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14. Integrin alphaIIb promoter-targeted expression of gene products in megakaryocytes derived from retrovirus-transduced human hematopoietic cells

Author

Wilcox, David A., Olsen, John C., Ishizawa, Lori, Griffith, Michael, and White, Gilbert C., II

Subjects
Gene expression -- Research, Hematopoietic stem cells -- Research, Science and technology
Abstract

Megakaryocyte-specific expression of the platelet-adhesion receptor, integrin [Alpha]IIb[Beta]3, is caused by the presence of regulatory elements of the [Alpha]IIb promoter that direct high-level, selective gene transcription early in megakaryocytopoiesis. To develop methods for targeted expression of transgenes, we transduced human CD34+ peripheral blood cells with a murine leukemia virus (MuLV) vector controlled by the human integrin [Alpha]IIb promoter (nucleotides -889 to +35). A naturally occurring cDNA encoding the [Pl.sup.A2] alloantigen form (Pro33) of the integrin [Beta]3 subunit was subcloned into this construct (-889[Pl.sup.A2][Beta]3) and transduced into cells that endogenously synthesized [pl.sup.A1][Beta]3 ([Leu.sub.33]) as a marker for detection of provirus-derived [Beta]3. The ability of this vector to target expression of [pl.sup.A2][Beta]3 to megakaryocytes was first examined in cell lines. Immunoblot analysis with human anti-[Pl.sup.A2] alloserum detected synthesis of [pl.sup.A2][Beta]3 in transduced promegakaryocytic cells; however, [Pl.sup.A2][Beta]3 protein was not detected in transduced epithelial cells. Human hematopoietic CD34+ cells were transduced with -889[Pl.sup.A2][Beta]3 virions and induced to differentiate with megakaryocyte growth and development factor. A hybrid [Alpha]IIb[Beta]3 complex was formed in progeny megakaryocytes where provirus-derived [pl.sup.A2][Beta]3 was detected associated with endogenous [Alpha]IIb subunit. Another [Alpha]IIb promoter-driven MuLV vector (-889nlacZ) encoding Escherichia coli [Beta]-galactosidase was used to demonstrate that transgene expression was selectively targeted to the megakaryocyte progeny of transduced CD34+ cells. These studies demonstrate the feasibility of using [Alpha]IIb promoter-driven MuLV vectors for gene transfer of hematopoietic CD34+ cells to target transgene expression in developing megakaryocytes and platelets and indicate potential applications toward human gene therapy for platelet disorders.

Published
1999

21. End-stage liver disease in persons with hemophilia and transfusion-associated infections

Author

Goedert, James J., Eyster, M. Elaine, Lederman, Michael M., Mandalaki, Titica, de Moerloose, Philippe, White, Gilbert C., II, Angiolillo, Anne L., Luban, Naomi L.C., Sherman, Kenneth E., Manco-Johnson, Marilyn, Preiss, Liliana, Leissinger, Cindy, Kessler, Craig M., Cohen, Alan R., DiMichele, Donna, Hilgartner, Margaret W., Aledort, Louis M., Kroner, Barbara L., Rosenberg, Philip S., and Hatzakis, Angelos

Published
2002
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23. AIDS-associated non-Hodgkin's lymphomas as primary and secondary AIDS diagnoses in hemophiliacs

Author

Ragni, Margaret V., Belle, Steven H., Jaffe, Ronald, Locker, Joseph, Duerstein, Sandra L., Bass, Debra C., Addiego, Joseph E., Aledort, Louis M., Barron, Lloyd E., Brettler, Doreen B., Buchanan, George R., Gill, Joan C., Ewenstein, Bruce M., Green, David, Hilgartner, Margaret W., Hoots, W. Keith, Kisker, C. Thomas, Lovrien, Everett W., Rutherford, Cynthia J., Sanders, Natalie L., Smith, Kenneth J., Stabler, Sally P., Swindells, Susan, White, Gilbert C., III, and Kingsley, Lawrence A.

