RESUMO
NUT carcinoma (NC) is an aggressive cancer with no effective treatment. About 70% of NUT carcinoma is associated with chromosome translocation events that lead to the formation of a BRD4::NUTM1 fusion gene. Because the BRD4::NUTM1 gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model for NUT carcinoma that recapitulates the human t(15;19) chromosome translocation in mice. We demonstrated that the mouse t(2;17) syntenic chromosome translocation, forming the Brd4::Nutm1 fusion gene, could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with enrichment of undifferentiated cells. Similar to the reports of human NC incidence, Brd4::Nutm1 can induce NC from a broad range of tissues with a strong phenotypical variability. The consistent induction of poorly differentiated carcinoma demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC that will lead to better understanding and therapy development for NC.
Assuntos
Proteínas que Contêm Bromodomínio , Proteínas de Neoplasias , Proteínas Nucleares , Proteínas de Fusão Oncogênica , Fatores de Transcrição , Animais , Camundongos , Carcinoma/genética , Carcinoma/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Translocação Genética/genéticaRESUMO
In order to find out to what extent ovarian aging could be compensated by the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatments, a total of 4102 women above the age of 35 undergoing 6489 complete cycles from 2009 to 2015 with follow-up visits until 2017 were retrospectively analyzed. Cumulative live birth rates (CLBRs) across multiple IVF/ICSI cycles were compared in the study population stratified by age and ovarian reserve (classified by the POSEIDON criteria). Younger patients (aged between 35 and 40) could well benefit from repeat IVF treatments, with the optimal CLBRs ranging from 62%-72% for up to four complete cycles. However, the CLBRs sharply declined to 7.7%-40% in older patients (>40yrs). In light of ovarian reserve, the optimal-estimated-four-cycle CLBR of younger patients (35-40yrs) in POSEIDON group 2 could approached to those with normal ovarian response (non-POSEIDON), with 57.3%-70% versus 74.5%-81% respectively. However, the CLBR of older patients (>40yrs) in POSEIDON group 2 only reached 50% of their counterparts. Extending the number of IVF cycles beyond three or four is effective for advanced-aged women, especially in younger normal responders (non-POSEIDON) and unexpected poor/suboptimal responders (POSEIDON group 2). The real turning point at which female fecundity dropped after multiple IVF cycles is at the age of 40.
