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6. α4β1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the α4-cytoplasmic domain

Author

Alon, Ronen, Feigelson, Sara W, Manevich, Eugenia, Rose, David M, Schmitz, Julia, Overby, Darryl R, Winter, Eitan, Grabovsky, Valentin, Shinder, Vera, Matthews, Benjamin D, Sokolovsky-Eisenberg, Maya, Ingber, Donald E, Benoit, Martin, and Ginsberg, Mark H

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cell Adhesion, Cell Adhesion Molecules, Cytoplasm, Cytoskeletal Proteins, Cytoskeleton, Humans, Immunoglobulins, Integrin alpha4, Integrin alpha4beta1, Jurkat Cells, Ligands, Mucoproteins, Mutation, Paxillin, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Recombinant Proteins, Stress, Mechanical, Talin, Transfection, Vascular Cell Adhesion Molecule-1, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which alpha4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the alpha4 tail that disrupts paxillin binding, alpha4(Y991A), reduced talin association to the alpha4beta1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed alpha4beta1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal alpha4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions.

Published
2005

7. Alpha4beta1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the alpha4-cytoplasmic domain.

Author

Alon, Ronen, Feigelson, Sara W, Manevich, Eugenia, Rose, David M, Schmitz, Julia, Overby, Darryl R, Winter, Eitan, Grabovsky, Valentin, Shinder, Vera, Matthews, Benjamin D, Sokolovsky-Eisenberg, Maya, Ingber, Donald E, Benoit, Martin, and Ginsberg, Mark H

Subjects
Jurkat Cells, Cytoplasm, Cytoskeleton, Humans, Immunoglobulins, Cytoskeletal Proteins, Talin, Integrin alpha4beta1, Vascular Cell Adhesion Molecule-1, Mucoproteins, Integrin alpha4, Recombinant Proteins, Ligands, Transfection, Cell Adhesion, Protein Conformation, Protein Structure, Tertiary, Protein Binding, Mutation, Stress, Mechanical, Paxillin, Protein Structure, Tertiary, Stress, Mechanical, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which alpha4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the alpha4 tail that disrupts paxillin binding, alpha4(Y991A), reduced talin association to the alpha4beta1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed alpha4beta1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal alpha4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions.

Published
2005

8. Author Correction: The mid-developmental transition and the evolution of animal body plans

Author

Levin, Michal, Anavy, Leon, Cole, Alison G., Winter, Eitan, Mostov, Natalia, Khair, Sally, Senderovich, Naftalie, Kovalev, Ekaterina, Silver, David H., Feder, Martin, Fernandez-Valverde, Selene L., Nakanishi, Nagayasu, Simmons, David, Simakov, Oleg, Larsson, Tomas, Liu, Shang-Yun, Jerafi-Vider, Ayelet, Yaniv, Karina, Ryan, Joseph F., Martindale, Mark Q., Rink, Jochen C., Arendt, Detlev, Degnan, Sandie M., Degnan, Bernard M., Hashimshony, Tamar, and Yanai, Itai

Published
2019
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9. The mid-developmental transition and the evolution of animal body plans

Author

Levin, Michal, Anavy, Leon, Cole, Alison G., Winter, Eitan, Mostov, Natalia, Khair, Sally, Senderovich, Naftalie, Kovalev, Ekaterina, Silver, David H., Feder, Martin, Fernandez-Valverde, Selene L., Nakanishi, Nagayasu, Simmons, David, Simakov, Oleg, Larsson, Tomas, Liu, Shang-Yun, Jerafi-Vider, Ayelet, Yaniv, Karina, Ryan, Joseph F., Martindale, Mark Q., Rink, Jochen C., Arendt, Detlev, Degnan, Sandie M., Degnan, Bernard M., Hashimshony, Tamar, and Yanai, Itai

Subjects
Gene expression -- Research, Embryonic development -- Research, Morphology (Animals) -- Research, Zoological research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Animals are grouped into ~35 'phyla' based upon the notion of distinct body plans (1-4). Morphological and molecular analyses have revealed that a stage in the middle of development--known as [...]

