RESUMO
Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αß T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Transplante de Rim , Síndrome Nefrótica , Osteocondrodisplasias , Doenças da Imunodeficiência Primária , Arteriosclerose/genética , Arteriosclerose/terapia , Rejeição de Enxerto/prevenção & controle , Humanos , Síndromes de Imunodeficiência/terapia , Rim/fisiologia , Transplante de Rim/efeitos adversos , Síndrome Nefrótica/genética , Síndrome Nefrótica/terapia , Osteocondrodisplasias/genética , Osteocondrodisplasias/terapia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/terapia , Embolia Pulmonar/genética , Embolia Pulmonar/terapia , Condicionamento Pré-Transplante/métodosRESUMO
Several studies have made strong efforts to understand how age and parity modulate the risk of breast cancer. A holistic understanding of the dynamic regulation of the morphological, cellular, and molecular milieu of the mammary gland offers insights into the drivers of breast cancer development as well as into potential prophylactic interventions, the latter being a longstanding ambition of the research and clinical community aspiring to eradicate the disease. In this review we discuss mechanisms that react to pregnancy signals, and we delineate the nuances of pregnancy-associated dynamism that contribute towards either breast cancer development or prevention. Further definition of the molecular basis of parity and breast cancer risk may allow the elaboration of tools to predict and survey those who are at risk of breast cancer development.
Assuntos
Neoplasias da Mama/prevenção & controle , Complicações na Gravidez/prevenção & controle , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Epigenômica , Feminino , Humanos , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo , Fatores de RiscoRESUMO
Chromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs) are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs). BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs.