Mitochondrial Dysfunction of Alveolar and Circulating Immune Cells During Acute Respiratory Distress...
Lung DiseasesMechanical Ventilation1 moreSepsis leads to a deregulated host response that can lead to organ failure. During sepsis, experimental and clinical data suggest the occurrence of mitochondrial dysfunctions, particularly in circulating muscle and monocytes, which may contribute to organ failure and death. Lower respiratory infection is the leading cause of death from infectious causes. Mechanical ventilation (MV) is required in 20% of cases of bacterial pneumopathy with Streptococcus pneumoniae (S.p.) , with mortality reaching 50%. There are then frequently criteria for acute respiratory distress syndrome (ARDS), combining bilateral lung involvement and marked hypoxemia. Cyclic stretching of lung cells induced by MV causes sterile inflammation and tissue damage (i.e. ventilator-induced lung injury [VILI]), which can cause cellular dysfunction that alter the immune response, particularly during ARDS. This is why the application of a so-called protective MV is then required. However, this does not prevent about one-third of patients from showing signs of alveolar overdistension, as evidenced by an increase in motor pressure (MP) (MP≥ 15 cmH2O), associated with an increase in mortality. The deleterious effects of MV could be explained by the occurrence of mitochondrial abnormalities. Indeed, the cyclic stretching of lung cells leads to dysfunction in the respiratory chain and the production of free oxygen radicals (FOS), altering membrane permeability. These phenomena could promote VILI, facilitate the translocation of bacteria from the lung to the systemic compartment and lead to alterations in immune response. In our model of S.p. pneumopathy in rabbits, animals on MV develop more severe lung disorders (lack of pulmonary clearance of bacteria, bacterial translocation in the blood, excess mortality), compared to animals on spontaneous ventilation (SV). Intracellular pulmonary mitochondrial DNA (mtDNA) concentrations, a reflection of the mitochondrial pool, are significantly decreased in ventilated rabbits compared to SV rabbits and in infected rabbits compared to uninfected rabbits. At the same time, the mitochondrial content of circulating cells decreased early (H8) in all infected rabbits, but was only restored in rabbits in SV, those who survived pneumonia (Blot et al, poster ECCMID 2015, submitted article). These data suggest an alteration in the mechanisms that restore mitochondrial homeostasis (mitochondrial biogenesis and mitophagy) during the dual infection/MV agression, which may explain the observed excess mortality. Other work by our team illustrates the importance of these phenomena by showing in a mouse model of polymicrobial infection that inhibition of mitophagia in macrophages promotes survival (Patoli et al, in preparation). Human data on this subject are non-existent. The phenomena of mitochondrial dysfunction nevertheless deserve to be explored in humans during the combined MV/pneumopathy aggression in order to understand its possible impact on the effectiveness of the host's immune response. In a personalized medicine approach, these data would open up prospects for targeted therapies, capable of activating mitochondrial biogenesis and/or modulating mitophagia, to prevent organ dysfunction and mortality during severe CALs treated with antibiotic therapy.
Acalabrutinib + Liso-Cel In R/R Aggressive B-Cell Lymphomas
Refractory Aggressive B-cell LymphomasRefractory B-Cell Non-Hodgkin Lymphoma14 moreThis research is being done to assess the effectiveness and safety of acalabrutinib combined with lisocabtagene maraleucel (liso-cel) for people with relapsed/refractory aggressive B-cell lymphoma. This research study involves the study drug acalabrutinib in combination with lisocabtagene maraleuce
Addressing Root Causes for Gun Violence Prevention (ARC-GVP)
ViolenceAdolescent2 moreThe goal of this study is to help build the evidence base for a locally-relevant youth firearm violence prevention program in Washington D.C., a city experiencing disparities in youth firearm violence outcomes. The main question it aims to answer is: How is youth participation in the summer youth employment program, the True Reasons I Grabbed the Gun Evolved from Risk (The T.R.I.G.G.E.R Project), which is designed to address root causes of gun violence, associated with individual youth behavioral outcomes, including pro-social involvement, aggression, and firearm-related attitudes and behaviors?
An AI Platform Integrating Imaging Data and Models, Supporting Precision Care Through Prostate Cancer's...
