Person: Zukerberg, Lawrence
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Zukerberg
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Lawrence
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Zukerberg, Lawrence
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Publication Oncogenic Collaboration of the Cyclin D1 (PRAD1, bcl‐1) Gene with a Mutated p53 and an Activated ras Oncogene in Neoplastic Transformation(Blackwell Publishing Ltd, 1996) Uchimaru, Kaoru; Endo, Koichi; Fujinuma, Haruko; Zukerberg, Lawrence; Arnold, Andrew; Motokura, ToruCyclin D1 is one of the key regulators in G1 progression in the cell cycle and is also a candidate oncogene (termed PRAD1 or bcl‐1) in several types of human tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated form of p53 (p53‐mt) in neoplastic transformation. Transfection of cyclin D1 alone or in combination with ras or with p53‐mt was not sufficient for focus formation of rat embryonic fibroblasts. However, focus formation induced by co‐transfection of ras and p53‐mt was enhanced in the presence of the cyclin D1‐expression plasmid. Co‐transfection of ras‐ and p53‐mt‐transformants with the cyclin D1‐expression plasmid resulted in reduced serum dependency in vitro, Furthermore, the transformants expressing exogenous cyclin D1 grew faster than those without the cyclin D1 plasmid when injected into nude mice. These observations strengthen the significance of cyclin D1 overexpression through gene rearrangement or gene amplification observed in human tumors as a step in multistep oncogenesis; deregulated expression of cyclin D1 may reduce the requirement for growth factors and may stimulate in vivo growth.Publication The Rectal Tonsil: A Reactive Lymphoid Proliferation That May Mimic Lymphoma(Ovid Technologies (Wolters Kluwer Health), 2008) Farris, Alton B.; Lauwers, Gregory Y.; Ferry, Judith; Zukerberg, LawrenceThe rectal tonsil (RT), a localized reactive proliferation of lymphoid tissue occurring in the rectum, can cause diagnostic difficulty; and awareness of this entity can prevent a misdiagnosis of lymphoma. A clinicopathologic analysis of 11 cases of RT was performed to determine the features that can aid in the recognition of this entity. The patients (6 males and 5 females) were middle-aged adults, except for 1 case affecting a young boy (age range, 1 to 62 y; mean, 49 y). All presented with either rectal bleeding or abdominal pain, or had the lesion found on routine screening. Endoscopic descriptions, available in all cases, reported a raised, polypoid lesion in 8 cases, a nodule in 2 cases, and a "mass" in 1 case. Histologically, all cases were composed of a lymphoid proliferation involving the lamina propria or submucosa. Lymphoid follicles could be identified in all cases, although some were difficult to appreciate without immunostains for follicular dendritic cells. Five cases showed overlying cryptitis and mild architectural distortion, but no cases showed crypt obliteration or crypt abscesses. Intraepithelial lymphocytes were present in 9 cases, and 5 cases showed nondestructive lymphoepithelial lesions. During a mean follow-up of 5.8 years, none showed a recurrence or developed lymphoma. In conclusion, RT, with its distinctive features, is an important entity to recognize. Familiarity with the range of histologic features characteristic of the RT is critical in avoiding misinterpretation as lymphoma.Publication CDX2 Expression in the Intestinal-Type Gastric Epithelial Neoplasia: Frequency and Significance.