Sheba Cancer Research Center

Ramat Gan, Israel

Sheba Cancer Research Center

Ramat Gan, Israel
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Nevo-Caspi Y.,Safra Childrens Hospital | Amariglio N.,Sheba Cancer Research Center | Rechavi G.,Sheba Cancer Research Center | Rechavi G.,Tel Aviv University | And 2 more authors.
Shock | Year: 2011

Regulating gene expression is part of a cell's response to hypoxia. A-to-I RNA editing is an epigenetic phenomenon that can contribute to RNA and protein levels and to isoform diversity. In this study, we identified alterations in the levels of RNA editing following hypoxic stress in three genes: MED13, STAT3, and F11R. Changes in editing levels were associated with changes in RNA levels. These results suggest that A-to-I RNA editing may be one of the mechanisms used by cells to regulate changes in gene expression after hypoxia. These findings could lead to a novel therapeutic approach and better health care for children with hypoxemia. Copyright © 2011 by the Shock Society.

Greenberger S.,Sheba Medical Center | Greenberger S.,Sheba Cancer Research Center | Berkun Y.,Edmond and Lilly Safra Childrens Hospital | Berkun Y.,Lilly Safra Childrens Hospital | And 5 more authors.
Journal of the American Academy of Dermatology | Year: 2013

Background: Previous reports on the cutaneous manifestations of ataxia-telangiectasia (A-T) have relied on data from small series, in patients not genetically tested for A-T. Objective: The aim of our study was to characterize the dermatologic manifestations in patients with A-T followed up at the national A-T clinic in Israel. Methods: This retrospective cross-sectional study included 32 patients followed up at a multidisciplinary A-T clinic from 2010 to 2012. Complete skin examination was done by a single dermatologist. Information about mutations and neurologic status was extracted from the patients' charts. Relevant demographic, clinical, and laboratory characteristics of all patients were collected and summarized. Results: Of the 32 patients, 97% had ocular telangiectasia, the hallmark of the disease. Telangiectasia on other body parts was less frequent. Pigmentary anomalies included café-au-lait macules (84%), hypopigmented macules (44%), and melanocytic nevi (37%). A facial papulosquamous rash was found in 41% of cases. Other manifestations included hypertrichosis and birdlike facies. We did not observe premature hair graying or poliosis. No genotype-phenotype correlation was found in terms of skin manifestations. Limitations: There was a modest sample size, because of the rarity of the disease. Conclusion: Recognition of the ocular and dermatologic manifestations of A-T can facilitate early diagnosis in a child with neurologic deterioration. © 2012 by the American Academy of Dermatology, Inc.

Matic J.,Max Planck Institute for Intelligent Systems (Stuttgart) | Matic J.,University of Heidelberg | Deeg J.,Max Planck Institute for Intelligent Systems (Stuttgart) | Deeg J.,University of Heidelberg | And 6 more authors.
Nano Letters | Year: 2013

Anti-CD3 (aCD3) nanoarrays fabricated by self-assembled nanopatterning combined with site-directed protein immobilization techniques represent a novel T cell stimulatory platform that allows tight control over ligand orientation and surface density. Here, we show that activation of primary human CD4+ T cells, defined by CD69 upregulation, IL-2 production and cell proliferation, correlates with aCD3 density on nanoarrays. Immobilization of aCD3 through nanopatterning had two effects: cell activation was significantly higher on these surfaces than on aCD3-coated plastics and allowed unprecedented fine-tuning of T cell response. © 2013 American Chemical Society.

PubMed | Helmholtz Center Munich, University of Bonn, University Childrens Hospital, Sheba Cancer Research Center and 9 more.
Type: | Journal: American journal of human genetics | Year: 2017

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH

Karst A.M.,Dana-Farber Cancer Institute | Levanon K.,Dana-Farber Cancer Institute | Levanon K.,Sheba Cancer Research Center | Duraisamy S.,Dana-Farber Cancer Institute | And 5 more authors.
Gynecologic Oncology | Year: 2011

Background: Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma. Methods: STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign (n = 12) and malignant (n = 13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions ("p53 signatures"), potential transitional precursor lesions ("proliferative p53 signatures"), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively. Results: STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in > 80% of high-grade serous ovarian carcinomas and cell lines. Conclusions: STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis. © 2011 Elsevier Inc. All rights reserved.

Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University | Shapira-Frommer R.,Sheba Medical Center | Itzhaki O.,Ella Institute of Melanoma | And 18 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies. Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning. Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. ©2013 AACR.