Published
2016

10. Peripheral blood cellular dynamics of Rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs

Author

Jelinsky, Scott A., primary, Hedman, Åsa K., additional, Winter, Eitan, additional, Yoosuf, Niyaz, additional, Benita, Yair, additional, Berg, Louise, additional, Brynedal, Boel, additional, Folkersen, Lasse, additional, Klareskog, Lars, additional, Maciejewski, Mateusz, additional, Sirota-Madi, Alexandra, additional, Spector, Yael, additional, Ziemek, Daniel, additional, Padyukov, Leonid, additional, and Shen-Orr, Shai S., additional

Published
2022
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11. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions

Author

Kolodkin-Gal, Dror, primary, Roitman, Lior, additional, Ovadya, Yossi, additional, Azazmeh, Narmen, additional, Assouline, Benjamin, additional, Schlesinger, Yehuda, additional, Kalifa, Rachel, additional, Horwitz, Shaul, additional, Khalatnik, Yonatan, additional, Hochner-Ger, Anna, additional, Imam, Ashraf, additional, Demma, Jonathan Abraham, additional, Winter, Eitan, additional, Benyamini, Hadar, additional, Elgavish, Sharona, additional, Khatib, Areej AS, additional, Meir, Karen, additional, Atlan, Karine, additional, Pikarsky, Eli, additional, Parnas, Oren, additional, Dor, Yuval, additional, Zamir, Gideon, additional, Ben-Porath, Ittai, additional, and Krizhanovsky, Valery, additional

Published
2021
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12. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions.

Author

Kolodkin-Gal, Dror, Roitman, Lior, Ovadya, Yossi, Azazmeh, Narmen, Assouline, Benjamin, Schlesinger, Yehuda, Kalifa, Rachel, Horwitz, Shaul, Khalatnik, Yonatan, Hochner-Ger, Anna, Imam, Ashraf, Demma, Jonathan Abraham, Winter, Eitan, Benyamini, Hadar, Elgavish, Sharona, Khatib, Areej A. S., Meir, Karen, Atlan, Karine, Pikarsky, Eli, and Parnas, Oren

Subjects
PANCREATIC intraepithelial neoplasia, PRECANCEROUS conditions, CELL growth
Published
2022
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13. Initial sequencing and comparative analysis of the mouse genome

