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152. Consensus Recommendations for Current Treatments and Accelerating Clinical Trials for Patients With Neurofibromatosis Type 2

Author

Blakeley, Jaishri O., Evans, Gareth D., Adler, John, Brackmann, Derald, Chen, Ruihong, Ferner, Rosalie E., Hanemann, Oliver C., Harris, Gordon, Huson, Susan M., Jacob, Abraham, Kalamarides, Michel, Karajannis, Matthias A., Korf, Bruce R., Mautner, Victor–Felix, McClatchey, Andrea I., Miao, Harry, Plotkin, Scott R., Slattery, William, III, Stemmer–Rachamimov, Anat O., Welling, Bradley D., Wen, Patrick Y., Widemann, Brigitte, Hunter–Schaedle, Kim, and Giovannini, Marco

Published
2012
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153. A 31-year-old man with an apparent seizure and a mass in the right parietal lobe

Author

Ropper, Allan H. and Stemmer-Rachamimov, Anat

Subjects
Schistosomiasis -- Case studies
Abstract

A 31-year-old man who had traveled in East Africa was diagnosed with schistosomiasis when he had a seizure about five months after his trip. An MRI scan of his head showed a mass in his brain, which was found on biopsy to be the egg of the flatworm that causes schistosomiasis.

Published
2001

156. EPCO-04. GENOMIC AND EPIGENOMIC HALLMARKS OF SCHWANNOMATOSIS SCHWANNOMAS

Author

Mansouri, Sheila, primary, Suppiah, Suganth, additional, Mamatjan, Yasin, additional, Paganini, Irene, additional, Liu, Jeff, additional, Karimi, Shirin, additional, Patil, Vikas, additional, Nassiri, Farshad, additional, Singh, Olivia, additional, Sundaravadanam, Yogi, additional, Rath, Prisni, additional, Sestini, Robert, additional, Gensini, Francesca, additional, Agnihotri, Sameer, additional, Blakeley, Jaishri, additional, Ostrow, Kimberly, additional, Largaespada, David, additional, Plotkin, Scott, additional, Stemmer-Rachamimov, Anat, additional, Ferrer, Marcela Maria, additional, Pugh, Trevor, additional, Aldape, Kenneth, additional, Papi, Laura, additional, and Zadeh, Gelareh, additional

Published
2020
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157. Correction to: Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Author

Mansouri, Sheila, primary, Suppiah, Suganth, additional, Mamatjan, Yasin, additional, Paganini, Irene, additional, Liu, Jeffrey C., additional, Karimi, Shirin, additional, Patil, Vikas, additional, Nassiri, Farshad, additional, Singh, Olivia, additional, Sundaravadanam, Yogi, additional, Rath, Prisni, additional, Sestini, Roberta, additional, Gensini, Francesca, additional, Agnihotri, Sameer, additional, Blakeley, Jaishri, additional, Ostrow, Kimberly, additional, Largaespada, David, additional, Plotkin, Scott R., additional, Stemmer-Rachamimov, Anat, additional, Ferrer, Marcela Maria, additional, Pugh, Trevor J., additional, Aldape, Kenneth D., additional, Papi, Laura, additional, and Zadeh, Gelareh, additional

Published
2020
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158. Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Author

Mansouri, Sheila, primary, Suppiah, Suganth, additional, Mamatjan, Yasin, additional, Paganini, Irene, additional, Liu, Jeffrey C., additional, Karimi, Shirin, additional, Patil, Vikas, additional, Nassiri, Farshad, additional, Singh, Olivia, additional, Sundaravadanam, Yogi, additional, Rath, Prisni, additional, Sestini, Roberta, additional, Gensini, Francesca, additional, Agnihotri, Sameer, additional, Blakeley, Jaishri, additional, Ostrow, Kimberly, additional, Largaespada, David, additional, Plotkin, Scott R., additional, Stemmer-Rachamimov, Anat, additional, Ferrer, Marcela Maria, additional, Pugh, Trevor J., additional, Aldape, Kenneth D., additional, Papi, Laura, additional, and Zadeh, Gelareh, additional