Nevo Y.,Hebrew University of Jerusalem | Kamhi E.,Weizmann Institute of Science | Jacob-Hirsch J.,Sheba Cancer Research Center | Amariglio N.,Sheba Cancer Research Center | And 4 more authors.
Nucleic Acids Research | Year: 2012

Sequences that conform to the 5′ splice site (5′SS) consensus are highly abundant in mammalian introns. Most of these sequences are preceded by at least one in-frame stop codon; thus, their use for splicing would result in pre-maturely terminated aberrant mRNAs. In normally grown cells, such intronic 5′SSs appear not to be selected for splicing. However, under heat shock conditions aberrant splicing involving such latent 5′SSs occurred in a number of specific gene transcripts. Using a splicing-sensitive microarray, we show here that stress-induced (e.g. heat shock) activation of latent splicing is widespread across the human transcriptome, thus highlighting the possibility that latent splicing may underlie certain diseases. Consistent with this notion, our analyses of data from the Gene Expression Omnibus (GEO) revealed widespread activation of latent splicing in cells grown under hypoxia and in certain cancers such as breast cancer and gliomas. These changes were found in thousands of transcripts representing a wide variety of functional groups; among them are genes involved in cell proliferation and differentiation. The GEO analysis also revealed a set of gene transcripts in oligodendroglioma, in which the level of activation of latent splicing increased with the severity of the disease. © 2012 The Author(s).

Dratviman-Storobinsky O.,The Krieger Eye Research Laboratory | Cohen Y.,Sheba Cancer Research Center | Frenkel S.,Hebrew University of Jerusalem | Pe'er J.,Hebrew University of Jerusalem | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2010

PURPOSE. Somatic mutations in codon 209 of the GNAQ gene are the first initiating events to be identified in uveal melanoma. The purpose of this study was to search for GNAQ209 mutations in conjunctival melanocytic lesions. METHODS. Forty archival samples of conjunctival melanocytic lesions (conjunctival nevi, primary acquired melanosis, and conjunctival melanoma), 27 samples of uveal melanoma, and 11 samples of uveal melanoma metastases to the liver (3 of which matched primary uveal melanoma samples)-a total of 78 samples from 75 patients- were examined for the presence of GNAQ209 mutations by using chip-based, matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometry. Direct sequencing was also performed. RESULTS. The GNAQ209 mutation was identified in 12 (44.5%) uveal melanoma samples and 4 (36.5%) of the 11 metastases of uveal melanoma. It was not detected in any of the other melanocytic lesions. CONCLUSIONS. The GNAQ209 mutation rate in uveal melanoma in this study is in line with the rate in other reports. The finding of the same genotype in the primary tumors and their metastases suggests that mutation in GNAQ is an early event in uveal melanoma tumorigenesis. The lack of GNAQ mutations in conjunctival melanocytic lesions suggests the involvement of a different tumorigenic pathway from that of uveal melanoma. © Association for Research in Vision and Ophthalmology.

Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University | Hershkovitz L.,Ella Institute of Melanoma | Schachter J.,Ella Institute of Melanoma | Treves A.J.,Sheba Cancer Research Center
Clinical and Developmental Immunology | Year: 2010

Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TIL) in combination with lymphodepletion has proven to be an effective treatment for metastatic melanoma patients, with an objective response rate in 50%-70% of the patients. It is based on the ex vivo expansion and activation of tumor-specific T lymphocytes extracted from the tumor and their administration back to the patient. Various TIL-ACT trials, which differ in their TIL generation procedures and patient preconditioning, have been reported. In the latest clinical studies, genetically engineered peripheral T cells were utilized instead of TIL. Further improvement of adoptive T cell transfer depends on new investigations which seek higher TIL quality, increased durable response rates, and aim to treat more patients. Simplifying this therapy may encourage cancer centers worldwide to adopt this promising technology. This paper focuses on the latest progress regarding adoptive T cell transfer, comparing the currently available protocols and discussing their advantages, disadvantages, and implication in the future. © 2010 Liat Hershkovitz et al.

Rashi-Elkeles S.,Tel Aviv University | Elkon R.,Tel Aviv University | Shavit S.,Tel Aviv University | Lerenthal Y.,Tel Aviv University | And 6 more authors.
Molecular Oncology | Year: 2011

The cellular response to DNA damage is vital for maintaining genomic stability and preventing undue cell death or cancer formation. The DNA damage response (DDR), most robustly mobilized by double-strand breaks (DSBs), rapidly activates an extensive signaling network that affects numerous cellular systems, leading to cell survival or programmed cell death. A major component of the DDR is the widespread modulation of gene expression. We analyzed together six datasets that probed transcriptional responses to ionizing radiation (IR) - our novel experimental data and 5 published datasets - to elucidate the scope of this response and identify its gene targets. According to the mRNA expression profiles we recorded from 5 cancerous and non-cancerous human cell lines after exposure to 5 Gy of IR, most of the responses were cell line-specific. Computational analysis identified significant enrichment for p53 target genes and cell cycle-related pathways among groups of up-regulated and down-regulated genes, respectively. Computational promoter analysis of the six datasets disclosed that a statistically significant number of the induced genes contained p53 binding site signatures. p53-mediated regulation had previously been documented for subsets of these gene groups, making our lists a source of novel potential p53 targets. Real-time qPCR and chromatin immunoprecipitation (ChIP) assays validated the IR-induced p53-dependent induction and p53 binding to the respective promoters of 11 selected genes. Our results demonstrate the power of a combined computational and experimental approach to identify new transcriptional targets in the DNA damage response network. © 2011 Federation of European Biochemical Societies.

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