Mostrando recursos 1 - 20 de 6.700

  1. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin

    Palchaudhuri, Rahul; Saez, Borja; Hoggatt, Jonathan George; Schajnovitz, Amir; Sykes, David Brian; Tate, Tiffany A; Czechowicz, Agnieszka; Kfoury, Youmna Sami; Ruchika, FNU; Rossi, Derrick J; Verdine, Gregory L.; Mansour, Michael Karim; Scadden, David Thomas
    Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone...

  2. Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

    Chattopadhyay, Shrikanta; Stewart, Alison L.; Mukherjee, Siddhartha; Huang, Cherrie; Hartwell, Kimberly A.; Miller, Peter Grant; Subramanian, Radhika; Carmody, Leigh C.; Yusuf, Rushdia Zareen; Sykes, David Brian; Paulk, Joshiawa; Vetere, Amedeo; Vallet, Sonia; Santo, Loredana; Cirstea, Diana D.; Hideshima, Teru; Dan?ík, Vlado; Majireck, Max M.; Hussain, Mahmud M.; Singh, Shambhavi; Quiroz, Ryan; Iaconelli, Jonathan; Karmacharya, Rakesh; Tolliday, Nicola J.; Clemons, Paul A.; Moore, Malcolm A.S.; Stern, Andrew M.; Shamji, Alykhan Farid; Ebert, Benjamin L.; Golub, Todd Robert; Raje, Noopur; Scadden, David Thomas; Schreiber, Stuart L.
    Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to...

  3. Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

    Chattopadhyay, Shrikanta; Stewart, Alison L.; Mukherjee, Siddhartha; Huang, Cherrie; Hartwell, Kimberly A.; Miller, Peter Grant; Subramanian, Radhika; Carmody, Leigh C.; Yusuf, Rushdia Zareen; Sykes, David Brian; Paulk, Joshiawa; Vetere, Amedeo; Vallet, Sonia; Santo, Loredana; Cirstea, Diana D.; Hideshima, Teru; Dan?ík, Vlado; Majireck, Max M.; Hussain, Mahmud M.; Singh, Shambhavi; Quiroz, Ryan; Iaconelli, Jonathan; Karmacharya, Rakesh; Tolliday, Nicola J.; Clemons, Paul A.; Moore, Malcolm A.S.; Stern, Andrew M.; Shamji, Alykhan Farid; Ebert, Benjamin L.; Golub, Todd Robert; Raje, Noopur; Scadden, David Thomas; Schreiber, Stuart L.
    Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to...

  4. Reproductive Health Screening Disparities and Sexual Orientation in a Cohort Study of U.S. Adolescent and Young Adult Females

    Charlton, Brittany Michelle; Corliss, Heather L.; Missmer, Stacey Ann; Frazier, A. Lindsay; Rosario, Margaret; Kahn, Jessica A.; Austin, Sydney Bryn
    Purpose To examine sexual orientation group disparities in Pap and STI/HPV tests among adolescents and young adult females. Methods Survey data from 4,224 adolescents and young adults aged 17-25 who responded to the 2005 wave questionnaire of the Growing Up Today Study were examined cross-sectionally with multivariable generalized estimating equations regression. We examined associations between sexual orientation and reproductive health care utilization as well as abnormal results with completely heterosexuals as the referent group, controlling for age, race/ethnicity, geographic region, and sexual history. Results After accounting for sociodemographics and sexual history, mostly heterosexual/bisexual females had 30% lower odds of having a Pap test within the...

  5. Reproductive Health Screening Disparities and Sexual Orientation in a Cohort Study of U.S. Adolescent and Young Adult Females

    Charlton, Brittany Michelle; Corliss, Heather L.; Missmer, Stacey Ann; Frazier, A. Lindsay; Rosario, Margaret; Kahn, Jessica A.; Austin, Sydney Bryn
    Purpose To examine sexual orientation group disparities in Pap and STI/HPV tests among adolescents and young adult females. Methods Survey data from 4,224 adolescents and young adults aged 17-25 who responded to the 2005 wave questionnaire of the Growing Up Today Study were examined cross-sectionally with multivariable generalized estimating equations regression. We examined associations between sexual orientation and reproductive health care utilization as well as abnormal results with completely heterosexuals as the referent group, controlling for age, race/ethnicity, geographic region, and sexual history. Results After accounting for sociodemographics and sexual history, mostly heterosexual/bisexual females had 30% lower odds of having a Pap test within the...

  6. Sexual orientation differences in teen pregnancy and hormonal contraceptive use: an examination across 2 generations

    Charlton, Brittany Michelle; Corliss, Heather L.; Missmer, Stacey Ann; Rosario, Margaret; Spiegelman, Donna Lynn; Austin, Sydney Bryn
    OBJECTIVE: To examine whether sexual orientation is associated with disparities in teen pregnancy and hormonal contraception use among adolescent females in 2 intergenerational cohorts. STUDY DESIGN: Data were collected from 91,003 women in the Nurses' Health Study II (NHSII), born between 1947-1964, and 6463 of their children, born between 1982-1987, enrolled in the Growing Up Today Study (GUTS). Log-binomial models were used to estimate risk ratios for teen pregnancy and hormonal contraception use in sexual minorities compared with heterosexuals and metaanalysis techniques were used to compare the 2 cohorts. RESULTS: Overall, teen hormonal contraception use was lower and teen pregnancy was higher in NHSII than...

  7. Sexual orientation differences in teen pregnancy and hormonal contraceptive use: an examination across 2 generations

    Charlton, Brittany Michelle; Corliss, Heather L.; Missmer, Stacey Ann; Rosario, Margaret; Spiegelman, Donna Lynn; Austin, Sydney Bryn
    OBJECTIVE: To examine whether sexual orientation is associated with disparities in teen pregnancy and hormonal contraception use among adolescent females in 2 intergenerational cohorts. STUDY DESIGN: Data were collected from 91,003 women in the Nurses' Health Study II (NHSII), born between 1947-1964, and 6463 of their children, born between 1982-1987, enrolled in the Growing Up Today Study (GUTS). Log-binomial models were used to estimate risk ratios for teen pregnancy and hormonal contraception use in sexual minorities compared with heterosexuals and metaanalysis techniques were used to compare the 2 cohorts. RESULTS: Overall, teen hormonal contraception use was lower and teen pregnancy was higher in NHSII than...

  8. A Cervical Abnormality Risk Prediction Model

    Charlton, Brittany Michelle; Carwile, Jenny L.; Michels, Karin B.; Feldman, Sarah
    Objective—HPV infections and abnormal Pap tests are common, and most do not progress to cervical cancer. Since it is difficult to predict which mild Pap abnormalities will develop into precancerous lesions, many women undergo painful and costly evaluations, and even unnecessary treatment. The objective of this study was to develop a risk prediction model based on clinical and demographic information to identify women most likely to develop significant precancerous lesions (CIN2/3 or AIS) among women with mild Pap abnormalities (ASCUS/LSIL). Materials and Methods—The Abnormal Pap Smear Registry includes women who received treatment at the Brigham and Women’s Hospital/Dana Farber Cancer Institute Pap...

  9. A Cervical Abnormality Risk Prediction Model

    Charlton, Brittany Michelle; Carwile, Jenny L.; Michels, Karin B.; Feldman, Sarah
    Objective—HPV infections and abnormal Pap tests are common, and most do not progress to cervical cancer. Since it is difficult to predict which mild Pap abnormalities will develop into precancerous lesions, many women undergo painful and costly evaluations, and even unnecessary treatment. The objective of this study was to develop a risk prediction model based on clinical and demographic information to identify women most likely to develop significant precancerous lesions (CIN2/3 or AIS) among women with mild Pap abnormalities (ASCUS/LSIL). Materials and Methods—The Abnormal Pap Smear Registry includes women who received treatment at the Brigham and Women’s Hospital/Dana Farber Cancer Institute Pap...

  10. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses' Health Study: prospective cohort study

    Charlton, Brittany Michelle; Rich-Edwards, Janet Wilson; Colditz, Graham Andrew; Missmer, Stacey Ann; Rosner, Bernard Alfred; Hankinson, Susan Elizabeth; Speizer, Frank E.; Michels, Karin B.
    Objective: To determine whether use of oral contraceptives is associated with all cause and cause specific mortality. Design: Prospective cohort study. Setting: Nurses’ Health Study, data collected between 1976 and 2012. Population: 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982. Main outcome measures: Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives. Results: In our population of 121 577 women with information on oral contraceptive use, 63 626 were...

  11. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses' Health Study: prospective cohort study

    Charlton, Brittany Michelle; Rich-Edwards, Janet Wilson; Colditz, Graham Andrew; Missmer, Stacey Ann; Rosner, Bernard Alfred; Hankinson, Susan Elizabeth; Speizer, Frank E.; Michels, Karin B.
    Objective: To determine whether use of oral contraceptives is associated with all cause and cause specific mortality. Design: Prospective cohort study. Setting: Nurses’ Health Study, data collected between 1976 and 2012. Population: 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982. Main outcome measures: Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives. Results: In our population of 121 577 women with information on oral contraceptive use, 63 626 were...

  12. Oral Contraceptive Use and Colorectal Cancer in the Nurses' Health Study I and II

    Charlton, Brittany Michelle; Wu, Kana; Zhang, Xuehong; Giovannucci, Edward L.; Fuchs, Charles Stewart; Missmer, Stacey Ann; Rosner, Bernard Alfred; Hankinson, Susan Elizabeth; Willett, Walter C.; Michels, Karin B.
    Background—It remains unclear if oral contraceptive (OC) use is associated with the incidence of colorectal cancer. Few studies have examined this association by duration of OC use, time since last OC use, and different cancer subsites. Methods—Among 88,691 participants of the Nurses’ Health Study I (NHSI) and 93,080 participants of the Nurses’ Health Study II (NHSII), we assessed OC use every 2 years between 1976-2010 and categorized it as ever use, duration of use, and time since last use. We included incident colorectal cancer cases through 2010 (NHSI: age at diagnosis=36-88, N=1,764, NHSII: age at diagnosis=33-64, N=206). Multivariable hazard ratios and...

  13. Oral Contraceptive Use and Colorectal Cancer in the Nurses' Health Study I and II

    Charlton, Brittany Michelle; Wu, Kana; Zhang, Xuehong; Giovannucci, Edward L.; Fuchs, Charles Stewart; Missmer, Stacey Ann; Rosner, Bernard Alfred; Hankinson, Susan Elizabeth; Willett, Walter C.; Michels, Karin B.
    Background—It remains unclear if oral contraceptive (OC) use is associated with the incidence of colorectal cancer. Few studies have examined this association by duration of OC use, time since last OC use, and different cancer subsites. Methods—Among 88,691 participants of the Nurses’ Health Study I (NHSI) and 93,080 participants of the Nurses’ Health Study II (NHSII), we assessed OC use every 2 years between 1976-2010 and categorized it as ever use, duration of use, and time since last use. We included incident colorectal cancer cases through 2010 (NHSI: age at diagnosis=36-88, N=1,764, NHSII: age at diagnosis=33-64, N=206). Multivariable hazard ratios and...

  14. Poverty and common mental disorders in developing countries

    Patel, Vikram Harshad; Kleinman, Arthur Michael
    A review of English-language journals published since 1990 and three global mental health reports identified 11 community studies on the association between poverty and common mental disorders in six low- and middle-income countries. Most studies showed an association between indicators of poverty and the risk of mental disorders, the most consistent association being with low levels of education. A review of articles exploring the mechanism of the relationship suggested weak evidence to support a specific association with income levels. Factors such as the experience of insecurity and hopelessness, rapid social change and the risks of violence and physical ill-health may...

  15. Poverty and common mental disorders in developing countries

    Patel, Vikram Harshad; Kleinman, Arthur Michael
    A review of English-language journals published since 1990 and three global mental health reports identified 11 community studies on the association between poverty and common mental disorders in six low- and middle-income countries. Most studies showed an association between indicators of poverty and the risk of mental disorders, the most consistent association being with low levels of education. A review of articles exploring the mechanism of the relationship suggested weak evidence to support a specific association with income levels. Factors such as the experience of insecurity and hopelessness, rapid social change and the risks of violence and physical ill-health may...

  16. Anthropology in the Clinic: The Problem of Cultural Competency and How to Fix It

    Kleinman, Arthur Michael; Benson, Peter

  17. Anthropology in the Clinic: The Problem of Cultural Competency and How to Fix It

    Kleinman, Arthur Michael; Benson, Peter

  18. Mental Health and the Global Agenda

    Becker, Anne E.; Kleinman, Arthur Michael

  19. Mental Health and the Global Agenda

    Becker, Anne E.; Kleinman, Arthur Michael

  20. Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells

    Choi, Jiho; Huebner, Aaron; Clement, Kendell; Walsh, Ryan M.; Savol, Andrej J; Lin, Kaixuan; Gu, Hongcang; Di Stefano, Bruno; Brumbaugh, Justin; Kim, Sang-Yong; Sharif, Jafar; Rose, Christopher M.; Mohammad, Arman; Odajima, Junko; Charron, Jean; Shioda, Toshihiro; Gnirke, Andreas; Gygi, Steven P.; Koseki, Haruhiko; Sadreyev, Ruslan; Xiao, Andrew; Meissner, Alexander; Hochedlinger, Konrad
    Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo1. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore,...

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