(Nature Publishing Group, 2010) Park, Do Youn; Srivastava, Amitabh; Kim, Gwang Ha; Mino-Kenudson, Mari; Deshpande, Vikram; Zukerberg, Lawrence; Song, Geum Am; Lauwers, Gregory Y.CDX2 is an intestinal transcription factor responsible for regulating the proliferation and differentiation of intestinal epithelial cells. In gastric adenocarcinoma, CDX2 expression is known to be associated with limited invasiveness and intestinal phenotypes. The aims of this study were to analyze CDX2 expression in a series of well-characterized cases of gastric epithelial dysplasia, based on the morphologic and mucin phenotypes, and also to analyze CDX2 expression along the metaplasia–dysplasia–carcinoma sequence. CDX2 expression was evaluated in 69 cases of gastric epithelial dysplasia, 88 cases of intestinal-type early gastric cancers, and 56 cases of advanced gastric cancers. Increased CDX2 expression was more frequently associated with adenomatous-type gastric epithelial dysplasia (27/31, 87%) compared with foveolar (7/15, 47%) or hybrid (10/23, 44%) types of gastric epithelial dysplasia (P=0.001). CDX2 expression correlated with an increase in CD10 expression (P=0.005), and a decrease in MUC5AC expression (P=0.001) in gastric epithelial dysplasia. CDX2 expression was also gradually decreased from gastric epithelial dysplasia, to early and advanced gastric cancers (present in 64, 40 and 27% of the cases, respectively). A negative correlation was also observed between CDX2 expression and the depth of tumor invasion. Our results indicate that CDX2 expression is associated with specific morphological and mucin phenotypes of gastric epithelial dysplasias, and decreases progressively with the advancing stage of gastric cancers, suggesting a possible tumor suppressor role for CDX2.Publication Chronic Sclerosing Sialadenitis (Küttner Tumor) Is an IgG4-associated Disease(Ovid Technologies (Wolters Kluwer Health), 2010) Geyer, Julia Turbiner; Ferry, Judith; Harris, Nancy; Stone, John; Zukerberg, Lawrence; Lauwers, Gregory Y.; Pilch, Ben Z.; Deshpande, VikramBACKGROUND: Chronic sclerosing sialadenitis is a fibroinflammatory disease of the salivary glands, characteristically of the submandibular gland. One prior Asian study proposed that chronic sclerosing sialadenitis is a part of the spectrum of IgG4-associated disease. This association has not been confirmed in Western populations. We therefore, investigated the relationship between IgG4 and chronic sclerosing sialadenitis, and compared the histomorphologic features of this condition with those of chronic sialadenitis-not otherwise specified, Sjögren syndrome, and lymphoepithelial sialadenitis. MATERIALS AND METHODS: We evaluated 13 cases of chronic sclerosing sialadenitis and compared them with 15 cases of chronic sialadenitis-not otherwise specified, 8 lip biopsies from individuals with Sjögren syndrome, and 4 cases of lymphoepithelial sialadenitis. Immunohistochemistry for IgG, and IgG4 was carried out. IgG4-positive plasma cells were quantified and the IgG4/IgG ratio was calculated. RESULTS: Seven patients with chronic sclerosing sialadenitis were female and 6 were male. Their mean age was 61 years (range: 27 to 80). Twelve chronic sclerosing sialadenitis cases involved the submandibular gland (bilaterally in 3) and in 1 there was a parotid lesion. Three of these 12 cases had manifestations of IgG4-associated systemic disease. Morphologically these specimens had preservation of lobular architecture, hypercellular interlobular fibrosis, florid lymphoid hyperplasia, and numerous plasma cells. Obliterative phlebitis was observed in 6 cases. The histologic features of chronic sclerosing sialadenitis were reminiscent of autoimmune pancreatitis, and were either not observed or were present only focally in cases of chronic sialadenitis, Sjögren syndrome, and lymphoepithelial sialadenitis.Eleven of 12 evaluable cases showed an increased number of IgG4 plasma cells with a mean of 229/high-power field (HPF) (range 75 to 608) and an overall IgG4/IgG ratio of 0.86 (range 0.5 to 1). The only patient whose biopsy lacked IgG4-positive plasma cells had pathologic evidence of cytomegalovirus infection. Chronic sclerosing sialadenitis cases, in comparison with the other 3 groups studied, showed a