RESUMEN
The physiologic impact of pulsatile flow (PF) on end-organ perfusion during cardiopulmonary bypass (CPB) is controversial. Using an intra-aortic balloon pump (IABP) to maintain PF during CPB for patients undergoing heart transplantation (HT) may impact end-organ perfusion, with implications for postoperative outcomes. A single-center retrospective study of 76 patients bridged to HT with IABP was conducted between January 2018 and December 2022. Beginning in May 2022, patients received IABP-generated PF during CPB at an internal rate of 80 beats/minute. Fifty-eight patients underwent HT with the IABP turned off (IABP-Off), whereas 18 patients underwent HT with IABP-generated PF (IABP-On). The unmatched IABP-On group experienced shorter organ ischemia times (180 vs. 203 minutes, p = 0.015) and CPB times (104 vs. 116 minutes, p = 0.022). The cohort was propensity matched according to age, organ ischemia time, and CPB time. Elevations in postoperative lactates in the immediate (2.8 vs. 1.5, p = 0.062) and 24 hour (4.7 vs. 2.4, p = 0.084) postoperative periods trended toward significance in the matched IABP-Off group. There was no difference in postoperative vasoactive inotropic score (VIS), postoperative creatinine, or length of stay. This limited preliminary data suggest that maintaining counterpulsation to generate PF during CPB may improve end-organ perfusion in this patient population as suggested by lower postoperative lactate levels.
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Internado y Residencia , Quirófanos , Humanos , Competencia Clínica , Corazón , Grupo de Atención al PacienteRESUMEN
BACKGROUND: Lung transplants from donation after circulatory death (DCD) have been scarcely used in the United States. Concerns about the warm ischemic injury, resource mal-utilization due to the uncertain timing of death, and public scrutiny may be some factors involved. METHODS: Survival for recipients of a donation after brain death (DBD) versus DCD was analyzed by using the United Network for Organ Sharing and our institutional database. A propensity-matching and Cox regression analysis was performed for 25 characteristics. Primary graft dysfunction metrics were compared. RESULTS: A total of 389 of 20,905 lung transplantations (2%) were performed by using DCDs in the United States, and 15 of 128 (12%) at our institution. Five and 10-year survival for DBDs was 55% and 30% and 59% and 33% for DCDs, respectively. Propensity-matched analysis of 311 DBD/DCD pairs did not demonstrate any difference in survival. On Cox regression, DCD was not associated with impaired survival. Male sex, Karnofsky class greater than 50, double lung transplantation, and transplantation year were predictors of improved survival. Age, creatinine, pulmonary fibrosis, retransplantation, extracorporeal membrane oxygenation, allocation score, and donor age were predictors of worse survival. Primary graft dysfunction at time 0 was worse for recipients of DCDs (p = 0.005) but equivalent at 24, 48, and 72 hours. CONCLUSIONS: DCD lung transplants remain underused in the United States. Nevertheless, survival is similar to DBD. Primary graft dysfunction metrics for DCDs are worse than DBDs on intensive care arrival but improved subsequently.
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Trasplante de Pulmón/estadística & datos numéricos , Adulto , Muerte Encefálica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Disfunción Primaria del Injerto/mortalidad , Estudios Prospectivos , Tasa de Supervivencia , Obtención de Tejidos y Órganos , Estados UnidosRESUMEN
Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. SIGNIFICANCE: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165-76. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
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Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Femenino , Humanos , Ratones , Ratones Transgénicos , Recurrencia Local de NeoplasiaRESUMEN
CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by phosphorylation of stress kinases JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Pharmacologic inhibitors of JNK/p38 MAPK conferred protection from P1446A-mediated apoptosis. Treatment with P1446A led to a dramatic induction of NOXA in a JNK-dependent manner, and sensitized CLL cells to ABT-737, a BH3-mimetic. We observed concurrent activation of apoptosis stress-inducing kinase 1 (ASK1) and its interaction with inositol-requiring enzyme 1 (IRE1) and tumor necrosis factor receptor-associated factor 2 (TRAF2) in CLL cells treated with P1446A, providing insights into upstream regulation of JNK in this setting. Consistent with previous reports on limited functionality of ER stress mechanism in CLL cells, treatment with P1446A failed to induce an extensive unfolded protein response. This study provides rationale for additional investigations of P1446A in CLL.