Published
2020
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159. Abstract 6670: Combined signals from tumor and immune cells predict outcomes of checkpoint inhibition in melanoma

Author

Freeman, Samuel S., primary, Sade-Feldman, Moshe, additional, Kim, Jaegil, additional, Stewart, Chip, additional, Ravi, Arvind, additional, Arniella, Monica, additional, Yizhak, Keren, additional, Leshchiner, Ignaty, additional, Elagina, Liudmila, additional, Spiro, Oliver, additional, Livitz, Dimitri, additional, Rosebrock, Daniel, additional, Aguet, François, additional, Carrot-Zhang, Jian, additional, Gonye, Anna, additional, Ha, Gavin, additional, Lin, Ziao, additional, Chen, Jonathan H., additional, Frederick, Dennie T., additional, Barzily-Rokni, Michal, additional, Hammond, Marc R., additional, Vitzthum, Hans, additional, Blackmon, Shauna M., additional, Jiao, Yunxin J., additional, Lawrence, Donald P., additional, Duncan, Lyn M., additional, Stemmer-Rachamimov, Anat, additional, Wargo, Jennifer A., additional, Flaherty, Keith T., additional, Boland, Genevieve M., additional, Sullivan, Ryan J., additional, Meyerson, Matthew, additional, Getz, Gad, additional, and Hacohen, Nir, additional

Published
2020
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160. IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice

Author

Richardson, Leland G., primary, Nieman, Linda T., additional, Stemmer-Rachamimov, Anat O., additional, Zheng, Xijin S., additional, Stafford, Khalifa, additional, Nagashima, Hiroaki, additional, Miller, Julie J., additional, Kiyokawa, Juri, additional, Ting, David T., additional, Wakimoto, Hiroaki, additional, Cahill, Daniel P., additional, Choi, Bryan D., additional, and Curry, William T., additional

Published
2020
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173. TMOD-23. PRECLINICAL DRUG EVALUATION IN A GENETICALLY ENGINEERED MINIPIG MODEL OF NEUROFIBROMATOSIS TYPE 1

Author

Osum, Sara, primary, Stemmer-Rachamimov, Anat, additional, Widemann, Brigitte, additional, Dombi, Eva, additional, Vitte, Jeremie, additional, Dahiya, Sonika, additional, Rizvi, Tilat, additional, Ratner, Nancy, additional, Messiaen, Ludwine, additional, Gutmann, David, additional, Giovannini, Marco, additional, Moertel, Christopher, additional, Largaespada, David, additional, and Watson, Adrienne, additional

Published
2019
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175. Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1

Author

Cheah, Pike See, primary, Prabhakar, Shilpa, additional, Zhang, Xuan, additional, Zinter, Max, additional, Gianatasio, Maria, additional, Bronson, Roderick, additional, Kwiatkowski, David, additional, Stemmer-Rachamimov, Anat, additional, Maguire, Casey, additional, Sena-Esteves, Miguel, additional, Tannous, Bakhos, additional, and Breakefield, Xandra, additional

Published
2019
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177. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