significantly higher number of IgG4 positive plasma cells (P<0.05). Patients with chronic sialadenitis-not otherwise specified had a median number of only 16 IgG4-positive plasma cells/HPF (range 2 to 44), with an IgG4/IgG ratio of 0.14 (range 0.02 to 0.28). The Sjögren syndrome patients had a median of 1 IgG4-positive plasma cell/HPF (range 0 to 3), with an IgG4/IgG ratio of 0.02 (range 0 to 0.07). Patients with lymphoepithelial sialadenitis had a median of 0 IgG4-positive plasma cells per HPF. CONCLUSION: Chronic sclerosing sialadenitis has a characteristic morphologic appearance. This morphologic appearance, in conjunction with the elevated IgG4 expression, distinguishes chronic sclerosing sialadenitis from other inflammatory diseases of the salivary glands. Chronic sclerosing sialadenitis belongs to the spectrum of IgG4-related diseases.Publication MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma(BioMed Central, 2016) Guan, Yichun; Guo, Lankai; Zukerberg, Lawrence; Rueda, Bo; Styer, AaronBackground: Human uterine leiomyoma (fibroids; LYO) are the most common benign neoplasms in reproductive-aged women. Dysregulated extracellular matrix and irregular LYO reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression are thought to be mediated by aberrant microRNA (miR) expression. The relationship of miR-15b and RECK expression in LYO has not been studied. Methods: The expression levels of miR-15b and RECK were determined by quantitative RT-PCR, Western blot, and immunohistochemistry in cultures derived from commercial primary leiomyoma (cpLYO) and myometrial (cpMYO) cell lines and leiomyoma (pLYO) and myometrium (pMYO) tissue from surgical samples respectively. The relationship between miR-15b and RECK expression in cpLYO and pLYO (compared to their respective myometrial controls) was evaluated following transfection of cell cultures with either miR-15b mimic or inhibitor. Results: Elevated levels of miR-15b were observed in cpLYO (2.82-fold; p = 0.04) and pLYO cell (1.30-fold; p = 0.0001) cultures respectively compared to corresponding MYO cell controls. Following transfection with miR-15b mimic, cpLYO cells (0.62-fold; p < 0.0001) and pLYO cells (0.68-fold; p < 0.0001) demonstrated reduced RECK protein expression. Following transfection with miR-15b inhibitor, cpLYO cells (1.20-fold; p < 0.0001) and pLYO cells (1.31-fold; p = 0.0007) demonstrated elevated RECK protein expression. RECK protein expression was reduced in pLYO tissues (0.73-fold; p < 0.0001) and pLYO (0.47-fold; p = 0.047) cells when compared to the corresponding MYO tissue controls. Conclusion: Our findings suggest that miR-15b negatively regulates RECK expression in LYO, and increased miR-15b and decreased RECK expression may contribute to the pathobiology of LYO. The functional significance of miR-15b and RECK expression warrants further investigation as potential therapeutic targets for the treatment of human LYO.Publication mTORC1 in the Paneth Cell Niche Couples Intestinal Stem Cell Function to Calorie Intake(Nature Publishing Group, 2012) Katajisto, Pekka; Lamming, Dudley W.; Gültekin, Yetis; Bauer-Rowe, Khristian E.; Sengupta, Shomit; Birsoy, Kivanc; Dursun, Abdulmetin; Yilmaz, V. Onur; Selig, Martin; Nielson, G. Petur; Sabatini, David M.; Yilmaz, Omer; Mino-Kenudson, Mari; Zukerberg, Lawrence; Bhan, Atul; Deshpande, VikramHow adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.Publication Adenomatous and Foveolar Gastric Dysplasia: Distinct Patterns of Mucin Expression and Background Intestinal Metaplasia(Ovid Technologies (Wolters Kluwer Health), 2008) Park, Do Youn; Srivastava, Amitabh; Kim, Gwang Ha; Mino-Kenudson, Mari; Deshpande, Vikram; Zukerberg, Lawrence; Song, Geum Am; Lauwers, Gregory Y.Gastric epithelial dysplasia (GED) can be morphologically categorized into adenomatous (or intestinal) and foveolar (or gastric) types. Although limited genetic