Author

Chinwalla, Asif T., Cook, Lisa L., Delehaunty, Kimberly D., Fewell, Ginger A., Fulton, Lucinda A., Fulton, Robert S., Graves, Tina A., Hillier, LaDeana W., Mardis, Elaine R., McPherson, John D., Miner, Tracie L., Nash, William E., Nelson, Joanne O., Nhan, Michael N., Pepin, Kymberlie H., Pohl, Craig S., Ponce, Tracy C., Schultz, Brian, Thompson, Johanna, Trevaskis, Evanne, Waterston, Robert H., Wendl, Michael C., Wilson, Richard K., Yang, Shiaw-Pyng, An, Peter, Berry, Eric, Birren, Bruce, Bloom, Toby, Brown, Daniel G., Butler, Jonathan, Daly, Mark, David, Robert, Deri, Justin, Dodge, Sheila, Foley, Karen, Gage, Diane, Gnerre, Sante, Holzer, Timothy, Jaffe, David B., Kamal, Michael, Karlsson, Elinor K., Kells, Cristyn, Kirby, Andrew, Kulbokas, III, Edward J., Lander, Eric S., Landers, Tom, Leger, J. P., Levine, Rosie, Lindblad-Toh, Kerstin, Mauceli, Evan, Mayer, John H., McCarthy, Megan, Meldrim, Jim, Mesirov, Jill P., Nicol, Robert, Nusbaum, Chad, Seaman, Steven, Sharpe, Ted, Sheridan, Andrew, Singer, Jonathan B., Santos, Ralph, Spencer, Brian, Stange-Thomann, Nicole, Vinson, Jade P., Wade, Claire M., Wierzbowski, Jamey, Wyman, Dudley, Zody, Michael C., Birney, Ewan, Goldman, Nick, Kasprzyk, Arkadiusz, Mongin, Emmanuel, Rust, Alistair G., Slater, Guy, Stabenau, Arne, Ureta-Vidal, Abel, Whelan, Simon, Ainscough, Rachel, Attwood, John, Bailey, Jonathon, Barlow, Karen, Beck, Stephan, Burton, John, Clamp, Michele, Clee, Christopher, Coulson, Alan, Cuff, James, Curwen, Val, Cutts, Tim, Davies, Joy, Eyras, Eduardo, Grafham, Darren, Gregory, Simon, Hubbard, Tim, Hunt, Adrienne, Jones, Matthew, Joy, Ann, Leonard, Steven, Lloyd, Christine, Matthews, Lucy, McLaren, Stuart, McLay, Kirsten, Meredith, Beverley, Mullikin, James C., Ning, Zemin, Oliver, Karen, Overton-Larty, Emma, Plumb, Robert, Potter, Simon, Quail, Michael, Rogers, Jane, Scott, Carol, Searle, Steve, Shownkeen, Ratna, Sims, Sarah, Wall, Melanie, West, Anthony P., Willey, David, Williams, Sophie, Abril, Josep F., Guigo, Roderic, Parra, Genis, Agarwal, Pankaj, Agarwala, Richa, Church, Deanna M., Hlavina, Wratko, Maglott, Donna R., Sapojnikov, Victor, Alexandersson, Marina, Pachter, Lior, Antonarakis, Stylianos E., Dermitzakis, Emmanouil T., Reymond, Alexandre, Ucla, Catherine, Baertsch, Robert, Diekhans, Mark, Furey, Terrence S., Hinrichs, Angela, Hsu, Fan, Karolchik, Donna, Kent, W. James, Roskin, Krishna M., Schwartz, Matthias S., Sugnet, Charles, Weber, Ryan J., Bork, Peer, Letunic, Ivica, Suyama, Mikita, Torrents, David, Zdobnov, Evgeny M., Botcherby, Marc, Brown, Stephen D., Campbell, Robert D., Jackson, Ian, Bray, Nicolas, Couronne, Olivier, Dubchak, Inna, Poliakov, Alex, Rubin, Edward M., Brent, Michael R., Flicek, Paul, Keibler, Evan, Korf, Ian, Batalov, S., Bult, Carol, Frankel, Wayne N., Carninci, Piero, Hayashizaki, Yoshihide, Kawai, Jun, Okazaki, Yasushi, Cawley, Simon, Kulp, David, Wheeler, Raymond, Chiaromonte, Francesca, Collins, Francis S., Felsenfeld, Adam, Guyer, Mark, Peterson, Jane, Wetterstrand, Kris, Copley, Richard R., Mott, Richard, Dewey, Colin, Dickens, Nicholas J., Emes, Richard D., Goodstadt, Leo, Ponting, Chris P., Winter, Eitan, Dunn, Diane M., von Niederhausern, Andrew C., Weiss, Robert B., Eddy, Sean R., Johnson, L. Steven, Jones, Thomas A., Elnitski, Laura, Kolbe, Diana L., Eswara, Pallavi, Miller, Webb, O'Connor, Michael J., Schwartz, Scott, Muzny, Donna M., Glusman, Gustavo, Smit, Arian, Green, Eric D., Hardison, Ross C., Yang, Shan, Haussler, David, Hua, Axin, Roe, Bruce A., Kucherlapati, Raju S., Montgomery, Kate T., Li, Jia, Li, Ming, Lucas, Susan, Ma, Bin, McCombie, W. Richard, Morgan, Michael, Pevzner, Pavel, Tesler, Glenn, Schultz, Jorg, Smith, Douglas R., Tromp, John, and Worley, Kim C.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Mouse Genome Sequencing Consortium ; Genome Sequencing Center: ; Asif T. Chinwalla [1, 47]; Lisa L. Cook [1]; Kimberly D. Delehaunty [1]; Ginger A. Fewell [1]; Lucinda A. Fulton [...]

Published
2002
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15. A SNP Map of the Rat Genome Generated from cDNA Sequences

Author

Zimdahl, Heike, Nyakatura, Gerald, Brandt, Petra, Schulz, Herbert, Hummel, Oliver, Fartmann, Berthold, Brett, David, Droege, Marcus, Monti, Jan, Lee, Young-Ae, Sun, Yinyan, Zhao, Shaying, Winter, Eitan E., Ponting, Chris P., Chen, Yuan, Kasprzyk, Arek, Birney, Ewan, Ganten, Detlev, and Hubner, Norbert

Published
2004

19. A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Author

Clark Susan, Guenther Thomas, Spain Sarah, Jones Angela, Rowan Andrew, Harvey John J, Schaschl Helmut, Teixeira Ana, Winter Eitan, Ranta Susanna, Howarth Kimberley, Stewart Aengus, Silver Andrew, and Tomlinson Ian

