PubMed Health⌕ Search

Biomedical subjects

Jonathan N Glickman

Publications and source records attributed to Jonathan N Glickman.

At least 19 recordsLinked to original sources
PubMed2007

A mutation in separase causes genome instability and increased susceptibility to epithelial cancer.

Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.

Animals↗
PubMed2006

Mucin core polypeptide expression in the progression of neoplasia in Barrett's esophagus.

We have previously demonstrated a specific pattern of mucin (MUC) core polypeptide expression in Barrett's esophagus (BE) characterized by MUC1 and MUC6 positivity in goblet cells in a proportion of cases. The aim of this study was to determine the pattern of MUC expression associated with the development and progression of dysplasia in BE. Endoscopic mucosal biopsies from 35 patients with BE (10 with no dysplasia, 6 with indefinite for dysplasia, 12 with low-grade dysplasia [LGD], and 7 biopsies with high-grade dysplasia [HGD]) were immunostained (ABC method) with antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6. The extent and pattern of staining for each marker was evaluated in intestinalized Barrett's epithelium and in the various grades of dysplasia. For cases with dysplasia, staining was evaluated separately in nondysplastic epithelium adjacent to (<1 cm) and distant from (>2 cm) areas of dysplasia. In nondysplastic BE, MUC1, MUC2, MUC3, MUC5AC, and MUC6 stained 40%, 100%, 100%, 100%, and 90% of cases, respectively, in goblet or nongoblet columnar epithelium. With the progression of dysplasia (from metaplasia to indefinite, LGD and HGD), there was a significant decrease in expression of MUC1, MUC2, and MUC3, and alterations in the staining patterns of MUC5 and MUC6. In fact, MUC1 and MUC3 were entirely absent from all cases of HGD. Interestingly, BE-associated adenocarcinomas showed an MUC phenotype distinct from that of HGD, with expression of MUC1 and MUC3 in 47% and 67% of cases, and expression of MUC1 in a membranous pattern. There was no significant difference in MUC staining in nondysplastic BE between patients with and without dysplasia. Alterations in MUC expression occur in the progression of dysplasia in BE. However, none of these markers helps identify a subgroup of patients at increased risk for neoplasia.

Adenocarcinoma↗
PubMed2006

Carcinoid tumors.

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed2006

Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.

The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn in the epithelium is shown here to be associated with secretion of IgG into the lumen that allows for defense against an epithelium-associated pathogen (Citrobacter rodentium). This pathway of host resistance to a bacterial pathogen as mediated by FcRn involves retrieval of bacterial antigens from the lumen and initiation of adaptive immune responses in regional lymphoid structures. Epithelial-associated FcRn, through its ability to secrete and absorb IgG, may thus integrate luminal antigen encounters with systemic immune compartments and as such provide essential host defense and immunoregulatory functions at the mucosal surfaces.

Animals↗
PubMed2006

CT features of hepatic venoocclusive disease and hepatic graft-versus-host disease in patients after hematopoietic stem cell transplantation.

OBJECTIVE: We conducted this study to evaluate whether CT scans could be used to differentiate hepatic venoocclusive disease from hepatic graft-versus-host disease in patients treated with hematopoietic stem cell transplantation. SUBJECTS AND METHODS: We retrospectively evaluated 18 patients (eight women, 10 men; mean age, 42.4 years) after hematopoietic stem cell transplantation with biopsy-proven hepatic venoocclusive disease (n = 5), hepatic graft-versus-host disease (n = 6), or both (n = 7). Two radiologists reviewed abdominal and pelvic CT scans for hepatomegaly (> 18 cm), splenomegaly (> 13 cm), size of main portal and right hepatic veins, presence of periportal edema, gallbladder wall edema, hydropic gallbladder, ascites, and small-bowel wall thickening. CT and histopathology findings were correlated using analysis of variance and Fisher-Free-man-Holton tests. RESULTS: Ascites and periportal edema were present in all five patients with venoocclusive disease, but of six patients with graft-versus-host disease, ascites was seen in two (p < 0.05) and periportal edema in only one (p < 0.05). Small-bowel wall thickening was encountered in five patients with graft-versus-host disease and in none with venoocclusive disease (p < 0.05). The right hepatic vein diameter in patients with venoocclusive disease (mean, 0.27 cm) was significantly smaller than the right hepatic vein diameter in patients with graft-versus-host disease (mean, 0.87 cm; p < 0.05). CONCLUSION: In patients treated with hematopoietic stem cell transplantation, CT findings of periportal edema, ascites, and a narrow right hepatic vein suggest venoocclusive disease rather than graft-versus-host disease. Small-bowel wall thickening suggests graft-versus-host disease.

Adult↗
PubMed2006

Brenner tumors of the ovary: sonographic and computed tomographic imaging features.