Author

Neftel, Cyril, primary, Laffy, Julie, additional, Filbin, Mariella G., additional, Hara, Toshiro, additional, Shore, Marni E., additional, Rahme, Gilbert J., additional, Richman, Alyssa R., additional, Silverbush, Dana, additional, Shaw, McKenzie L., additional, Hebert, Christine M., additional, Dewitt, John, additional, Gritsch, Simon, additional, Perez, Elizabeth M., additional, Gonzalez Castro, L. Nicolas, additional, Lan, Xiaoyang, additional, Druck, Nicholas, additional, Rodman, Christopher, additional, Dionne, Danielle, additional, Kaplan, Alexander, additional, Bertalan, Mia S., additional, Small, Julia, additional, Pelton, Kristine, additional, Becker, Sarah, additional, Bonal, Dennis, additional, Nguyen, Quang-De, additional, Servis, Rachel L., additional, Fung, Jeremy M., additional, Mylvaganam, Ravindra, additional, Mayr, Lisa, additional, Gojo, Johannes, additional, Haberler, Christine, additional, Geyeregger, Rene, additional, Czech, Thomas, additional, Slavc, Irene, additional, Nahed, Brian V., additional, Curry, William T., additional, Carter, Bob S., additional, Wakimoto, Hiroaki, additional, Brastianos, Priscilla K., additional, Batchelor, Tracy T., additional, Stemmer-Rachamimov, Anat, additional, Martinez-Lage, Maria, additional, Frosch, Matthew P., additional, Stamenkovic, Ivan, additional, Riggi, Nicolo, additional, Rheinbay, Esther, additional, Monje, Michelle, additional, Rozenblatt-Rosen, Orit, additional, Cahill, Daniel P., additional, Patel, Anoop P., additional, Hunter, Tony, additional, Verma, Inder M., additional, Ligon, Keith L., additional, Louis, David N., additional, Regev, Aviv, additional, Bernstein, Bradley E., additional, Tirosh, Itay, additional, and Suvà, Mario L., additional

Published
2019
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179. Gene therapy with apoptosis-associated speck-like protein, a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo

Author

Ahmed, Sherif G, primary, Abdelnabi, Ahmed, additional, Maguire, Casey A, additional, Doha, Mohamed, additional, Sagers, Jessica E, additional, Lewis, Rebecca M, additional, Muzikansky, Alona, additional, Giovannini, Marco, additional, Stemmer-Rachamimov, Anat, additional, Stankovic, Konstantina M, additional, Fulci, Giulia, additional, and Brenner, Gary J, additional

Published
2019
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181. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

Author

Sade-Feldman, Moshe, primary, Yizhak, Keren, additional, Bjorgaard, Stacey L., additional, Ray, John P., additional, de Boer, Carl G., additional, Jenkins, Russell W., additional, Lieb, David J., additional, Chen, Jonathan H., additional, Frederick, Dennie T., additional, Barzily-Rokni, Michal, additional, Freeman, Samuel S., additional, Reuben, Alexandre, additional, Hoover, Paul J., additional, Villani, Alexandra-Chloé, additional, Ivanova, Elena, additional, Portell, Andrew, additional, Lizotte, Patrick H., additional, Aref, Amir R., additional, Eliane, Jean-Pierre, additional, Hammond, Marc R., additional, Vitzthum, Hans, additional, Blackmon, Shauna M., additional, Li, Bo, additional, Gopalakrishnan, Vancheswaran, additional, Reddy, Sangeetha M., additional, Cooper, Zachary A., additional, Paweletz, Cloud P., additional, Barbie, David A., additional, Stemmer-Rachamimov, Anat, additional, Flaherty, Keith T., additional, Wargo, Jennifer A., additional, Boland, Genevieve M., additional, Sullivan, Ryan J., additional, Getz, Gad, additional, and Hacohen, Nir, additional

Published
2019
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183. Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

Author

Roy Jennifer, Engler David A, Betensky Rebecca A, Plotkin Scott, Mohapatra Gayatry, James Marianne, Stemmer-Rachamimov Anat, Nunes Fabio, Shen Yiping, Ramesh Vijaya, and Gusella James F

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas. Methods We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH). Results Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors. Conclusion Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

Published
2009
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187. Characterization of cells from patient-derived fibrovascular membranes in proliferative diabetic retinopathy

Author

Kim, Leo A., Wong, Lindsay L., Amarnani, Dhanesh S., Bigger-Allen, Alexander A., Hu, Yang, Marko, Christina K., Eliott, Dean, Shah, Vinay A., McGuone, Declan, Stemmer-Rachamimov, Anat O., Gai, Xiaowu, D’Amore, Patricia A., and Arboleda-Velasquez, Joseph F.