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

Abstract Background Mitotic recombination is important for inactivating tumour suppressor genes by copy-neutral loss of heterozygosity (LOH). Although meiotic recombination maps are plentiful, little is known about mitotic recombination. The APC gene (chr5q21) is mutated in most colorectal tumours and its usual mode of LOH is mitotic recombination. Methods We mapped mitotic recombination boundaries ("breakpoints") between the centromere (~50 Mb) and APC (~112 Mb) in early colorectal tumours. Results Breakpoints were non-random, with the highest frequency between 65 Mb and 75 Mb, close to a low copy number repeat region (68–71 Mb). There were, surprisingly, few breakpoints close to APC, contrary to expectations were there constraints on tumorigenesis caused by uncovering recessive lethal alleles or if mitotic recombination were mechanistically favoured by a longer residual chromosome arm. The locations of mitotic and meiotic recombination breakpoints were correlated, suggesting that the two types of recombination are influenced by similar processes, whether mutational or selective in origin. Breakpoints were also associated with higher local G+C content. The recombination and gain/deletion breakpoint maps on 5q were not, however, associated, perhaps owing to selective constraints on APC dosage in early colorectal tumours. Since polymorphisms within the region of frequent mitotic recombination on 5q might influence the frequency of LOH, we tested the 68–71 Mb low copy number repeat and nearby tagSNPs, but no associations with colorectal cancer risk were found. Conclusion LOH on 5q is non-random, but local factors do not greatly influence the rate of LOH at APC or explain inter differential susceptibility to colorectal tumours.

Published
2009
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20. TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains?

Author

Winter, Eitan and Ponting, Chris P.

Subjects
Membrane proteins -- Research, Epilepsy -- Genetic aspects, Mental retardation -- Genetic aspects, Sphingolipids -- Research, Biological sciences, Chemistry
Abstract

A family of membrane-associated proteins related to yeast Lag1p and mammalian TRAM has been identified. The family includes the protein product of CLN8, a gene mutated in progressive epilepsy with mental retardation. Mouse CLN8 is also mutated in the mnd/mnd mouse, a model for neuronal ceroid lipofuscinoses. The identification of these homologues has potential implications for our understanding of ceramide synthesis, lipid regulation and protein translocation in the endoplasmic reticulum.

Published
2002

21. Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Dalin, Simona, Regev, Aviv, Root, David, Granit, Roy Z., Masury, Hadas, Condiotti, Reba, Fixler, Yaakov, Gabai, Yael, Glikman, Tzofia, Winter, Eitan, Nevo, Yuval, Carmon, Einat, Sella, Tamar, Sonnenblick, Amir, Peretz, Tamar, Lehmann, Ulrich, Paz, Keren, Piccioni, Federica, Ben-Porath, Ittai, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Dalin, Simona, Regev, Aviv, Root, David, Granit, Roy Z., Masury, Hadas, Condiotti, Reba, Fixler, Yaakov, Gabai, Yael, Glikman, Tzofia, Winter, Eitan, Nevo, Yuval, Carmon, Einat, Sella, Tamar, Sonnenblick, Amir, Peretz, Tamar, Lehmann, Ulrich, Paz, Keren, Piccioni, Federica, and Ben-Porath, Ittai

Abstract

Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+and one K14−daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+cells in the population. EZH2 and Notch increase the numbers of K14+cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition.

Published
2018

22. Mammalian BEX, WEX and GASP genes: Coding and non-coding chimaerism sustained by gene conversion events

Author

Ponting Chris P and Winter Eitan E

Subjects
Evolution, QH359-425
Abstract

Abstract Background The identification of sequence innovations in the genomes of mammals facilitates understanding of human gene function, as well as sheds light on the molecular mechanisms which underlie these changes. Although gene duplication plays a major role in genome evolution, studies regarding concerted evolution events among gene family members have been limited in scope and restricted to protein-coding regions, where high sequence similarity is easily detectable. Results We describe a mammalian-specific expansion of more than 20 rapidly-evolving genes on human chromosome Xq22.1. Many of these are highly divergent in their protein-coding regions yet contain a conserved sequence motif in their 5' UTRs which appears to have been maintained by multiple events of concerted evolution. These events have led to the generation of chimaeric genes, each with a 5' UTR and a protein-coding region that possess independent evolutionary histories. We suggest that concerted evolution has occurred via gene conversion independently in different mammalian lineages, and these events have resulted in elevated G+C levels in the encompassing genomic regions. These concerted evolution events occurred within and between genes from three separate protein families ('brain-expressed X-linked' [BEX], WWbp5-like X-linked [WEX] and G-protein-coupled receptor-associated sorting protein [GASP]), which often are expressed in mammalian brains and associated with receptor mediated signalling and apoptosis. Conclusion Despite high protein-coding divergence among mammalian-specific genes, we identified a DNA motif common to these genes' 5' UTR exons. The motif has undergone concerted evolution events independently of its neighbouring protein-coding regions, leading to formation of evolutionary chimaeric genes. These findings have implications for the identification of non protein-coding regulatory elements and their lineage-specific evolution in mammals.

