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Background: Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status., Patients and Methods: We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers., Results: A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers., Conclusions: The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments of endogenous DNA, inducing inflammation by NFκB. The p66ShcA adaptor protein plays an important role in both ischemic myocardial damage and immune responses. We hypothesized that p66ShcA adaptor protein promotes DNA-sensing signaling via the TLR9 pathway after myocardial infarction. TLR9 protein expression increased in cardiac tissue from patients with end-stage heart failure due to ischemic heart disease. Myocardial ischemia in mice in vivo induced gene expression of key TLR9 pathway proteins (MyD88 and Unc93b1). In this model, a functional link between TLR9 and p66ShcA was revealed as; (i) ischemia-induced upregulation of TLR9 protein was abrogated in myocardium of p66ShcA knockout mice; (ii) when p66ShcA was overexpressed in NFkB reporter cells stably expressing TLR9, NFkB-activation increased during stimulation with the TLR9 agonist CpG B; (iii) in cardiac fibroblasts, p66ShcA overexpression caused TLR9 upregulation. Co-immunoprecipitation showed that ShcA proteins and TLR9 may be found in the same protein complex, which was dissipated upon TLR9 stimulation in vivo. A proximity assay confirmed the co-localization of TLR9 and ShcA proteins. The systemic immune response after myocardial ischemia was dampened in p66ShcA knockout mice as interleukin-4, -17 and -22 expression in mononuclear cells isolated from spleens was reduced. In conclusion, p66ShcA adaptor may be an interaction partner and a regulator of the TLR9 pathway post-infarction., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib., Patients and Methods: Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice., Results: A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities., Conclusions: The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Arrhythmogenic Cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes. AC hearts show fibro-fatty myocardial replacement, which favors stress-related life-threatening arrhythmias, predominantly in the young and athletes. AC lacks effective therapies, as its pathogenesis is poorly understood. Recently, we showed that cardiac Mesenchymal Stromal Cells (cMSCs) contribute to adipose tissue in human AC hearts, although the underlying mechanisms are still unclear., Purpose: We hypothesize that the sympathetic neurotransmitter, Neuropeptide Y (NPY), participates to cMSC adipogenesis in human AC., Methods: For translation of our findings, we combined in vitro cytochemical, molecular and pharmacologic assays on human cMSCs, from myocardial biopsies of healthy controls and AC patients, with the use of existing drugs to interfere with the predicted AC mechanisms. Sympathetic innervation was inspected in human autoptic heart samples, and NPY plasma levels measured in healthy and AC subjects., Results: AC cMSCs expressed higher levels of pro-adipogenic isotypes of NPY-receptors (i.e. Y1-R, Y5-R). Consistently, NPY enhanced adipogenesis in AC cMSCs, which was blocked by FDA-approved Y1-R and Y5-R antagonists. AC-associated PKP2 reduction directly caused NPY-dependent adipogenesis in cMSCs. In support of the involvement of sympathetic neurons (SNs) and NPY in AC myocardial remodeling, patients had elevated NPY plasma levels and, in human AC hearts, SNs accumulated in fatty areas and were close to cMSCs., Conclusions: Independently from the disease origin, AC causes in cMSCs a targetable gain of responsiveness to NPY, which leads to increased adipogenesis, thus playing a role in AC myocardial remodeling., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: While most prior research has focused on extreme heat, few assessed the immediate health effects of winter storms and associated power outages (PO), although severe storms have become more frequent. This study evaluates the joint and independent health effects of winter storms and PO, snow versus ice-storm, effects by time window (peak timing, winter/transitional months) and the impacts on critical care indicators including numbers of comorbidity, procedure, length of stay and cost., Methods: We use distributed lag nonlinear models to assess the impacts of winter storm/PO on hospitalizations due to cardiovascular, lower respiratory diseases (LRD), respiratory infections, food/water-borne diseases (FWBD) and injuries in New York State on 0-6 lag days following storm/PO compared with non-storm/non-PO periods (references), while controlling for time-varying factors and PM 2.5 . The storm-related hospitalizations are described by time window. We also calculate changes in critical care indicators between the storm/PO and control periods., Results: We found the joint effects of storm/PO are the strongest (risk ratios (RR) range: 1.01-1.90), followed by that of storm alone (1.02-1.39), but not during PO alone. Ice storms have stronger impacts (RRs: 1.04-3.15) than snowstorms (RRs: 1.03-2.21). The storm/PO-health associations, which occur immediately, and some last a whole week, are stronger in FWBD, October/November, and peak between 3:00-8:00 p.m. Comorbidity and medical costs significantly increase after storm/PO., Conclusion: Winter storms increase multiple diseases, comorbidity and medical costs, especially when accompanied by PO or ice storms. Early warnings and prevention may be critical in the transitional months and afternoon rush hours., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study presents an evaluation of the implementation quality of the Chilean program Crecer Jugando (CJ), a 16 weekly sessions group-based parenting program for children 0 to 4 years old and their primary caregivers aiming at promoting positive caregiver-child interaction. The implementation of CJ in two public health care centers (HCC) in Chile's Metropolitan Region was assessed based on Donabedian's theoretical model, focusing on the dimensions of the program's structure (e.g., infrastructure and supplies), processes (e.g., coordination of CJ team with the HCCs, participants' attendance, CJ team interaction with participating children), and preliminary outcomes (i.e., parenting stress, caregiver-child interaction). A total of 63 main caregiver-child dyads participated in the study, which took place over a six-month period. Results indicated that the CJ program was feasible to be implemented in two HCCs and would benefit from improving the coordination with the HCCs and the quality of interaction of the CJ team with participating children. After participation in the CJ program, caregivers showed a decrease in their parenting stress. Lessons learned are discussed., (Copyright © 2019. Published by Elsevier Ltd.)

