PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture

Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins

Background: Cross-reactivity against human coronaviruses with Flebogamma® DIF and Gamunex®-C, two available intravenous immunoglobulins (IVIG), has been reported. In this study, these IVIG were tested for neutralization activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Materials & methods: Neutralization capacity of lots of IVIG manufactured prior to COVID-19 pandemic was assessed against these viruses in cell culture. Infectivity neutralization was quantified by percent reduction in plaque-forming units and/or cytopathic/cytotoxic methods. Results: All IVIG preparations showed neutralization of SARS-CoV-2 isolates. All IVIG lots produced neutralization of SARS-CoV. No IVIG preparation showed significant neutralizing activity against MERS-CoV. Conclusion: The tested IVIG contain antibodies with significant in vitro cross-neutralization capacity against SARS-CoV-2 and SARS-CoV, but not MERS-CoV. These preparations are currently under evaluation as potential therapies for COVID-19.Neutralization experiments were funded by Grifols, the manufacturer of Flebogamma DIF and Gamunex-C. JM Díez, C Romero and R Gajardo are full-time employees of Grifols. J Vergara-Alert, J Rodon, M Bello-Perez and JM Honrubia, J Segal ´ es and L ´ Enjuanes declare having no other conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No outsourced writing assistance was utilized in the production of this manuscript.Peer reviewe

Syncope Time Frames for Adverse Events after Emergency Department Presentation : An Individual Patient Data Meta-Analysis

Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. We combined individual patients' data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7-10 days, 1 month and 1 year after ED evaluation. We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7-10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7-10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7-10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial

Single Intracoronary Injection of Encapsulated Antagomir‐92a Promotes Angiogenesis and Prevents Adverse Infarct Remodeling

BACKGROUND: Small and large preclinical animal models have shown that antagomir‐92a‐based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR‐92a inhibition in noncardiac organs prevents the translation of nonvectorized miR‐targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir‐92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should “acute” be added before “myocardial infarction” (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects. METHODS AND RESULTS: In a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir‐92a encapsulated in specific microspheres (9 μm poly‐d,‐lactide‐co‐glycolide [PLGA]) inhibited miR‐92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8×, 2×, and 5×‐fold inhibition at 1, 3, and 10 days). Downregulation of miR‐92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir‐92a, encapsulated placebo, or saline [n=8, 9, 9]; P=0.001), reduced regional wall‐motion dysfunction (P=0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P=0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin‐PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2). CONCLUSIONS: Early single intracoronary administration of encapsulated antagomir‐92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI

Management of heart failure with reduced ejection fraction after ESC 2016 heart failure guidelines: the Linx Registry

Aims: In May 2016, a new version of the European Society of Cardiology (ESC) Guidelines for the management of heart failure (HF) was released. The aim of this study was to describe the management of HF with reduced ejection fraction after the publication of ESC Guidelines. Methods and results: The Linx registry is a multicentre, observational, cross-sectional study from 14 Catalan hospitals that enrolled 1056 patients with HF and reduced left ventricular ejection fraction (≤40%) from 1 February to 30 April 2017 in outpatient cardiology clinics. Results were compared between hospitals according to their level of complexity in our own registry and compared with previously published registries similar to ours. Sacubitril/valsartan was prescribed to 23.9% of patients in our population, as a consequence, use of angiotensin-converting enzyme inhibitor and angiotensin receptor blockers in monotherapy decreased to 48.1% and 16.9%, respectively, and prescription of beta-blockers (91.8%), mineralocorticoid receptor antagonists (72.7%), and ivabradine (21.4%) remained similar to previous registries. Target doses of beta-blockers (25.4%), angiotensin-converting enzyme inhibitors (24.9%), angiotensin receptor blockers (7.7%), sacubitril/valsartan (8.1%), and mineralocorticoid receptor antagonists (19.7%) were accomplished in a low proportion of patients. Our results also suggest that prescription and up-titration of class I HF drugs were greater in hospitals with higher level of complexity. Conclusions: The Linx registry shows an appropriate adherence to pharmacological recommendations from ESC HF Guidelines despite a low proportion of patients reached target doses. Almost one-quarter of patients were under treatment with sacubitril/valsartan a few months after ESC HF Guidelines recommendations

Sex-Related Differences in Patients With Unexplained Syncope and Bundle Branch Block : Lower Risk of AV Block and Lesser Need for Cardiac Pacing in Women