OBJECTIVE: The purpose of this study was to describe the sonographic appearance of ovarian Brenner tumors with computed tomographic (CT) correlation. METHODS: Twenty-two female patients (age range, 32-78 years; mean, 58 years) with 25 ovarian Brenner tumors were identified from pathologic records from 1990 to 2005. Corresponding pathologic reports and images (17 sonographic and 14 CT) were reviewed independently. RESULTS: Tumors ranged in size from 0.3 to 12 cm (mean, 2.5 cm); all were benign. Sixteen (64%) of 25 were found incidentally. Eight (36%) of 22 patients had a total of 12 associated benign ovarian neoplasms (1 was contralateral); 3 patients had bilateral Brenner tumors. Eight (47%) of 17 tumors were not seen on sonography, and 5 (36%) of 14 were not seen on CT. Of the tumors seen on imaging, most were solid (67% on sonography and 78% on CT). Four tumors appeared at least partially cystic, of which 3 had coexistent cystic ovarian lesions. CONCLUSIONS: Brenner tumors are most often solid neoplasms found incidentally and frequently seen in association with other benign ovarian epithelial neoplasms.

Adult↗
PubMed2005

A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.

A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.

Animals↗
PubMed2005

Validation of genomics-based prognostic tests in malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme. EXPERIMENTAL DESIGN: Gene expression data using high-density oligonucleotide microarrays (approximately 22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio-based prognostic tests. The predictive nature of these newly discovered markers and gene ratio-based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR. RESULTS: Previously described MPM prognostic genes and gene ratio-based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio-based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment. CONCLUSIONS: The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.

Adult↗
PubMed2005

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis.

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid) is an antiinflammatory lipid mediator derived from omega-3 fatty acid eicosapentaenoic acid (EPA). At the local site of inflammation, aspirin treatment enhances EPA conversion to 18R-oxygenated products, including RvE1, which carry potent antiinflammatory signals. Here, we obtained evidence for reduced leukocyte infiltration in a mouse peritonitis model, where the administration of EPA and aspirin initiated the generation of RvE1 in the exudates. Similar results were obtained with the administration of synthetic RvE1, which blocked leukocyte infiltration. RvE1 also protected against the development of 2,4,6-trinitrobenzene sulfonic acid-induced colitis. The beneficial effect was reflected by increased survival rates, sustained body weight, improvement of histologic scores, reduced serum anti-2,4,6-trinitrobenzene sulfonic acid IgG, decreased leukocyte infiltration, and proinflammatory gene expression, including IL-12 p40, TNF-alpha, and inducible nitric oxide synthase. Thus, the endogenous lipid mediator RvE1 counter-regulates leukocyte-mediated tissue injury and proinflammatory gene expression. These findings show an endogenous mechanism that may underlie the beneficial actions of omega-3 EPA and provide targeted approaches for the treatment of intestinal inflammation.

Animals↗
PubMed2005

Interinstitutional variability and effect of tissue fixative on the interpretation of a Barrett cytokeratin 7/20 immunoreactivity pattern in Barrett esophagus.

A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies. Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined. To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0). Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.

Barrett Esophagus↗
PubMed2005

Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling.

Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n = 40), normal lung specimens (n = 4), normal pleura specimens (n = 5), and MPM and SV40-immortalized mesothelial cell lines (n = 5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma that correlated loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (ie, software) to create and explore complex physiological pathways. Combined, all of these data may advance our understanding of mesothelioma tumorigenesis, pathobiology, or both.

Blotting, Western↗
PubMed2005

CT and MRI features of pure acinar cell carcinoma of the pancreas in adults.

OBJECTIVE: We sought to describe the CT and MRI features of pure acinar cell carcinoma of the pancreas in adults. MATERIALS AND METHODS: Eleven patients (six women and five men; mean age, 64 years) with acinar cell carcinoma, documented by pathologic examination of resected specimens, underwent CT (n=9) or MRI (n=2) examinations. Two radiologists evaluated imaging studies and determined, by consensus, the following data for each tumor: size, location, margination, internal density or signal intensity, and contrast enhancement pattern. In addition, they assessed the presence of calcification, pancreatic or bile duct dilation, and metastases. Imaging features were correlated with gross and microscopic pathologic features of the tumors. RESULTS: Masses were distributed throughout the pancreas (head, n=5; body, n=2; and tail, n=4). The mean largest dimensions were 6.0 x 5.3 cm (range, from 2 x 1.7 to 15 x 11 cm). Tumors were oval (n=5), round (n=4), or lobular (n=2). Ten (91%) masses were well marginated; nine (82%) were exophytic. Five (45%) masses enhanced homogeneously; the remaining tumors contained cystic areas. All masses enhanced less than the surrounding pancreas. Three (27%) masses contained calcifications. Four (80%) masses invaded the duodenum. Common bile and pancreatic duct dilatation was present in two and three patients, respectively. One patient had metastatic liver disease at presentation. CONCLUSION: Pure acinar cell carcinoma of the pancreas is usually an exophytic, oval or round, well-marginated, and hypovascular mass on CT and MRI. It typically is completely solid when small and contains cystic areas due to necrosis when large.

Adult↗
PubMed2004

Insights into developmental mechanisms and cancers in the mammalian intestine derived from serial analysis of gene expression and study of the hepatoma-derived growth factor (HDGF).

The vertebrate intestine is a model for investigating inductive cellular interactions and the roles of epithelial stem cells in tissue regeneration, and for understanding parallels between development and cancer. We have used serial analysis of gene expression to measure transcript levels across stages in mouse intestine development. The data (http://genome.dfci.harvard.edu/GutSAGE) identify novel differentiation products, potential effectors of epithelial-mesenchymal interactions, and candidate markers and regulators of intestinal epithelium. Transcripts that decline significantly during intestine development frequently are absent from the adult gut. We show that a significant proportion of such genes may be reactivated in human colon cancers. As an example, hepatoma-derived growth factor (HDGF) mRNA is expressed prominently in early gut tissue, with substantially reduced levels after villous epithelial differentiation. HDGF expression is dramatically increased in human colorectal cancers, especially in tumors proficient in DNA mismatch repair, and thus represents a novel marker for a distinctive tumor subtype. HDGF overexpression in fetal intestine explants inhibits maturation, suggesting a role in epithelial differentiation. To investigate the molecular basis for HDGF functions, we isolated components of a nuclear HDGF complex, including heterogeneous nuclear ribonucleoproteins implicated in processing RNA. These genes are regulated in tandem with HDGF during intestine development and one factor, TLS/Fus, is commonly overexpressed in colon cancers. Tumor expression of fetal genes may underlie similarities between developing and malignant tissues, such as self-renewal, invasion and angiogenesis. Our findings also advance understanding of HDGF functions and implicate this developmentally regulated gene in RNA metabolic pathways that may influence malignant behaviors in colorectal cancer.

Animals↗
PubMed2004

Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1.

Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.

Animals↗
PubMed2004

Pediatric patients with untreated ulcerative colitis may present initially with unusual morphologic findings.

BACKGROUND: Anecdotal observations by the authors of this study, together with the results of a few previous smaller studies, suggest that children with new-onset (previously untreated) ulcerative colitis (UC) may occasionally present with discontinuous disease, relative or absolute rectal sparing, and may lack histologic features ofchronicity. Therefore, the objectives of this study were to determine the clinical and pathologic features of new-onset UC in children and to compare the initial presentation of UC in this group with a control group of adults. DESIGN: Routinely processed rectal and colonic mucosal biopsies from 73 pediatric (male/female ratio 33/40, mean age 11.5 years, range 2.5-18 years) and 38 adult patients (male/female ratio 15/23, mean age 41.5 years, range 27-64 years) who presented with new-onset UC were evaluated for a variety of clinical and pathologic features, including duration of symptoms prior to presentation, crypt architectural (e.g., atrophy, branching) and nonarchitectural (e.g., basal plasmacytosis, Paneth cell metaplasia) features of chronicity, degree of active inflammation, and distribution and extent of disease. RESULTS: A significant proportion of children with new-onset UC had patchiness of microscopic features of chronicity (21% of patients), relative (23%), or absolute (3%), rectal sparing, and had little or no crypt architectural distortion in their rectal biopsies (8%). These features were not observed in adult patients with UC. In addition, a higher proportion of children with UC initially presented with subtotal or with pancolitis compared with the adults (42% vs. 11%; P < 0.002). CONCLUSIONS: A significant proportion of children with new-onset UC may show unusual patterns of disease. Pathologists should be aware of these findings since they have significant implications for the differential diagnosis of pediatric inflammatory bowel disease.

Adolescent↗
PubMed2004

Gastroesophageal junction smooth muscle remodeling after endoluminal gastroplication.

OBJECTIVES: Endoluminal gastroplication (ELGP) is an endoscopic mucosal suturing procedure for the treatment of gastroesophageal reflux disease. The antireflux mechanism of the mucosal suture remains poorly understood. The aim of this study is to investigate any morphologic changes in the smooth muscle layer induced by the mucosal sutures placed at the gastroesophageal junction. METHODS: ELGPs were performed using endoscopic suturing devices with placement of two or three circumferential sutures within 2 cm of the squamocolumnar junction. Eight patients with subsequent symptom resolution underwent endoscopic ultrasound (EUS) to evaluate the muscularis propria layer at the gastroesophageal junction. A swine model was used for EUS and histopathologic correlation study. Six control and 15 ELGP pigs were evaluated with EUS and histological examination of the gastroesophageal junction smooth muscle layer. RESULTS: Focal thickening of the muscularis propria layer near the suture region (2.3 +/- 0.4 mm vs 1.4 +/- 0.3 mm, p < 0.01) was found in eight patients with symptomatic resolution. In ELGP pigs, the smooth muscle layer thickness increased by 2.6 mm near the suture site by EUS. By histology, the total and circular smooth muscle layer thickness increased by 2.1 mm and 1.9 mm, respectively. CONCLUSIONS: Focal thickening of smooth muscle layer occurs at the gastroesophageal junction after ELGP in patients with gastroesophageal reflux disease. This finding was reproduced in a swine model and localized hypertrophy was found to be entirely due to an increase in the circular smooth muscle layer.

Animals↗