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1.
Artigo em Inglês | MEDLINE | ID: mdl-36167642

RESUMO

OBJECTIVE: Because the heterogeneity of patients in intensive care units (ICUs) and family members represents a challenge to palliative care delivery, we aimed to determine if distinct phenotypes of palliative care needs exist. METHODS: Prospective cohort study conducted among family members of adult patients undergoing mechanical ventilation in six medical and surgical ICUs. The primary outcome was palliative care need measured by the Needs at the End-of-Life Screening Tool (NEST, range from 0 (no need) to 130 (highest need)) completed 3 days after ICU admission. We also assessed quality of communication, clinician-family relationship and patient centredness of care. Latent class analysis of the NEST's 13 items was used to identify groups with similar patterns of serious palliative care needs. RESULTS: Among 257 family members, latent class analysis yielded a four-class model including complex communication needs (n=26, 10%; median NEST score 68.0), family spiritual and cultural needs (n=21, 8%; 40.0) and patient and family stress needs (n=43, 31%; 31.0), as well as a fourth group with fewer serious needs (n=167, 65%; 14.0). Interclass differences existed in quality of communication (median range 4.0-10.0, p<0.001), favourable clinician-family relationship (range 34.6%-98.2%, p<0.001) and both the patient centredness of care Eliciting Concerns (median range 4.0-5.0, p<0.001) and Decision-Making (median range 2.3-4.5, p<0.001) scales. CONCLUSIONS: Four novel phenotypes of palliative care need were identified among ICU family members with distinct differences in the severity of needs and perceived quality of the clinician-family interaction. Knowledge of need class may help to inform the development of more person-centred models of ICU-based palliative care.

2.
Cell Rep ; 33(5): 108341, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147463

RESUMO

Dysregulated gene expression is a common feature of cancer and may underlie some aspects of tumor progression, including tumor relapse. Here, we show that recurrent mammary tumors exhibit global changes in gene expression and histone modifications and acquire dependence on the G9a histone methyltransferase. Genetic ablation of G9a delays tumor recurrence, and pharmacologic inhibition of G9a slows the growth of recurrent tumors. Mechanistically, G9a activity is required to silence pro-inflammatory cytokines, including tumor necrosis factor (TNF), through H3K9 methylation at gene promoters. G9a inhibition induces re-expression of these cytokines, leading to p53 activation and necroptosis. Recurrent tumors upregulate receptor interacting protein kinase-3 (RIPK3) expression and are dependent upon RIPK3 activity. High RIPK3 expression renders recurrent tumors sensitive to necroptosis following G9a inhibition. These findings demonstrate that G9a-mediated silencing of pro-necroptotic proteins is a critical step in tumor recurrence and suggest that G9a is a targetable dependency in recurrent breast cancer.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Inflamação/patologia , Neoplasias Mamárias Animais/enzimologia , Neoplasias Mamárias Animais/patologia , Recidiva Local de Neoplasia/patologia , Animais , Morte Celular , Sobrevivência Celular , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Neoplasias Mamárias Animais/genética , Camundongos Nus , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fatores de Risco , Transcrição Gênica , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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