Published
2005
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23. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models

Author

Minzel, Waleed, primary, Venkatachalam, Avanthika, additional, Fink, Avner, additional, Hung, Eric, additional, Brachya, Guy, additional, Burstain, Ido, additional, Shaham, Maya, additional, Rivlin, Amitai, additional, Omer, Itay, additional, Zinger, Adar, additional, Elias, Shlomo, additional, Winter, Eitan, additional, Erdman, Paul E., additional, Sullivan, Robert W., additional, Fung, Leah, additional, Mercurio, Frank, additional, Li, Dansu, additional, Vacca, Joseph, additional, Kaushansky, Nathali, additional, Shlush, Liran, additional, Oren, Moshe, additional, Levine, Ross, additional, Pikarsky, Eli, additional, Snir-Alkalay, Irit, additional, and Ben-Neriah, Yinon, additional

Published
2018
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24. Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer

Author

Granit, Roy Z., primary, Masury, Hadas, additional, Condiotti, Reba, additional, Fixler, Yaakov, additional, Gabai, Yael, additional, Glikman, Tzofia, additional, Dalin, Simona, additional, Winter, Eitan, additional, Nevo, Yuval, additional, Carmon, Einat, additional, Sella, Tamar, additional, Sonnenblick, Amir, additional, Peretz, Tamar, additional, Lehmann, Ulrich, additional, Paz, Keren, additional, Piccioni, Federica, additional, Regev, Aviv, additional, Root, David E., additional, and Ben-Porath, Ittai, additional

Published
2018
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27. Determinants of Response to Anti CD-19 CAR-T Cells for Diffuse Large B-Cell Lymphoma in Pre-Treatment Peripheral Blood Mononuclear Cells Using Single-Cell RNA-Seq

Author

Ram, Ron, Katzenelenbogen, Yonatan, Gurevich Shapiro, Anna, Winter, Eitan, Barboy, Oren, Zada, Mor, Halevi, Shahar, David, Eyal, Avivi Mazza, Irit, and Amit, Ido

Abstract

Background:Chimeric antigen receptor T (CAR-T) cell therapy has become the standard of care in patients with relapsed/refractory diffuse large cell lymphoma (R/R DLBCL), providing durable remission in 40% of patients. Lack of response is likely to be attributed to inter- and intra-patient variability, including PBMC heterogeneity and apheresis material composition, CAR-T infusion product, in-vivo expansion and activity of CAR-T cells and the development of tumor-intrinsic mechanisms. Current methods for evaluating CAR-T cell activation and potency have limited predictive value for clinical outcomes. To address this challenge, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) obtained from patients with R/R LBCL patients at the time of apheresis for the manufacturing of anti-CD19 CAR-T cell therapy. Methods: Between 10/2020 and 03/2022, 31 patients who underwent lymphopheresis were enrolled. Samples were obtained - 1) At day of lymphopheresis from peripheral blood; 2) On the day of infusion of CAR-T from the product; and 3) On day +7 after infusion from peripheral blood. All patients had day +30 PET-CT. In addition, PBMCs samples from healthy donors were used as control to analyze baseline characteristics compared to the DLBCL patients. PBMCs from patients of healthy donors were purified from frozen blood samples by density gradient separation, stained using human CD45 antibody and loaded onto a 10x Chromium system. libraries were generated using the 10X Genomics Chromium Single Cell 3' Kit. The data was processed and analyzed using the Seurat R package. The study was approved by the local Ethic committee. Results:Patient characteristics: 31 RR DLBCL patients (42% females; median age 72, range 47-81 years), all treated with CAR-T cells therapy as third line of therapy, participated in the study. All patients underwent lymphopheresis, followed by CAR-T production. Disease status at lymphodepletion was complete remission (CR, n=4, 13%), partial remission (n=6, 19%), and progressive disease (n=21, 68%) and patients received either tisagenlecleucel (n=20, 65%) or axicabtagene ciloleucel (n=11, 35%) . PET scan performed on day 30 post treatment revealed that 68% and 32% obtained CR, and PD, respectively. scRNA analysis revealed differences in PBMC composition between healthy donors and LBCL patients (Figure 1A), with lower levels of naïve and memory T cells and elevated levels of activated monocytes in LBCL patients, suggesting a shift towards an inflamed and pre-dysfunctional immune state. Categorization of LBCL patients into responders (PR/CR on day +30 PET-CT) and non-responders (PD on day +30 PET-CT) revealed differences in immune cell subsets between responders and non-responders (Figure 2A), with enriched inflammation-related pathways in non-responders, In contrast, responders exhibited a distinct healthy-like immune profiles, particularly high levels of naive T cells, similar to that obtained in their age matched healthy controls. Of note, non-responders showed alterations in immune cell subsets, including increased levels of T regulatory cells and effector NK cells. Furthermore, non-responders demonstrated a prominent inflammatory immune profile, characterized by gene pathways related to inflammation and activation, such as type I and III IFN-G, and TNFb response (Figure 1B). Notably, an IFN-G score was significantly higher in non-responder's monocytes subpopulations, compared to responders. Conclusions:These findings indicate that the success of CAR-T therapy could be determined by the molecular characteristics and subpopulation distribution of each patient's PBMC. The diverse immune profiles of DLBCL patients might impact the effectiveness of their immune cells in generating successful CAR-T products or providing a conducive environment for CAR T cells to combat cancer. Furthermore, these findings emphasize the potential of scRNA-seq in evaluating PBMC from CAR-T patients prior to treatment, allowing the potential calculation of an “immune potency score” associated with the probability of a positive outcome from CAR-T treatment of DLBCL patients. This score could potentially be used by oncologists in decision-making processes to determine the appropriate candidates for CAR-T therapy.

