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Beersheba, Israel

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.

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.

Greenberger S.,Sheba Medical Center | Greenberger S.,Sheba Cancer Research Center | Berkun Y.,Pediatric Rheumatology Unit | Berkun Y.,Sheba Medical Center | 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.

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.

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.

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