Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19

Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO /FiO  < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model. Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO /FiO prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO /FiO  < 80 (HR 0.55; 95% CI 0.40-0.77). In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality

Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States

Rationale &amp; objectiveUnderlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes.Study designRetrospective cohort study.Settings &amp; participants4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units&nbsp;(ICUs) at 68 hospitals across the United States.Predictor(s)Presence (vs absence) of pre-existing kidney disease.Outcome(s)In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary).Analytical approachWe used standardized differences to compare patient characteristics (values&gt;0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations.ResultsDialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]).LimitationsPotential residual confounding.ConclusionsFindings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population

Obesity, inflammatory and thrombotic markers, and major clinical outcomes in critically ill patients with COVID‐19 in the US

Objective This study aimed to determine whether obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID‐19. Methods The primary outcome was in‐hospital mortality in adults with COVID‐19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI‐RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable‐adjusted models were used. Results Among the 4,908 study patients, mean (SD) age was 60.9 (14.7) years, 3,095 (62.8%) were male, and 2,552 (52.0%) had obesity. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m2 was associated with a greater risk of ARDS and AKI‐RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers. Conclusions In critically ill patients with COVID‐19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI‐RRT. The lack of an association between BMI and circulating biomarkers calls into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID‐19 by upregulating systemic inflammatory and prothrombotic pathways