The role of extracellular matrix on liver stem cell fate: A dynamic relationship in health and disease

The liver stem cell niche is a specialized and dynamic microenvironment with biomechanical and biochemical characteristics that regulate stem cell behavior. This is feasible due to the coordination of a complex network of secreted factors, small molecules, neural, blood inputs and extracellular matrix (ECM) components involved in the regulation of stem cell fate (self-renewal, survival, and differentiation into more mature phenotypes like hepatocytes and cholangiocytes). In this review, we describe and summarize all the major components that play essential roles in the liver stem cell niche, in particular, growth factor signaling and the biomechanical properties of the ECM

Role of the 4Kscore test as a predictor of reclassification in prostate cancer active surveillance

Background: Management of active surveillance (AS) in low-risk prostate cancer (PCa) patients could be improved with new biomarkers, such as the 4Kscore test. We analyze its ability to predict tumor reclassification by upgrading at the confirmatory biopsy at 6 months. Methods: Observational, prospective, blinded, and non-randomized study, within the Spanish National Registry on AS (AEU/PIEM/2014/0001; NCT02865330) with 181 patients included after initial Bx and inclusion criteria: PSA =10 ng/mL, cT1c-T2a, Grade group 1, =2 cores, and =5 mm/50% length core involved. Central pathological review of initial and confirmatory Bx was performed on all biopsy specimens. Plasma was collected 6 months after initial Bx and just before confirmatory Bx to determine 4Kscore result. In order to predict reclassification defined as Grade group =2, we analyzed 4Kscore, percent free to total (%f/t) PSA ratio, prostate volume, PSA density, family history, body mass index, initial Bx, total cores, initial Bx positive cores, initial Bx % of positive cores, initial Bx maximum cancer core length and initial Bx cancer % involvement. Wilcoxon rank-sum test, non-parametric trend test or Fisher’s exact test, as appropriate established differences between groups of reclassification. Results: A total of 137 patients met inclusion criteria. Eighteen patients (13.1%) were reclassified at confirmatory Bx. The %f/t PSA ratio and 4Kscore showed differences between the groups of reclassification (Yes/No). Using 7.5% as cutoff for the 4Kscore, we found a sensitivity of 89% and a specificity of 29%, with no reclassifications to Grade group 3 for patients with 4Kscore below 7.5% and 2 (6%) missed Grade group 2 reclassified patients. Using this threshold value there is a biopsy reduction of 27%. Additionally, 4Kscore was also associated with changes in tumor volume. Conclusions: Our preliminary findings suggest that the 4Kscore may be a useful tool in the decision-making process to perform a confirmatory Bx in active surveillance management

Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study

Background: Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing. Methods: This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993–95), ISAAC Phase III (2001–03), or both. We included individuals from two age groups (children aged 6–7 years and adolescents aged 13–14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders. Findings: Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993–2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0·37, 95% CI –0·69 to –0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (–1·37, –2·47 to –0·27], in children and –1·67, –2·70 to –0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries. Interpretation: Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma. Funding: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III

Lipid (per) oxidation in mitochondria:an emerging target in the ageing process?

Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease

The upgrade of the ALICE TPC with GEMs and continuous readout

The upgrade of the ALICE TPC will allow the experiment to cope with the high interaction rates foreseen for the forthcoming Run 3 and Run 4 at the CERN LHC. In this article, we describe the design of new readout chambers and front-end electronics, which are driven by the goals of the experiment. Gas Electron Multiplier (GEM) detectors arranged in stacks containing four GEMs each, and continuous readout electronics based on the SAMPA chip, an ALICE development, are replacing the previous elements. The construction of these new elements, together with their associated quality control procedures, is explained in detail. Finally, the readout chamber and front-end electronics cards replacement, together with the commissioning of the detector prior to installation in the experimental cavern, are presented. After a nine-year period of R&D, construction, and assembly, the upgrade of the TPC was completed in 2020.publishedVersio

Design, construction and operation of the ProtoDUNE-SP Liquid Argon TPC

The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber (LArTPC) that was constructed and operated in the CERN North Area at the end of the H4 beamline. This detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment (DUNE), which will be constructed at the Sandford Underground Research Facility (SURF) in Lead, South Dakota, USA. The ProtoDUNE-SP detector incorporates full-size components as designed for DUNE and has an active volume of $7\times 6\times 7.2$~m$^3$. The H4 beam delivers incident particles with well-measured momenta and high-purity particle identification. ProtoDUNE-SP's successful operation between 2018 and 2020 demonstrates the effectiveness of the single-phase far detector design. This paper describes the design, construction, assembly and operation of the detector components

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700