Subjects
Non-Hodgkin's lymphomas -- Demographic aspects, AIDS (Disease) -- Complications, Health
Abstract

The occurrence of AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) in hemophiliacs may be increasing in the later stages of AIDS diagnoses and may be linked with longer periods of immunosuppression. Of 33 HIV-infected hemophiliacs, those with NHL as their second AIDS-related disease were older and had lower CD4 counts following longer phases of immunosupression compared to those with NHL as their first AIDS-related disease. Antiretroviral therapy was responsible for an increase in survival rate as well as the prolonged immunosupression.

Published
1996

25. Wound infection rates after invasive procedures in HIV-1 seropositive versus HIV-1 seronegative hemophiliacs

Author

Buehrer, Jeffrey L., Weber, David J., Meyer, Anthony A., Becherer, Paul R., Rutala, William A., Wilson, Brejetta, Smiley, M. Lynn, and White, Gilbert C., II

Subjects
Hemophilia -- Physiological aspects, HIV infection -- Complications, Hemophiliacs, Surgical wound infections -- Physiological aspects, Surgical wound infections -- Risk factors, Health
Abstract

Patients who test positive for the human immunodeficiency virus and have gone on to develop either acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) are known to have a high incidence of bacterial infections. It is not known if patients who are HIV-positive but have not developed ARC or AIDS are also at increased risk of infection. It is estimated that there are about 1.5 million such people in the United States. There is concern about the risks involved in operating on these asymptomatic patients, because many have decreased immune function at a subclinical level, i.e. detectable only with laboratory or other testing. A study was undertaken to compare the operative risks of two groups of hemophiliacs, one group HIV-positive and the other HIV-negative. A retrospective review identified 102 hemophiliac patients who had undergone surgery; these patients were cross-referenced to patients in an ongoing study of hemophiliac patients who are HIV-positive. This cross-referencing revealed 83 patients with known HIV status who had undergone 169 operations. These patients were grouped according to HIV-positive status, HIV-negative status, or unclear HIV status (those patients who had surgery before their HIV status had been established). The wound infection rates of the three groups were: HIV-positive, 1.4 percent; unclear HIV status 1.5 percent; HIV-negative 0 percent. There was no significant difference in wound infection rates. It is concluded that surgery in HIV-positive, non-AIDS patients, does not carry an increased risk of wound infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1990

29. ERGIC-53 Gene Structure and Mutation Analysis in 19 Combined Factors V and VIII Deficiency Families

Author

Nichols, William C., Terry, Valeri H., Wheatley, Matthew A., Yang, Angela, Zivelin, Ariella, Ciavarella, Nicola, Stefanile, Caterina, Matsushita, Tadashi, Saito, Hidehiko, de Bosch, Norma B., Ruiz-Saez, Arlette, Torres, Argimiro, Thompson, Arthur R., Feinstein, Donald I., White, Gilbert C., Negrier, Claude, Vinciguerra, Christine, Aktan, Melih, Kaufman, Randal J., Ginsburg, David, and Seligsohn, Uri

Published
1999
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33. Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Author

Gao, Juan, primary, Huang, Ming, additional, Lai, Jingjing, additional, Mao, Kaijun, additional, Sun, Peisen, additional, Cao, Zhongyuan, additional, Hu, Youpei, additional, Zhang, Yingying, additional, Schulte, Marie L., additional, Jin, Chaozhi, additional, Wang, Jian, additional, White, Gilbert C., additional, Xu, Zhen, additional, and Ma, Yan-Qing, additional

Published
2017
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34. Thrombosis in Cancer: Research Priorities Identified by a National Cancer Institute/National Heart, Lung, and Blood Institute Strategic Working Group

Author

Key, Nigel S., primary, Khorana, Alok A., additional, Mackman, Nigel, additional, McCarty, Owen J.T., additional, White, Gilbert C., additional, Francis, Charles W., additional, McCrae, Keith R., additional, Palumbo, Joseph S., additional, Raskob, Gary E., additional, Chan, Andrew T., additional, and Sood, Anil K., additional