Subjects
Adult, Male, Comparative Genomic Hybridization, Diabetic Retinopathy, Epiretinal Membrane, Cell Separation, Middle Aged, Immunohistochemistry, Actins, Platelet Endothelial Cell Adhesion Molecule-1, Glial Fibrillary Acidic Protein, Angiopoietin-1, Humans, Female, Cells, Cultured, Research Article, Cell Proliferation
Abstract

Purpose Epiretinal fibrovascular membranes (FVMs) are a hallmark of proliferative diabetic retinopathy (PDR). Surgical removal of FVMs is often indicated to treat tractional retinal detachment. This potentially informative pathological tissue is usually disposed of after surgery without further examination. We developed a method for isolating and characterizing cells derived from FVMs and correlated their expression of specific markers in culture with that in tissue. Methods FVMs were obtained from 11 patients with PDR during diabetic vitrectomy surgery and were analyzed with electron microscopy (EM), comparative genomic hybridization (CGH), immunohistochemistry, and/or digested with collagenase II for cell isolation and culture. Antibody arrays and enzyme-linked immunosorbent assay (ELISA) were used to profile secreted angiogenesis-related proteins in cell culture supernatants. Results EM analysis of the FVMs showed abnormal vessels composed of endothelial cells with large nuclei and plasma membrane infoldings, loosely attached perivascular cells, and stromal cells. The cellular constituents of the FVMs lacked major chromosomal aberrations as shown with CGH. Cells derived from FVMs (C-FVMs) could be isolated and maintained in culture. The C-FVMs retained the expression of markers of cell identity in primary culture, which define specific cell populations including CD31-positive, alpha-smooth muscle actin-positive (SMA), and glial fibrillary acidic protein-positive (GFAP) cells. In primary culture, secretion of angiopoietin-1 and thrombospondin-1 was significantly decreased in culture conditions that resemble a diabetic environment in SMA-positive C-FVMs compared to human retinal pericytes derived from a non-diabetic donor. Conclusions C-FVMs obtained from individuals with PDR can be isolated, cultured, and profiled in vitro and may constitute a unique resource for the discovery of cell signaling mechanisms underlying PDR that extends beyond current animal and cell culture models.

Published
2015

188. Using magnetic resonance microscopy to study the growth dynamics of a glioma spheroid in collagen I: A case study

Author

Dai Guangping, Weitz David A, Stemmer-Rachamimov Anat, Wang Zhihui, Vader David, Huang Shuning, Rosen Bruce R, and Deisboeck Thomas S

Subjects
Medical technology, R855-855.5
Abstract

Abstract Background Highly malignant gliomas are characterized by rapid growth, extensive local tissue infiltration and the resulting overall dismal clinical outcome. Gaining any additional insights into the complex interaction between this aggressive brain tumor and its microenvironment is therefore critical. Currently, the standard imaging modalities to investigate the crucial interface between tumor growth and invasion in vitro are light and confocal laser scanning microscopy. While immensely useful in cell culture, integrating these modalities with this cancer's clinical imaging method of choice, i.e. MRI, is a non-trivial endeavour. However, this integration is necessary, should advanced computational modeling be able to utilize these in vitro data to eventually predict growth behaviour in vivo. We therefore argue that employing the same imaging modality for both the experimental setting and the clinical situation it represents should have significant value from a data integration perspective. In this case study, we have investigated the feasibility of using a specific form of MRI, i.e. magnetic resonance microscopy or MRM, to study the expansion dynamics of a multicellular tumor spheroid in a collagen type I gel. Methods An U87mEGFR human giloblastoma multicellular spheroid (MTS) containing approximately 4·103 cells was generated and pipetted into a collagen I gel. The sample was then imaged using a T2-weighted 3D spoiled gradient echo pulse sequence on a 14T MRI scanner over a period of 12 hours with a temporal resolution of 3 hours at room temperature. Standard histopathology was performed on the MRM sample, as well as on control samples. Results We were able to acquire three-dimensional MR images with a spatial resolution of 24 × 24 × 24 μm3. Our MRM data successfully documented the volumetric growth dynamics of an MTS in a collagen I gel over the 12-hour period. The histopathology results confirmed cell viability in the MRM sample, yet displayed distinct patterns of cell proliferation and invasion as compared to control. Conclusion In this study, we demonstrate that a specific form of MRI, i.e. magnetic resonance microscopy or MRM, can be used to study the dynamic growth of a multicellular tumor spheroid (MTS) with a single cell scale spatial resolution that approaches the level of light microscopy. We argue that MRM can be employed as a complementary non-invasive tool to characterize microscopic MTS expansion, and thus, together with integrative computational modeling, may allow bridging of the experimental and clinical scales more readily.