Published
2023
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28. Elevated rates of protein secretion, evolution, and disease among tissue-specific genes

Author

Winter, Eitan E., Goodstadt, Leo, and Ponting, Chris P.

Subjects
Amino acid sequence -- Research, Mendel's law -- Research, Genetic research, Health
Abstract

It is demonstrated with the help of large data sets that when a gene is expressed highly in a small number of tissues its protein is more likely to be secreted and mutated in a genetic diseases with mendelian inheritance.

Published
2004

29. Spatiotemporal Gene Expression Analysis of the Caenorhabditis elegansGermline Uncovers a Syncytial Expression Switch

Author

Tzur, Yonatan B, Winter, Eitan, Gao, Jinmin, Hashimshony, Tamar, Yanai, Itai, and Colaiácovo, Monica P

Abstract

Developmental programs are executed by tightly controlled gene regulatory pathways. Here, we combined the unique sample retrieval capacity afforded by laser capture microscopy with analysis of mRNA abundance by CEL-Seq (cell expression by linear amplification and sequencing) to generate a spatiotemporal gene expression map of the Caenorhabditis eleganssyncytial germline from adult hermaphrodites and males. We found that over 6000 genes exhibit spatiotemporally dynamic expression patterns throughout the hermaphrodite germline, with two dominant groups of genes exhibiting reciprocal shifts in expression at late pachytene during meiotic prophase I. We found a strong correlation between restricted spatiotemporal expression and known developmental and cellular processes, indicating that these gene expression changes may be an important driver of germ cell progression. Analysis of the male gonad revealed a shift in gene expression at early pachytene and upregulation of subsets of genes following the meiotic divisions, specifically in early and late spermatids, mostly transcribed from the X chromosome. We observed that while the X chromosome is silenced throughout the first half of the gonad, some genes escape this control and are highly expressed throughout the germline. Although we found a strong correlation between the expression of genes corresponding to CSR-1-interacting 22G-RNAs during germ cell progression, we also found that a large fraction of genes may bypass the need for CSR-1-mediated germline licensing. Taken together, these findings suggest the existence of mechanisms that enable a shift in gene expression during prophase I to promote germ cell progression.

Published
2018
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30. A mitotic recombination map proximal to the APC locus on chromosome 5q and assessment of influences on colorectal cancer risk

Author

Howarth, Kimberley, primary, Ranta, Susanna, additional, Winter, Eitan, additional, Teixeira, Ana, additional, Schaschl, Helmut, additional, Harvey, John J, additional, Rowan, Andrew, additional, Jones, Angela, additional, Spain, Sarah, additional, Clark, Susan, additional, Guenther, Thomas, additional, Stewart, Aengus, additional, Silver, Andrew, additional, and Tomlinson, Ian, additional

Published
2009
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33. The Src Kinase p56 Up-regulates VLA-4 Integrin Affinity

Author

Feigelson, Sara W., primary, Grabovsky, Valentin, additional, Winter, Eitan, additional, Chen, Ling L., additional, Pepinsky, R. Blake, additional, Yednock, Ted, additional, Yablonski, Deborah, additional, Lobb, Roy, additional, and Alon, Ronen, additional

Published
2001
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35. Elevated Rates Protein Secretion, Evolution, and Disease Among Tissue-Specific Genes.