differences have been demonstrated between these subtypes, the expression of various mucins has not been systematically evaluated in this context. Endoscopic mucosal resections from 69 cases of GEDs were evaluated for the expression of MUC2, MUC5AC, MUC6, and CD10. The results were correlated with morphologic categorization and clinicopathologic parameters. GED was classified as adenomatous, foveolar, or hybrid (showing features of both types), on the basis of histologic evaluation. The neighboring intestinal metaplasia (IM) was also evaluated. An adenomatous morphology was seen in 45%, hybrid type in 33.3%, and a “pure” foveolar type was seen in 21.7% of the cases. Foveolar GED was often depressed/flat on endoscopy and showed a statistically significant association with high-grade morphology (P=0.046). Immunohistochemistry confirmed the histologic stratification. The foveolar and hybrid types were more often positive for MUC5AC (P=0.0001 for both) and negative for CD10 (P=0.019 and 0.016, respectively) as compared with adenomatous GED. High-grade morphology was associated with MUC5AC expression regardless of the morphologic phenotype (P=0.026). Foveolar (73.3%) and hybrid (86.9%) GEDs were associated more often with IM showing a retained expression of gastric type mucin than adenomatous GED (29%) (P<0.01 for both). In contrast, adenomatous type (58.1%) of GED was significantly associated with IM showing a complete intestinal phenotype (CD10+) compared with the foveolar (13.3%) and hybrid types (17.4%) of GED (P=0.005 for both comparisons). In conclusion, our study indicates that foveolar and adenomatous types of GED have distinct clinicopathologic features, mucin profiles, and association with different types of IM.Publication Clinicopathologic and Molecular Profiles of Microsatellite Unstable Barrett Esophagus-associated Adenocarcinoma(Ovid Technologies (Wolters Kluwer Health), 2011) Farris, Alton B.; Demicco, Elizabeth G.; Le, Long Phi; Finberg, Karin E.; Miller, Julie; Mandal, Rajni; Fukuoka, Junya; Cohen, Cynthia; Gaissert, Henning; Zukerberg, Lawrence; Lauwers, Gregory Y.; Iafrate, Anthony; Mino-Kenudson, MariMicrosatellite instability (MSI) has been reported in various tumors, with colon cancer as the prototype. However, little is known about MSI in Barrett esophagus (BE)-associated adenocarcinoma. Thus, the aim of this study was to compare the clinicopathologic and molecular features of BE-associated adenocarcinomas with and without MSI. The study cohort consisted of 76 patients with BE-associated adenocarcinomas (66 male, 10 female), with a mean age of 65.1 years. Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, PMS2, and CD3 and in situ hybridization for Epstein-Barr virus-encoded RNA were performed. MLH1 and PMS2 expression was lost by IHC in 5 cases (6.6%); of these, 5 showed high-level MSI (MSI-H) by polymerase chain reaction assay, and 4 showed hMLH1 promoter methylation. Histologically, tumors with MSI-H were heterogenous and included conventional adenocarcinomas with tumor-infiltrating lymphocytes (n=1), medullary carcinoma (n=2), signet ring cells (n=1), and signet ring cell and mucinous components (n=1). Compared with tumors negative for MSI by IHC, BE-associated adenocarcinomas with MSI-H were associated with older patient age (P=0.0060), lymphovascular invasion (P=0.027), and significantly larger numbers of tumor-infiltrating lymphocytes (P<0.0001). However, there was no statistical difference in overall survival between the 2 groups (P=0.285). In conclusion, MSI-H is uncommon in BE-associated adenocarcinomas, but is associated with clinicopathologic features fairly similar to sporadic microsatellite unstable colorectal cancers. Given the growing evidence that indicates lack of benefits from adjuvant therapy with fluorouracil in the colonic counterpart, it may be important to identify MSI-H in BE-associated adenocarcinomas.