Published
2008
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189. Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1.

Author

Isakson, Sara H, Isakson, Sara H, Rizzardi, Anthony E, Coutts, Alexander W, Carlson, Daniel F, Kirstein, Mark N, Fisher, James, Vitte, Jeremie, Williams, Kyle B, Pluhar, G Elizabeth, Dahiya, Sonika, Widemann, Brigitte C, Dombi, Eva, Rizvi, Tilat, Ratner, Nancy, Messiaen, Ludwine, Stemmer-Rachamimov, Anat O, Fahrenkrug, Scott C, Gutmann, David H, Giovannini, Marco, Moertel, Christopher L, Largaespada, David A, Watson, Adrienne L, Isakson, Sara H, Isakson, Sara H, Rizzardi, Anthony E, Coutts, Alexander W, Carlson, Daniel F, Kirstein, Mark N, Fisher, James, Vitte, Jeremie, Williams, Kyle B, Pluhar, G Elizabeth, Dahiya, Sonika, Widemann, Brigitte C, Dombi, Eva, Rizvi, Tilat, Ratner, Nancy, Messiaen, Ludwine, Stemmer-Rachamimov, Anat O, Fahrenkrug, Scott C, Gutmann, David H, Giovannini, Marco, Moertel, Christopher L, Largaespada, David A, and Watson, Adrienne L

Abstract

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies.

Published
2018

190. A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Author

Griveau, Amelie, Griveau, Amelie, Seano, Giorgio, Shelton, Samuel J, Kupp, Robert, Jahangiri, Arman, Obernier, Kirsten, Krishnan, Shanmugarajan, Lindberg, Olle R, Yuen, Tracy J, Tien, An-Chi, Sabo, Jennifer K, Wang, Nancy, Chen, Ivy, Kloepper, Jonas, Larrouquere, Louis, Ghosh, Mitrajit, Tirosh, Itay, Huillard, Emmanuelle, Alvarez-Buylla, Arturo, Oldham, Michael C, Persson, Anders I, Weiss, William A, Batchelor, Tracy T, Stemmer-Rachamimov, Anat, Suvà, Mario L, Phillips, Joanna J, Aghi, Manish K, Mehta, Shwetal, Jain, Rakesh K, Rowitch, David H, Griveau, Amelie, Griveau, Amelie, Seano, Giorgio, Shelton, Samuel J, Kupp, Robert, Jahangiri, Arman, Obernier, Kirsten, Krishnan, Shanmugarajan, Lindberg, Olle R, Yuen, Tracy J, Tien, An-Chi, Sabo, Jennifer K, Wang, Nancy, Chen, Ivy, Kloepper, Jonas, Larrouquere, Louis, Ghosh, Mitrajit, Tirosh, Itay, Huillard, Emmanuelle, Alvarez-Buylla, Arturo, Oldham, Michael C, Persson, Anders I, Weiss, William A, Batchelor, Tracy T, Stemmer-Rachamimov, Anat, Suvà, Mario L, Phillips, Joanna J, Aghi, Manish K, Mehta, Shwetal, Jain, Rakesh K, and Rowitch, David H

Abstract

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

Published
2018

194. Epigenomic, genomic, and transcriptomic landscape of schwannomatosis.

Author

Mansouri, Sheila, Suppiah, Suganth, Mamatjan, Yasin, Paganini, Irene, Liu, Jeffrey C., Karimi, Shirin, Patil, Vikas, Nassiri, Farshad, Singh, Olivia, Sundaravadanam, Yogi, Rath, Prisni, Sestini, Roberta, Gensini, Francesca, Agnihotri, Sameer, Blakeley, Jaishri, Ostrow, Kimberly, Largaespada, David, Plotkin, Scott R., Stemmer-Rachamimov, Anat, and Ferrer, Marcela Maria

