Mitophagy-Related Cell Death Mediated by Vacquinol-1 and TRPM7 Blockade in Glioblastoma IV

Glioblastoma IV (GBM) is one of the deadliest malignant diseases in adults and is characterized by a high mutation rate and multiple traits to suppress inborn and acquired immunity. We here approached autophagy-related cell death in newly established GBM cell lines derived from individual tumor isolates. Treatment with a small molecule, termed Vacquinol-1 (Vac) exhibited 100% GBM cell death, which was related to mitochondrial dysfunction, calcium-induced endoplasmic reticulum (ER)-stress, and autophagy. The toxicity of Vac was significantly increased by the inhibition of transient receptor potential cation channel, subfamily M, member 7 (TRPM7). TRPM7 is overexpressed in GBM as well as in many other tumors and thus may be a potential target by the natural compound carvacrol. Of note, at higher concentrations, Vac also induced growth inhibition and cell death in non-transformed cell types. However, in the presence of the TRPM7 inhibitor carvacrol, the tumor-selective effect of Vac was very much increased. Results given in the present study are based on long-term video microscopy using IncuCyteZOOM®, calcium measurements, and 3D ultrastructural analysis using the cryofixed material

Проект благоустройства овражной территории в пос. Кольцово (г. Новосибирск)

Объект исследования – овражная территория п. Кольцово (г. Новосибирск). Цель работы – разработка проекта благоустройства овражной территории в п. Кольцово (г. Новосибирск). В процессе исследования проводилось: изучение нормативно-правовой базы, исследование особенностей территории, рассмотрены основные положения по разработке проектов благоустройства. В результате исследования разработан проект благоустройства территории.The object of study is the ravine territory of Koltsovo (Novosibirsk). The purpose of the work is the development of a project to improve the ravine territory in Koltsovo (Novosibirsk). In the course of the study, the following was carried out: a study of the regulatory framework, a study of the peculiarities of the territory, the main provisions for the development of improvement projects were considered. As a result of the study, a project was developed to improve the territory

Immune phenotypes predict survival in patients with glioblastoma multiforme

Background: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. Methods: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. Results: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. Conclusions: Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention

Supportive Care Needs in Glioma Patients and Their Caregivers in Clinical Practice: Results of a Multicenter Cross-Sectional Study

Objective: Supportive care needs in glioma patients often remain unrecognized, and optimization in assessment is required. First, we aimed at assessing the support needed using a simple structured questionnaire. Second, we investigated the psychosocial burden and support requested from caregivers.Methods: Patients were assessed at three centers during their outpatient visits. They completed the Distress Thermometer (DT; score ≥ 6 indicated significant burden in brain tumor patients), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30+BN20, and the Patients' Perspective Questionnaire (PPQ) that assessed psychosocial distress as well as support requested and received by patients for specific domains (e.g., family, doctor, and mobile care). In each subgroup, patients' caregivers were assessed simultaneously by a questionnaire developed for the study. Multivariate backward logistic regressions were performed for investigating predictors of patients' request for support.Results: Assessments were conducted for 232 patients. Most patients (82%) had a high-grade glioma and a mean age of 52 years (range 20–87). The male to female ratio was 1.25:1. According to the PPQ results, 38% (87) of the patients felt depressed; 44% (103), anxious; and 39% (91), tense/nervous. Desired support was highest from doctors (59%) and psychologists (19%). A general request for support was associated with lower global health status (p = 0.03, odds ratio (OR) = 0.96, 95% CI: 0.92–0.99) according to EORTC QLQ-C30. Most of the assessed caregivers (n = 96) were life partners (64%; n = 61) who experienced higher distress than the corresponding patients (caregivers: 6.5 ± 2.5 vs. patients: 5.3 ± 2.4). When patients were on chemotherapy, caregivers indicated DT ≥ 6 significantly more frequently than patients themselves (p = 0.02).Conclusion: Our data showed that glioma patients and their caregivers were both highly burdened. The PPQ allowed us to evaluate the psychosocial support requested and perceived by patients, detect supportive care needs, and provide information at a glance. Patients in poorer clinical condition are at risk of having unmet needs. The caregivers' burden and unmet needs are not congruent with the patients' need for support. In particular, caregivers of patients on chemotherapy were more highly burdened than patients themselves

Medical treatment of pulmonary hypertension in adults with congenital heart disease : updated and extended results from the International COMPERA-CHD Registry

Funding Information: The authors are indebted to the COMPERA investigators and their staff. We explicitly thank Dr. Claudia S. Copeland for the professional editing of the final draft of the manuscript. Funding: COMPERA is funded by unrestricted grants from Acceleron, Actelion Pharmaceuticals (Janssen), Bayer, OMT and GSK. These companies were not involved in data analysis or the writing of this manuscript. Funding Information: ICMJE uniform disclosure form (available at https:// dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare. Publisher Copyright: © Cardiovascular Diagnosis and Therapy. All rights reserved.Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data. Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of followup, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of “Non-Eisenmenger PAH” patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described. Conclusions: Analyzing “real life data” from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the “Non-Eisenmenger PAH” group and to patients with complex CHD, including Fontan patients.publishersversionPeer reviewe

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy