RESUMO
PURPOSE: Previous studies have shown that bariatric surgery reduces the risk of cardiovascular outcomes. Less is known about the effects of bariatric surgery on psychiatric disorders. This cohort study compared the differential risk of psychiatric disorders between those who did and did not undergo bariatric surgery, from before until after the surgery. MATERIALS AND METHODS: We used PearlDiver-Mariner, a national all-payor claims database. Patients were followed for 1 year before and after the index date and a difference-in-differences (DiD) study design was executed. RESULTS: We included 56,661 bariatric surgery patients matched to 56,661 individuals with obesity. Among bariatric surgery patients, the risk of psychiatric was 18% 1 year before and increased to 70% 1 year after surgery. Among individuals with obesity, the risk of psychiatric disorders also increased from 1 year before to 1 year after, but by less (21% versus 46%). DiD analysis suggested that bariatric surgery was associated with a 27 percentage point differential increase in the risk of psychiatric disorders across all patients, representing a 135% relative increase. Results using 3 years as the pre- and post-periods lead to similar inferences. CONCLUSION: Preexisting psychiatric disorders are similarly prevalent among bariatric surgery patients and individuals with obesity. The prevalence of psychiatric disorders increased over time for both groups, but to a larger extent among bariatric surgery patients. Adequate treatment for psychiatric disorders and appropriate implementation of behavioral health interventions may be needed to reduce the burden of psychiatric disorders following bariatric surgery.
Assuntos
Cirurgia Bariátrica , Transtornos Mentais , Obesidade Mórbida , Cirurgia Bariátrica/psicologia , Estudos de Coortes , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Obesidade/complicações , Obesidade/cirurgia , Obesidade Mórbida/cirurgiaRESUMO
Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.
Assuntos
Antineoplásicos/farmacologia , Elementos Facilitadores Genéticos , Melanoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Metástase Neoplásica , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Differences in the way human and mouse fibroblasts experience senescence in culture had long puzzled researchers. While senescence of human cells is mediated by telomere shortening, Parrinello et al. demonstrated that senescence of mouse cells is caused by extreme oxygen sensitivity. It was hypothesized that the striking difference in oxygen sensitivity between mouse and human cells explains their different rates of aging. To test if this hypothesis is broadly applicable, we cultured cells from 16 rodent species with diverse lifespans in 3% and 21% oxygen and compared their growth rates. Unexpectedly, fibroblasts derived from laboratory mouse strains were the only cells demonstrating extreme sensitivity to oxygen. Cells from hamster, muskrat, woodchuck, capybara, blind mole rat, paca, squirrel, beaver, naked mole rat and wild-caught mice were mildly sensitive to oxygen, while cells from rat, gerbil, deer mouse, chipmunk, guinea pig and chinchilla showed no difference in the growth rate between 3% and 21% oxygen. We conclude that, although the growth of primary fibroblasts is generally improved by maintaining cells in 3% oxygen, the extreme oxygen sensitivity is a peculiarity of laboratory mouse strains, possibly related to their very long telomeres, and fibroblast oxygen sensitivity does not directly correlate with species' lifespan.
