Improved Recovery from Liver Fibrosis by Crenolanib

Chronic liver diseases are associated with excessive deposition of extracellular matrix proteins. This so-called fibrosis can progress to cirrhosis and impair vital functions of the liver. We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic stellate cells (HSC) involved in fibrogenesis. Rats were treated with thioacetamide (TAA) for 18 weeks to trigger fibrosis. After TAA treatment, the animals received Crenolanib for two weeks, which significantly improved recovery from liver fibrosis. Because Crenolanib predominantly inhibits the RTK platelet-derived growth factor receptor-β, impaired HSC proliferation might be responsible for this beneficial effect. Interestingly, blocking of RTK signaling by Crenolanib not only hindered HSC proliferation but also triggered their specification into hepatic endoderm. Endodermal specification was mediated by p38 mitogen-activated kinase (p38 MAPK) and c-Jun-activated kinase (JNK) signaling; however, this process remained incomplete, and the HSC accumulated lipids. JNK activation was induced by stress response-associated inositol-requiring enzyme-1α (IRE1α) in response to Crenolanib treatment, whereas β-catenin-dependent WNT signaling was able to counteract this process. In conclusion, the Crenolanib-mediated inhibition of RTK impeded HSC proliferation and triggered stress responses, initiating developmental processes in HSC that might have contributed to improved recovery from liver fibrosis in TAA-treated rats

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature

Background!#!Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates.!##!Methods!#!We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia.!##!Results!#!With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever.!##!Conclusions!#!Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011

Strategic R&D Programme on Technologies for Future Experiments - Annual Report 2020

This report summarises the activities and achievements of the strategic R&D programme on technologies for future experiments in the year 2020

Annual Report 2022

This report summarises the activities and main achievements of the CERN strategic R&D programme on technologies for future experiments during the year 202

Extension of the R&D Programme on Technologies for Future Experiments

we have conceived an extension of the R&D programme covering the period 2024 to 2028, i.e. again a 5-year period, however with 2024 as overlap year. This step was encouraged by the success of the current programme but also by the Europe-wide efforts to launch new Detector R&D collaborations in the framework of the ECFA Detector R&D Roadmap. We propose to continue our R&D programme with the main activities in essentially the same areas. All activities are fully aligned with the ECFA Roadmap and in most cases will be carried out under the umbrella of one of the new DRD collaborations. The program is a mix of natural continuations of the current activities and a couple of very innovative new developments, such as a radiation hard embedded FPGA implemented in an ASIC based on System-on-Chip technology. A special and urgent topic is the fabrication of Al-reinforced super-conducting cables. Such cables are a core ingredient of any new superconducting magnet such as BabyIAXO, PANDA, EIC, ALICE-3 etc. Production volumes are small and demands come in irregular intervals. Industry (world-wide) is no longer able and willing to fabricate such cables. The most effective approach (technically and financially) may be to re-invent the process at CERN, together with interested partners, and offer this service to the community

Annual Report 2023 and Phase-I Closeout

This report summarises the activities of the CERN strategic R&D programme on technologies for future experiments during the year 2023, and highlights the achievements of the programme during its first phase 2020-2023