Subjects
SOMATIC mutation, HETEROZYGOSITY, GENOMICS, GENE fusion, PERIPHERAL nerve tumors, DNA methylation
Abstract

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome. [ABSTRACT FROM AUTHOR]

Published
2021
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195. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

Author

Legius, Eric, Messiaen, Ludwine, Wolkenstein, Pierre, Pancza, Patrice, Avery, Robert A., Berman, Yemima, Blakeley, Jaishri, Babovic-Vuksanovic, Dusica, Cunha, Karin Soares, Ferner, Rosalie, Fisher, Michael J., Friedman, Jan M., Gutmann, David H., Kehrer-Sawatzki, Hildegard, Korf, Bruce R., Mautner, Victor-Felix, Peltonen, Sirkku, Rauen, Katherine A., Riccardi, Vincent, Schorry, Elizabeth, Stemmer-Rachamimov, Anat, Stevenson, David A., Tadini, Gianluca, Ullrich, Nicole J., Viskochil, David, Wimmer, Katharina, Yohay, Kaleb, Gomes, Alicia, Jordan, Justin T., Mautner, Victor, Merker, Vanessa L., Smith, Miriam J., Stevenson, David, Anten, Monique, Aylsworth, Arthur, Baralle, Diana, Barbarot, Sebastien, Barker, Fred, Ben-Shachar, Shay, Bergner, Amanda, Bessis, Didier, Blanco, Ignacio, Cassiman, Catherine, Ciavarelli, Patricia, Clementi, Maurizio, Frébourg, Thierry, Giovannini, Marco, Halliday, Dorothy, Hammond, Chris, Hanemann, C.O., Hanson, Helen, Heiberg, Arvid, Joly, Pascal, Kalamarides, Michel, Karajannis, Matthias, Kroshinsky, Daniela, Larralde, Margarita, Lázaro, Conxi, Le, Lu, Link, Michael, Listernick, Robert, MacCollin, Mia, Mallucci, Conor, Moertel, Christopher, Mueller, Amy, Ngeow, Joanne, Oostenbrink, Rianne, Packer, Roger, Papi, Laura, Parry, Allyson, Peltonen, Juha, Pichard, Dominique, Poppe, Bruce, Rezende, Nilton, Rodrigues, Luiz Oswaldo, Rosser, Tena, Ruggieri, Martino, Serra, Eduard, Steinke-Lange, Verena, Stivaros, Stavros Michael, Taylor, Amy, Toelen, Jaan, Tonsgard, James, Trevisson, Eva, Upadhyaya, Meena, Varan, Ali, Wilson, Meredith, Wu, Hao, Zadeh, Gelareh, Huson, Susan M., Evans, D. Gareth, and Plotkin, Scott R.

Abstract

By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).

Published
2021
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196. Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.

Author

Li, Ming, Li, Guoping, Kiyokawa, Juri, Tirmizi, Zain, Richardson, Leland G., Ning, Jianfang, Das, Saumya, Martuza, Robert L., Stemmer-Rachamimov, Anat, Rabkin, Samuel D., and Wakimoto, Hiroaki

Subjects
GLIOBLASTOMA multiforme, PERICYTES, STROMAL cells, CELL populations, BRAIN tumors, VACCINIA, FIBROBLASTS
Abstract

Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRβ represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the ability of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRβ+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells. [ABSTRACT FROM AUTHOR]

Published
2020
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198. An update on the CNS manifestations of neurofibromatosis type 2.

Author

Coy, Shannon, Rashid, Rumana, Stemmer-Rachamimov, Anat, and Santagata, Sandro

Subjects
NEUROFIBROMATOSIS 2, VESTIBULAR nerve, MULTIPLE tumors, SURGICAL excision, CENTRAL nervous system, BIOLOGY, MOLECULAR biology
Abstract

Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research. [ABSTRACT FROM AUTHOR]

Published
2020
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