 loci spread among the p53, K-ras, and Apc genes were detected following PCR amplification. Mutations were identified in 83% of successfully amplified samples and were variably present in each of the target sites: p53 (42%), Apc (37%), K-ras (28%), and BAT-26 (24%). Mutations were identified across all Dukes stages (CIS/A 6/8 [75%], B 41/51[80%], C 30/32 (94%), and D 6/9 [67%]). Our data suggest that this 20-marker mutation panel may be associated with more than 80% of cancers undetectable by FS. The adjunctive use of stool DNA mutation analysis using this marker panel in FS CRC screening programs may significantly increase the detection of proximal CRC.

Adenocarcinoma↗
PubMed2003

Macrocystic serous adenoma of the pancreas: radiologic-pathologic correlation.

OBJECTIVE: Macrocystic serous adenoma is a rare benign pancreatic neoplasm, recently described in the pathology literature. We describe the CT and MR imaging features in a series of five consecutive pathologically proven cases. MATERIALS AND METHODS: Of seven cases fulfilling the pathology criteria for macrocystic serous adenoma over an 11-year period, five patients underwent preoperative CT and MR imaging at our institution. In addition to the clinical presentation and pathologic features of the tumor, the following CT and MR imaging features were reviewed: size and location; wall thickness; internal septations; and presence of mural nodules, papillary projections, or calcifications. RESULTS: All patients but one were women (age range, 36-78 years; mean age, 48.6 years). The sizes of the tumors ranged from 1.5 to 5.0 cm (mean, 3.1 cm). Three (60%) of five tumors were located in the pancreatic head. The wall measured less than 2 mm in four lesions and 4 mm in one. No mural nodules, papillary projections, or calcifications were present. Lesions were unilocular (n = 3) or bilocular (n = 2). Excellent correlation of imaging features with gross pathology was observed. CONCLUSION: On CT and MR imaging, the macrocystic variant of serous adenoma typically appears as a small (< 5 cm), uni- or bilocular cyst with a thin (< 2 mm) wall that lacks mural nodules or calcifications. The imaging appearance of macrocystic serous adenoma is distinctly different from that of microcystic serous cystadenoma, but the imaging appearance of macrocystic serous adenoma is indistinguishable from mucinous cystadenoma and cystadenocarcinoma of the pancreas.

Cystadenoma, Serous↗
PubMed2003

Rectal inflammation as first manifestation of graft-vs-host disease: radiologic-pathologic findings.

Graft-vs-host disease (GVHD) is a common, life-threatening complication of bone marrow transplantation that frequently involves the gastrointestinal tract. Since symptoms are typically nonspecific, radiologic examination is often performed to reach a diagnosis. To the best of our knowledge, this is the first reported radiologic description of a case of rectal involvement as the first manifestation of GVHD. The differential diagnosis of segmental rectal wall thickening in a patient following bone marrow transplantation should include GVHD.

Adult↗
PubMed2002

Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice.

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3-/- mice exhibited normal numbers of both naive and mature CD4+ and CD8+ T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an alpha-galactosylceramide (alphaGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3-/- mice exhibited decreased IL-4 and, to a lesser extent, IFN-gamma production after alphaGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3-/- mice after alphaGalCer stimulation in vivo in contrast to IFN-gamma production, which was only transiently decreased under such stimulation. Notably, EBI3-/- mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis model, was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function.

Animals↗
PubMed2002

Activation-induced expression of carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T lymphocyte function.

Carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) consists of highly related homologs in humans and rodents that are characterized by significant alternate splicing generating isoforms capable of negative intracellular signaling by virtue of two immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic (cyt) tail. Although human T cells have been recently observed to express CEACAM1, the expression and function of CEACAM1 in mouse T cells have not been defined. Although resting mouse spleen T cells exhibited no evidence of CEACAM1 on the cell surface, CEACAM1 was rapidly up-regulated on CD4+ and CD8+ T cells after activation with either Con A or anti-CD3 without a requirement for either de novo transcription or translation due to the fact that CEACAM1 was present intracellularly before activation. Using a GST-CEACAM1-cytoplasmic tail fusion protein, it was shown that the cytoplasmic tail of CEACAM1 bound the src homology domain-containing phosphatase 1 and adaptor protein 1 complex in its phosphorylated and nonphosphorylated states, respectively. CEACAM1 ligation with an anti-CEACAM1 mAb resulted in inhibition of an allogeneic MLR and anti-CD3 plus anti-CD28 Ab-induced proliferation of spleen T cells in vitro and inhibition of a delayed-type hypersensitivity response to oxazolone in vivo. Inhibition of the delayed-type hypersensitivity response required that the anti-CEACAM1-specific mAb be present at the time of T cell sensitization. These studies support a role for CEACAM1 as a novel class of immunoreceptor tyrosine-based inhibition motif-bearing regulatory molecules on T cells that are active during early phases of the immune response in mice.

Adaptor Proteins, Vesicular Transport↗