Prostate CancerProstate Cancer Metastatic2 moreIn Europe, prostate cancer (PCa) is the second most frequent type of cancer in men and the third most lethal. Current clinical practices, often leading to overdiagnosis and overtreatment of indolent tumors, suffer from lack of precision calling for advanced AI models to go beyond SoA by deciphering non-intuitive, high-level medical image patterns and increase performance in discriminating indolent from aggressive disease, early predicting recurrence and detecting metastases or predicting effectiveness of therapies. To date efforts are fragmented, based on single-institution, size-limited and vendorspecific datasets while available PCa public datasets (e.g. US TCIA) are only few hundred cases making model generalizability impossible. The ProCAncer-I project brings together 20 partners, including PCa centers of reference, world leaders in AI and innovative SMEs, with recognized expertise in their respective domains, with the objective to design, develop and sustain a cloud based, secure European Image Infrastructure with tools and services for data handling. The platform hosts the largest collection of PCa multi-parametric (mp)MRI, anonymized image data worldwide (>17,000 cases), based on data donorship, in line with EU legislation (GDPR). Robust AI models are developed, based on novel ensemble learning methodologies, leading to vendor-specific and -neutral AI models for addressing 8 PCa clinical scenarios. To accelerate clinical translation of PCa AI models, we focus on improving the trust of the solutions with respect to fairness, safety, explainability and reproducibility. Metrics to monitor model performance and a causal explainability functionality are developed to further increase clinical trust and inform on possible failures and errors. A roadmap for AI models certification is defined, interacting with regulatory authorities, thus contributing to a European regulatory roadmap for validating the effectiveness of AI-based models for clinical decision making.
Active Surveillance SNEP Assay Registry Trial for Prostate Cancer
Prostate Cancer AggressivenessA multi-center, prospective active surveillance registry trial assessing the performance of a non-invasive blood test for indolent prostate cancer disease management.
Early Salvage Therapy for Patients With Advanced Features for Biochemical Relapse After Radical...
Prostate CancerThe primary objective of the trial is to compare the impact and safety of delayed salvage therapy (dSRT, i.e., SRT initiated at PSA values of 0.4-0.5 ng/ml) to those of early salvage therapy (eSRT, i.e., at PSA levels of 0.2 ng/ml) in patients with biochemical relapse after radical prostatectomy. The secondary objective of the trial is to perform analysis of the subgroups of patients to determine which patients are most likely to benefit from dSRT Exploratory objective of the trial is to determine whether selected molecular genetic parameters (172 candidate genes and molecular alterations) and known clinical parameters can be used to identify potential predictors of worse prognosis in patients with known risk factors for relapse after radical prostatectomy, thereby augmenting and refining patient stratification, optimizing their therapy, and clarifying the proper timing of multimodal therapy
Vorinostat and Combination Chemotherapy Before Donor Stem Cell Transplantation for the Treatment...
Recurrent Aggressive Non-Hodgkin LymphomaRecurrent B-Cell Non-Hodgkin Lymphoma5 moreThis phase II trial studies how well vorinostat and combination chemotherapy before donor stem cell transplantation work in treating patients with aggressive B-cell or T-cell non-Hodgkin lymphoma that has come back (relapsed). Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as busulfan, gemcitabine, and clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with combination chemotherapy before donor stem cell transplantation may help to control lymphoma.
Effectiveness Study of the Intervention "Stop Sexual Harassment" in Secondary School
Sexual HarassmentAnti-Gay Bias8 more"Stop sexual harassment" is a school based intervention tailored to reduce sexual- and gendered harassment among pupils in secondary school. The first aim of this study is to test to what extent "Stop sexual harassment" reduces sexual harassment and harassment based on sexual orientation and gender expression (gendered harassment) among 8th to 10th grade pupils in secondary school. The second aim of the study is to test to what extent the intervention increases teachers' responses to sexual- and gendered harassment among pupils. The intervention consists of eight lessons which address the prevention of sexual- and gendered harassment. METHOD: A minimum 32 schools with at least 3840 pupils will participate in a cluster randomized controlled trial. Participating schools will be randomly assigned to intervention schools and control schools. At the intervention schools, teachers will be introduced to "Stop sexual harassment" through a digital course which will provide them with a manual containing eight lessons to be held for the pupils. At the control schools there will not be any intervention. The effects of the intervention on pupils will be determined by assessing their experiences with sexual and gendered harassment, and internalized and externalized problems prior to the intervention (T1), shortly after the intervention (T2) and six moths after the intervention (T3). The effects of the intervention on teachers will be determined by assessing the teachers' experiences of responding to sexual and gendered harassment among pupils. HYPOTHESIS: It is expected that the intervention "Stop sexual harassment" will lead to reduced sexual and gendered harassment perpetration and victimization, and less internalized and externalized problems among the pupils in secondary school, and that teachers will more frequently take action when sexual- and gendered harassment is encountered among the pupils.
Relmacabtagene Autoleucel as Second-Line Therapy in Adult Patients With Aggressive B-cell NHL
LymphomaLarge B-Cell4 moreThe primary objective of this study is to asess the efficacy of Relmacabtagene autoleucel as second-line therapy in adult patients with aggressive B-cell Non-Hodgkins Lymphoma who are ineligible for haematopoietic stem cell transplantation.
The Effectiveness of Forensic Outpatient Systemic Therapy: a Multiple Case Experimental Design
Conduct DisorderAntisocial Behavior2 moreThe purpose of this study is to investigate the effectiveness and mediators of Forensic Outpatient Systemic Therapy (FAST).