Author

Winter, Eitan E., Goodstadt, Leo, and Ponting, Chris P.

Subjects
*GENE expression, *BIOLOGICAL variation, *TISSUES, *TISSUE-specific antigens, *BIOLOGICAL evolution, *GENES, *GENETICS
Abstract

Examines the variation in gene expression responsible for the functional and morphological specialization of tissues. Correlation of the tissue specificity of genes with gene evolution rates; Characterization of the selective pressures on protein-coding genes; Results on the analysis of disease genes.

Published
2004
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36. ArabidopsiseIF3e (INT-6) Associates with Both eIF3c and the COP9 Signalosome Subunit CSN7*

Author

Yahalom, Avital, Kim, Tae-Houn, Winter, Eitan, Karniol, Baruch, von Arnim, Albrecht G., and Chamovitz, Daniel A.

Abstract

The ArabidopsisCOP9 signalosome is a multisubunit repressor of photomorphogenesis that is conserved among eukaryotes. This complex may have a general role in development. As a step in dissecting the biochemical mode of action of the COP9 signalosome, we determined the sequence of proteins that copurify with this complex. Here we describe the association between components of the COP9 signalosome (CSN1, CSN7, and CSN8) and two subunits of eukaryotic translation initiation factor 3 (eIF3), eIF3e (p48, known also as INT-6) and eIF3c (p105). To obtain a biochemical marker for ArabidopsiseIF3, we cloned the Arabidopsisortholog of the eIF3 subunit eIF3b (PRT1). eIF3e coimmunoprecipitated with CSN7, and eIF3c coimmunoprecipitated with eIF3e, eIF3b, CSN8, and CSN1. eIF3e directly interacted with CSN7 and eIF3c. However, eIF3e and eIF3b cofractionated by gel filtration chromatography in a complex that was larger than the COP9 signalosome. Whereas eIF3, as detected through eIF3b, localized solely to the cytoplasm, eIF3e, like CSN7, was also found in the nucleus. This suggests that eIF3e and eIF3c are probably components of multiple complexes and that eIF3e and eIF3c associate with subunits of the COP9 signalosome, even though they are not components of the COP9 signalosome core complex. This interaction may allow for translational control by the COP9 signalosome.

Published
2001
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37. α4β< sub>1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with α4-cytoplasmic domain.

Author

Alon, Ronen, Feigelson, Sara W., Manevich, Eugenia, Rose, David M., Schmitz, Julia, Overby, Darryl R., Winter, Eitan, Grabovsky, Valentin, Shinder, Vera, Matthews, Benjamin D., Sokolovsky-Eisenberg, Maya, Ingber, Donald E., Benoit, Martin, and Ginsberg, Mark H.

Subjects
*CYTOPLASM, *CELL adhesion, *INTEGRINS, *CYTOSKELETON, *T cells
Abstract

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which α4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the α4 tail that disrupts paxillin binding, α4 (Y991A), reduced talin association to the α4β1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed α4β1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal α4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions. [ABSTRACT FROM AUTHOR]

Published
2005
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38. Genome sequence of the Brown Norway rat yields insights into mammalian evolution.

Author

Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M, Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, De Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Simons R, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Worley KC, Cooney AJ, D'Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E, Birney E, Mongin E, Ureta-Vidal A, Woodwark C, Zdobnov E, Bork P, Suyama M, Torrents D, Alexandersson M, Trask BJ, Young JM, Huang H, Wang H, Xing H, Daniels S, Gietzen D, Schmidt J, Stevens K, Vitt U, Wingrove J, Camara F, Mar Albà M, Abril JF, Guigo R, Smit A, Dubchak I, Rubin EM, Couronne O, Poliakov A, Hübner N, Ganten D, Goesele C, Hummel O, Kreitler T, Lee YA, Monti J, Schulz H, Zimdahl H, Himmelbauer H, Lehrach H, Jacob HJ, Bromberg S, Gullings-Handley J, Jensen-Seaman MI, Kwitek AE, Lazar J, Pasko D, Tonellato PJ, Twigger S, Ponting CP, Duarte JM, Rice S, Goodstadt L, Beatson SA, Emes RD, Winter EE, Webber C, Brandt P, Nyakatura G, Adetobi M, Chiaromonte F, Elnitski L, Eswara P, Hardison RC, Hou M, Kolbe D, Makova K, Miller W, Nekrutenko A, Riemer C, Schwartz S, Taylor J, Yang S, Zhang Y, Lindpaintner K, Andrews TD, Caccamo M, Clamp M, Clarke L, Curwen V, Durbin R, Eyras E, Searle SM, Cooper GM, Batzoglou S, Brudno M, Sidow A, Stone EA, Venter JC, Payseur BA, Bourque G, López-Otín C, Puente XS, Chakrabarti K, Chatterji S, Dewey C, Pachter L, Bray N, Yap VB, Caspi A, Tesler G, Pevzner PA, Haussler D, Roskin KM, Baertsch R, Clawson H, Furey TS, Hinrichs AS, Karolchik D, Kent WJ, Rosenbloom KR, Trumbower H, Weirauch M, Cooper DN, Stenson PD, Ma B, Brent M, Arumugam M, Shteynberg D, Copley RR, Taylor MS, Riethman H, Mudunuri U, Peterson J, Guyer M, Felsenfeld A, Old S, Mockrin S, and Collins F

