No Description available

No Description available

BACKGROUND AND RATIONALE: This is a direct continuation of SNF 182871/1, which investigated the impact of early-childhood environmental factors on lung functional growth and consequences for later respiratory morbidity in healthy term infants. We previously demonstrated that even low-level air pollution exposure during pregnancy and early childhood is associated with impaired lung functional growth in infancy and early childhood. Although the mechanisms are still unclear, they could be related to lung functional growth deficits or remodeling of the lung due to changes in the intrauterine environment. Air pollution is known to induce oxidative stress response and related autophagy and cellular senescence mechanisms, potentially playing a role in pollution-related lung pathology and in remodeling. As novel preliminary evidence in SNF 182871/1, we recently found that, in the cord blood of human infants, autophagy-related biomarkers are correlated with remodeling biomarkers. We also found that air pollution exposure during pregnancy is associated with biomarkers of autophagy and remodeling in the cord blood of healthy term infants. Interestingly, these mechanisms also play an important role in fetal development and preterm birth, and may thus theoretically contribute to the susceptibility of infants-and particularly preterm infants-to oxidative stress and air pollution effects. Indeed, as first evidence from SNF 182871/1, we also found an enhanced impact of air pollutants on lung function impairment of preterm infants. Furthermore, our own preliminary human data show that markers of autophagy, and remodeling already have significant differences between the cord blood of preterm infants compared to term infants at birth prior to early postnatal injury. Bringing this together, we hypothesize that the interaction of oxidative stress response, autophagy and remodeling could be a key mechanism involved in the complex host-environment interaction determining lung functional growth and related respiratory morbidity. Moreover, this response could be different in infants at risk for chronic respiratory symptoms, such preterm infants, infants born from asthmatic mothers or infants exposed to high levels of air pollution during pregnancy. OVERALL OBJECTIVES: We aim to expand the ongoing BILD cohort of (i) term infants with two risk subgroups, (ii) infants born preterm, and (iii) infants born to asthmatic mothers, and we will investigate the differences in response to prenatal air pollution in relation to the above key mechanisms. SPECIFIC AIMS: In comparison to healthy term infants, we will investigate in study phase 1, (i) whether the increased susceptibility of infants to prenatal air pollution in these three risk groups is related to differences in markers of oxidative stress response, autophagy, and remodeling in cord blood and in study phase 2, (ii) whether these pollution-related cord blood profiles are correlated to lung functional development and subsequent symptoms in the first year of life (primary outcomes) and at school age (secondary outcomes). We will replicate these findings in other birth cohorts from collaborators (Germany, Australia) with comparable outcome measures. METHODS: In our prospective BILD birth cohort of 1000 unselected healthy term infants, 400 preterm infants, and 200 infants from asthmatic mothers we will (i) estimate indoor and outdoor air pollution exposure during pregnancy and in early infancy, (ii) assess family, obstetric and birth history, cord-molecular biomarkers (metabolomics, gene expression, proteins), and infant lung function shortly after birth (including exhalomics) and at 6 years of age, as well as respiratory symptoms in the first year of life and at school age. EXPECTED RESULTS AND IMPACT: We expect a 26.03.2021 18:35:26 Page - 14 - significant correlation between air pollution exposure and oxidative stress response and lung remodeling in newborns with effects on lung function and clinical outcomes, the latter effects enhanced in the risk groups. Particularly for these risk groups, today's air pollution may already result in lung remodeling and subsequent impaired lung functional growth even at this early stage of life. Since early-life lung functional impairment often persists until school age and even late adulthood, it is a previously described early-life risk factor known to be associated with asthma in children and chronic obstructive respiratory airway diseases in the elderly. Thus, early-life environmental injury has a potentially very relevant impact on future global respiratory health, with unpredictable costs. We are one of the first groups to look into the impact of these air-pollution-induced mechanisms on oxidative stress response and lung remodeling, subsequent impairment of lung functional growth, and resulting human lung disease. Better understanding of these mechanisms might help the development of preventative and therapeutic strategies, particularly for at-risk infants.

Adoptive T cell therapy, which employs the patient's own cells as a weapon, is considered a breakthrough in the treatment of cancer. However, the production of such immunotherapy products lacks harmonisation with clinical studies. The EU-funded T-OP project aims to bridge this gap by bringing together interdisciplinary teams of scientists working in cell therapy, immunology, protein engineering and bioinformatics alongside large and medium-sized enterprises. The scientific work will focus on cytokines and their role in the therapeutic outcome of adoptive cell therapy, aiming to determine the optimal combination. The project's results will lead to the development of safer and improved immunotherapeutics.

Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. It can be caused by the underlying disease, prescribed drugs, or aspecific stimuli such as nausea and pain. Hyponatremia may be life-threatening if it develops acutely and causes cerebral edema with neurological symptoms. The treatment of acute symptomatic hyponatremia is therefore straight forward and implies the administration of hypertonic saline to treat cerebral edema. In contrast, the rationale for treatment of chronic hyponatremia - the most prevalent subtype - is less evident. There are no intervention studies to show that correcting chronic hyponatremia improves outcomes.Importantly, there is increasing data showing an association between chronic hyponatremia and complications such as falls or attention deficit, as well as increased risk of fractures and osteoporosis. It has also been reported that hyponatremia is associated with a poorer prognosis of cardiac, hepatic, kidney and pulmonary diseases as well as the overall outcome of ICU patients resulting in a significant association with an increased mortality and readmission risk. However, it is unclear whether these are merely associations or indicate causality: despite several retrospective analyses showing improvement of readmission and mortality rates, as well as some small uncontrolled studies reporting reduction of adverse events with plasma sodium correction, there is a complete lack of randomized clinical trials investigating whether correction of hyponatremia counteracts the increased risk of readmission and mortality. Thus, there is clinical equipoise on whether chronic hyponatremia should be treated or not. Therefore, the aim of this intervention study is to determine the benefits and harms of a targeted correction of plasma sodium concentration on the combined endpoint 30-day mortality and rehospitalization rate. Patients will be randomly assigned to targeted correction of plasma sodium concentration or standard care alone. Study Design: Pragmatic randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center study with blinded outcome assessment.Patients: Hospitalized patients with chronic hypotonic hyponatremia <130mmol/l. Patients requiring acute treatment with 3% saline infusion due to severe symptomatic hyponatremia, patients on dialysis, patients with acute liver failure, encephalopathic complications of liver failure or hepatorenal syndrome will be excluded. Intervention: Targeted correction of plasma sodium concentrationComparison: Current standard careOutcome measures: The primary objective is to investigate whether targeted correction of hyponatremia compared to standard care alone reduces the combined risk of death or rehospitalization within 30 days. Secondary objectives will include: Short- (30 days) and longterm (1 year) risk of death and rehospitalization; other clinical outcomes (neurocognition, quality of life, falls, fractures, length of hospital stay); Safety of the intervention; Exploratory analysis of biomarkers for hyponatremia. Main statistical hypothesis and sample size calculation:The intervention is superior to standard care by reducing the patients risk of death or re-hospitalization within 30 days from 23% to 18%. 2050 patients are required to detect an effect that is relevant for patients, clinicians and policy makers, i.e. an absolute reduction of 5% of the primary outcome (combined mortality and rehospitalization rate) with a statistical power of 80% (two-sided significance level 5%). With an assumed drop-out rate of 10 %, 2278 patients should be recruited.Importance: This study will influence future hyponatremia management on a national and international level regardless of its outcome:If the intervention results in a significant reduction of mortality and rehospitalization rate, hyponatremia awareness and its consecutive treatment during hospitalization will change substantially.If the intervention shows no effect on mortality and rehospitalization rate, hyponatremia will be recognized more as a marker of severity of the disease and not as its cause. Current treatment guidelines will be adapted.

GABAB receptors (GABABRs) are the G protein coupled receptors (GPCRs) for the neurotransmitter GABA. They are promising drug targets for the treatment of mental and neurological disorders. Kinetic properties of native GABABRs are neither reproduced by cloned receptors nor regulated by GPCR kinases and arrestins. These findings suggested that native GABABRs rely on additional proteins that alter their signaling. In collaboration with Bernd Fakler (University of Freiburg i. Br.) we have used a comprehensive proteomic approach to identify ~30 GABABR-associated proteins in the brain. These proteins now provide a means to study the functionality and architecture of native GABABRs in an unprecedented manner. Our data support that GABABRs are multiprotein complexes consisting of core components and interchangeable peripheral components. The core components include principal GABAB1 and GABAB2 receptor subunits, auxiliary K-channel tetramerization-domain (KCTD) subunits and the G protein. The KCTD subunits confer the fast activation kinetics and desensitization properties observed with native GABABRs to the cloned receptors. Peripheral components comprise known and novel effector channels, elements of the presynaptic release machinery, sushi domain (SD) interacting proteins and neuronal adhesion proteins. After the successful identification of native GABABR components we now plan to determine the functional relevance and mechanism of action of selected receptor components, bridging from molecular to in vivo studies. We propose to work on the KCTD proteins, G protein ß-subunits, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, SD-interacting proteins and elements of the presynaptic release machinery. Defined GABABRs receptor complexes in heterologous cells will be studied using established biochemical, biophysical and electrophysiological assays that probe for allosteric receptor regulation, receptor signaling and trafficking. The relevance of GABABR components for native receptor signaling will be analyzed using knock-out/knock-down approaches. Eventually we aim at interfering with the interaction of selected proteins at the receptor to influence receptor-mediated responses. We plan to use drug-like interfering peptides that penetrate the blood-brain barrier. This approach may open up new opportunities for the treatment of mental and neurological disorders.