Published
2016
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35. Prothrombotic antibodies targeting the spike protein's receptor-binding domain in severe COVID-19

Author

Zhu, Wen, Zheng, Yongwei, Yu, Mei, Witman, Nathan, Zhou, Lu, Wei, Jianhui, Zhang, Yongguang, Topchyan, Paytsar, Nguyen, Christine, Wang, David, Janecke, Rae, Padmanabhan, Anand, Baumann Kreuziger, Lisa, White, Gilbert C., Hari, Parameswaran, Gu, Tongjun, Fields, Alexander T., Kornblith, Lucy Z., Aster, Richard, Zhu, Jieqing, Cui, Weiguo, Jobe, Shawn, Graham, Mary Beth, Wang, Demin, and Wen, Renren

Abstract

•Patients with severe COVID-19 make prothrombotic antibodies linked to platelet activation, inflammation, and tissue damage markers.•A subset of antibodies to the RBD of the spike protein contributes to the pool of prothrombotic antibodies.

Published
2024
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37. Hemophilia: An Amazing 35-Year Journey from the Depths of HIV to the Threshold of Cure*

Author

White, Gilbert C.

Subjects
Factor VIII, Transfusion Reaction, HIV Infections, Articles, Genetic Therapy, Hepacivirus, History, 20th Century, Hemophilia A, Protein Engineering, History, 21st Century, Recombinant Proteins, hemic and lymphatic diseases, HIV-1, Humans, Blood Transfusion, Cloning, Molecular
Abstract

Methods developed in the early 1970s to highly purify factor VIII (FVIII) from the plasma of large numbers of blood donors led, for the first time, to concentrates of FVIII that enabled hemophiliac to self-treat, providing independence and opening the way to safe surgery and other treatments. But, with the introduction of blood-borne viruses such as HIV-1 and hepatitis C viruses into the blood supply, these concentrates also transmitted HIV and hepatitis to a high percentage of hemophiliacs. Nevertheless, from the depths of the AIDS epidemic in hemophilia came extraordinary scientific advances that led to recombinant FVIII, the identification of HIV as the agent causing AIDS, the eventual development of effective treatments for AIDS, gene transfer approaches using lentiviruses, and treatments for hepatitis C. All of these have improved the lives of current and future hemophiliacs and have brought us to the threshold of a cure.

Published
2010

38. Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin.

Author

Juan Gao, Ming Huang, Jingjing Lai, Kaijun Mao, Peisen Sun, Zhongyuan Cao, Youpei Hu, Yingying Zhang, Schulte, Marie L., Chaozhi Jin, Jian Wang, White, Gilbert C., Zhen Xu, and Yan-Qing Ma

Subjects
PROTEINS, PLATELET aggregation inhibitors, PAXILLIN
Abstract

Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies. [ABSTRACT FROM AUTHOR]

Published
2017
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41. Role Of B Cell Tolerance In PF4/Heparin Antibody Production

Author

Zheng, Yongwei, primary, Wang, Alexander W, additional, Yu, Mei, additional, Padmanabhan, Anand, additional, Tourdot, Benjamin E, additional, Newman, Debra K., additional, White, Gilbert C., additional, Aster, Richard H., additional, Wen, Renren, additional, and Wang, Demin, additional

Published
2013
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44. Integrin-independent role of CalDAG-GEFI in neutrophil chemotaxis

Author

Carbo, Carla, primary, Duerschmied, Daniel, additional, Goerge, Tobias, additional, Hattori, Hidenori, additional, Sakai, Jiro, additional, Cifuni, Stephen M, additional, White, Gilbert C, additional, Chrzanowska-Wodnicka, Magdalena, additional, Luo, Hongbo R, additional, and Wagner, Denisa D, additional

Published
2010
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