Subjects
Animals, Base Composition, Centromere genetics, Chromosomes, Mammalian genetics, CpG Islands genetics, DNA Transposable Elements genetics, DNA, Mitochondrial genetics, Gene Duplication, Humans, Introns genetics, Male, Mice, Models, Molecular, Mutagenesis, Polymorphism, Single Nucleotide genetics, RNA Splice Sites genetics, RNA, Untranslated genetics, Rats, Regulatory Sequences, Nucleic Acid genetics, Retroelements genetics, Sequence Analysis, DNA, Telomere genetics, Evolution, Molecular, Genome, Genomics, Rats, Inbred BN genetics
Abstract

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Published
2004
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39. Initial sequencing and comparative analysis of the mouse genome.

Author

Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigó R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, Karolchik D, Kasprzyk A, Kawai J, Keibler E, Kells C, Kent WJ, Kirby A, Kolbe DL, Korf I, Kucherlapati RS, Kulbokas EJ, Kulp D, Landers T, Leger JP, Leonard S, Letunic I, Levine R, Li J, Li M, Lloyd C, Lucas S, Ma B, Maglott DR, Mardis ER, Matthews L, Mauceli E, Mayer JH, McCarthy M, McCombie WR, McLaren S, McLay K, McPherson JD, Meldrim J, Meredith B, Mesirov JP, Miller W, Miner TL, Mongin E, Montgomery KT, Morgan M, Mott R, Mullikin JC, Muzny DM, Nash WE, Nelson JO, Nhan MN, Nicol R, Ning Z, Nusbaum C, O'Connor MJ, Okazaki Y, Oliver K, Overton-Larty E, Pachter L, Parra G, Pepin KH, Peterson J, Pevzner P, Plumb R, Pohl CS, Poliakov A, Ponce TC, Ponting CP, Potter S, Quail M, Reymond A, Roe BA, Roskin KM, Rubin EM, Rust AG, Santos R, Sapojnikov V, Schultz B, Schultz J, Schwartz MS, Schwartz S, Scott C, Seaman S, Searle S, Sharpe T, Sheridan A, Shownkeen R, Sims S, Singer JB, Slater G, Smit A, Smith DR, Spencer B, Stabenau A, Stange-Thomann N, Sugnet C, Suyama M, Tesler G, Thompson J, Torrents D, Trevaskis E, Tromp J, Ucla C, Ureta-Vidal A, Vinson JP, Von Niederhausern AC, Wade CM, Wall M, Weber RJ, Weiss RB, Wendl MC, West AP, Wetterstrand K, Wheeler R, Whelan S, Wierzbowski J, Willey D, Williams S, Wilson RK, Winter E, Worley KC, Wyman D, Yang S, Yang SP, Zdobnov EM, Zody MC, and Lander ES

Subjects
Animals, Base Composition, Conserved Sequence genetics, CpG Islands genetics, Gene Expression Regulation, Genes genetics, Genetic Variation genetics, Genome, Human, Genomics, Humans, Mice classification, Mice, Knockout, Mice, Transgenic, Models, Animal, Multigene Family genetics, Mutagenesis, Neoplasms genetics, Proteome genetics, Pseudogenes genetics, Quantitative Trait Loci genetics, RNA, Untranslated genetics, Repetitive Sequences, Nucleic Acid genetics, Selection, Genetic, Sequence Analysis, DNA, Sex Chromosomes genetics, Species Specificity, Synteny, Chromosomes, Mammalian genetics, Evolution, Molecular, Genome, Mice genetics, Physical Chromosome Mapping
Abstract

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

Published
2002
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