Optogenetics is a technique exploded in the last 10 years, which revolutionized several areas of biological research. The brightest side of this technology is the use of light to modulate non-invasively, with high spatial resolution and millisecond time scale, excitable cells genetically modified to express light-sensitive microbial ion channels (opsins). Neuroscience has first benefited from such fascinating strategy, in intact organisms. By shining light to specific neuronal subpopulations, optogenetics allowed unearth the mechanisms involved in cell-to-cell communication within the context of intact organs, such as the brain, formed by complex neuronal circuits. More recently, scientists looked at optogenetics as a tool to answer some of the questions, remained in the dark, of cardiovascular physiology. In this review, we focus on the application of optogenetics in the study of the heart, a complex multicellular organ, homing different populations of excitable cells, spatially and functionally interconnected. Moving from the first proof-of-principle works, published in 2010, to the present time, we discuss the in vitro and in vivo applications of optogenetics for the study of electrophysiology of the different cardiac cell types, and for the dissection of cellular mechanisms underlying arrhythmias. We also present how molecular biology and technology foster the evolution of cardiac optogenetics, with the aim to further our understanding of fundamental questions in cardiac physiology and pathology. Finally, we confer about the therapeutic potential of such biotechnological strategy for the treatment of heart rhythm disturbances (e.g. cardiac pacing, cardioversion)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Gene expression of regucalcin (Rgn), a calcium-binding protein, was investigated in kidney of male Wistar rats treated with proximal tubule segment-specific nephrotoxicants, namely hexachloro-1:3-butadiene (HCBD), specific for S(3) segment (pars recta) and potassium dichromate (chromate) specific for S(1)-S(2) segments (pars convoluta), according to age of animals and dose of chemicals. In the age-dependent study, male Wistar rats were treated with a single injection of HCBD (100mg/kg b.w. i.p.) or chromate (25 mg/kg b.w. s.c.) at 5 weeks or 12 weeks of age; in dose-response study, rats were treated with a single injection of three doses of HCBD (25, 50, and 100 mg/kg b.w. i.p.) or chromate (8, 12.5, and 25mg/kg b.w. s.c.) at 8 weeks of age. Forty-eight hours after treatment, Rgn and glutamine synthetase (GS) activity in kidney cortex, blood urea nitrogen (BUN) and plasma creatinine were measured; light microscopy was performed also. The results show that young rats are less susceptible to chromate (severe necrosis is evident only in adult rats), whereas age does not influence HCBD nephrotoxicity. Rgn is down regulated by HCBD at both age points, but not by chromate at 5 weeks of age. In addition, HCBD causes down-regulation of Rgn from the low dose in 8-week-old rats, whereas chromate causes the same effect at the high dose only. GS activity in kidney cortex shows a similar behavior, even if sensitive to low doses of chromate also, whereas BUN and creatinine increase after the high dose of both chemicals only. Accordingly, light microscopy shows a segment-specific, dose-dependent increase of severity of damage caused by the chemicals. Rgn gene expression appears a sensitive genomic marker to evaluate the renal impairment caused by chemicals and its down-regulation seems to be related to damage, early or already established, to S(3) segment of the proximal tubule.

We have characterized a novel unconventional myosin heavy chain, named MYO18B, that appears to be expressed mainly in human cardiac and skeletal muscles and, at lower levels, in testis. MYO18B transcript is detected in all types of striated muscles but at much lower levels compared to class II sarcomeric myosins, and it is up regulated after in vitro differentiation of myoblasts into myotubes. Phylogenetic analysis shows that this myosin belongs to the recently identified class XVIII, however, unlike the other member of this class, it seems to be unique to Vertebrate since it contains two large amino acid domains of unknown function at the N and C-termini. Immunolocalization of MYO18B protein in skeletal muscle cells shows that this myosin heavy chain is located in the cytoplasm of undifferentiated myoblasts. After in vitro differentiation into myotubes, a fraction of this protein is accumulated in a subset of myonuclei. This nuclear localization was confirmed by immunofluorescence experiments on primary cardiomyocytes and adult muscle sections. In the cytoplasm MYO18B shows a punctate staining, both in cardiac and skeletal fibers. In some cases, cardiomyocytes show a partial sarcomeric pattern of MYO18B alternating that of alpha-actinin-2. In skeletal muscle the cytoplasmic MYO18B results much more evident in the fast type fibers.