To analyze if there are sex-related differences in patients with unexplained syncope and bundle branch block (BBB). Despite increasing awareness that sex is a major determinant of the incidence, etiology, and the outcomes of different arrhythmias, no studies have examined differences in presentation and outcomes between men and women with syncope and BBB. Cohort study of consecutive patients with unexplained syncope and BBB was included from January 2010 to January 2021 with a median follow-up time of 3.4 years [interquartile range (IQR) 1.7-6.0 years]. They were evaluated by a stepwise workup protocol based on electrophysiological study (EPS) and long-term follow-up with an implantable cardiac monitor (ICM). Of the 443 patients included in the study, 165 (37.2%) were women. Compared with men, women had less diabetes (25.5 vs. 39.9%, p = 0.002) and less history of ischemic heart disease (IHD; 13.3 vs. 25.9%, p = 0.002). Left bundle branch block (LBBB) was more frequent in women (55.2 vs. 27.7%, p < 0.001) while right bundle branch block (RBBB) was more frequent in men (41.5 vs. 67.7%, p < 0.001). His to ventricle (HV) interval in the EPS was shorter in women (58 ms [IQR 52-71] vs. 60 ms [IQR 52-73], p = 0.035) and less women had an HV interval longer than 70 ms (28.5 vs. 38.1%, p = 0.039), however, EPS and ICM offered a similar diagnostic yield in both sexes (40.6 vs. 48.9% and 48.4% vs. 51.1%, respectively). Women had a lower risk of developing atrioventricular block (AVB) (adjusted odds ratio [OR] 0.44-95% CI 0.26-0.74, p = 0.002) and of requiring permanent pacemaker implantation (adjusted hazard ratio [HR] 0.72-95% CI: 0.52-0.99, p = 0.046). The mortality rate was lower in women (4.5 per 100 person-years [95% CI 3.1-6.4 per 100 person-years] vs. 7.3 per 100 person-years [95% CI 5.9-9.1 per 100 person-years]). Compared to men, women with unexplained syncope and BBB have a lower risk of AVB and of requiring cardiac pacing. A stepwise diagnostic approach has a similar diagnostic yield in both sexes, and it seems appropriate to guide the treatment and avoid unnecessary pacemaker implantation, especially in women. Risk of AVB and need for cardiac pacing. Left: Percentage of patients diagnosed with aAVB/sCD in both sexes. Right-top: Multivariate logistic regression analyses for risk of aAVB/sCD. Odds ratio and 95% CI are plotted. Right-bottom: Kaplan-Meier pacemaker-free survival estimates curves in both sexes. aAVB/sCD, advanced atrio-ventricular block or severe conduction disturbances; HR, hazard ratio; CI, confidence interval; y.o, years old; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; BBB, bundle branch block; LBBB, left bundle branch block; RBBB, right bundle branch block; LAFB, left anterior fascicular block

Management of Heart Failure with Reduced Ejection Fraction after ESC 2016 Heart Failure Guidelines : The Linx Registry

In May 2016, a new version of the European Society of Cardiology (ESC) Guidelines for the management of heart failure (HF) was released. The aim of this study was to describe the management of HF with reduced ejection fraction after the publication of ESC Guidelines. The Linx registry is a multicentre, observational, cross-sectional study from 14 Catalan hospitals that enrolled 1056 patients with HF and reduced left ventricular ejection fraction (≤40%) from 1 February to 30 April 2017 in outpatient cardiology clinics. Results were compared between hospitals according to their level of complexity in our own registry and compared with previously published registries similar to ours. Sacubitril/valsartan was prescribed to 23.9% of patients in our population, as a consequence, use of angiotensin-converting enzyme inhibitor and angiotensin receptor blockers in monotherapy decreased to 48.1% and 16.9%, respectively, and prescription of beta-blockers (91.8%), mineralocorticoid receptor antagonists (72.7%), and ivabradine (21.4%) remained similar to previous registries. Target doses of beta-blockers (25.4%), angiotensin-converting enzyme inhibitors (24.9%), angiotensin receptor blockers (7.7%), sacubitril/valsartan (8.1%), and mineralocorticoid receptor antagonists (19.7%) were accomplished in a low proportion of patients. Our results also suggest that prescription and up-titration of class I HF drugs were greater in hospitals with higher level of complexity. The Linx registry shows an appropriate adherence to pharmacological recommendations from ESC HF Guidelines despite a low proportion of patients reached target doses. Almost one-quarter of patients were under treatment with sacubitril/valsartan a few months after ESC HF Guidelines recommendations

PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition

PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs