La fouille préventive de la rue Paille-Maille à Metz a livré un dépotoir contenant trois meules rotatives et un mortier en basalte. La constitution de ce dépôt est fixée entre 25 et 45 ap. J.-C. ...grâce à la céramique. Ce contexte apporte des données nouvelles sur le matériel de mouture, qui est encore peu documenté en Lorraine.
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). ...However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells. Using patient-derived xenografts and specific inhibitors of BCL-2, BCL-XL, and MCL-1, we identified a greater reliance of lung SqCC cells on BCL-XL and MCL-1 compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitors alone provided a survival benefit in combination FGFR therapy in vivo. Only triple BCL-XL, MCL-1, and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC. Our work therefore provides a rationale for the inhibition of MCL-1, BCL-XL, and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.
De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we ...investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1
mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1
animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1
mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.
Methylfurans are methylated aromatic heterocyclic volatile organic compounds and primary or secondary pollutants in the atmosphere due to their capability to form secondary organic aerosols in ...presence of atmospheric oxidants. There is therefore a significant interest to monitor these molecules in the gas phase. High resolution spectroscopic studies of methylated furan compounds are generally limited to pure rotational spectroscopy in the vibrational ground state. This lack of results might be explained by the difficulties arisen from the internal rotation of the methyl group inducing non-trivial patterns in the rotational spectra. In this study, we discuss the benefits to assign the mm-wave rotational-torsional spectra of methylfuran with the global approach of the
-Cs code compared to local approaches such as XIAM and ERHAM. The global approach reproduces the observed rotational lines of 2-methylfuran and 3-methylfuran in the mm-wave region at the experimental accuracy for the ground vt=0 and the first torsional vt=1 states with a unique set of molecular parameters. In addition, the V3 and V6 parameters describing the internal rotation potential barrier may be determined with a high degree of accuracy with the global approach. Finally, a discussion with other heterocyclic compounds enables the study of the influence of the electronic environment on the hindered rotation of the methyl group.
Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug ...toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.
Abstract
Aims
The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large ...cohort of HTx recipients, compared with the general population.
Methods and results
Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years 95% confidence interval (CI), 9.7–15.9 in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53–0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048).
Conclusion
HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups.
Graphical Abstract
Graphical abstract
IntroductionCoronary artery calcifications (CAC) Agatston score has shown an excellent prognostic value and particularly in diabetic patients, with a very low rate of cardiovascular (CV) events in ...patients with zero CAC score. Recent studies have suggested that high-sensitive cardiac troponin I (hs-cTnI) and brain natriuretic peptide (BNP) may be useful to detect subclinical atherosclerosis.HypothesisTo assess the predictive value of hs-cTnI and BNP to predict zero CAC score in diabetic patients.MethodsBetween 2015 and 2019, CAC score was performed in consecutive patients with diabetes mellitus. Patients with symptoms, coronary artery disease or atrial fibrillation were excluded. Within 24h from CT examination, blood samples were taken to measure hs-cTnI and BNP. The relationship between hs-cTnI/BNP concentrations and zero CAC score was evaluated using univariate and multivariate binomial models, and nested models associated with Chi-squared test of independence.ResultsAmong 844 diabetic patients (61±7 years, 57% men, duration of diabetes 18 years), 35% had zero CAC score, 30% a score from 1-100, 19% from 101-400, and 16% >400. Hs-cTnI/BNP were associated with zero CAC score (OR 2.63, 95%CI1.51-5.01; p<0.001; OR 1.09, 95%CI1.01-1.22; p=0.03 respectively). In multivariate analysis, hs-cTnI/BNP were associated with zero CAC score (OR 2.38, 95%CI1.51-4.76; p=0.009; OR 1.18, 95%CI1.07-1.32; p=0.001 respectively). Among 77 variables, the multivariate model including age, gender, smoking, dyslipidaemia, duration of the diabetes, hypertension, diabetic neuropathy, hs-cTnI and BNP significantly discriminated the zero CAC score (AUC=0.81; p<0.001). In nested models, both hs-cTnI and BNP brought information to this multivariate model to predict zero CAC score (p<0.001).ConclusionsBiomarkers hs-cTnI and BNP are associated with zero CAC score in diabetic patients.
Product impacts on ecosystem quality have long been addressed by the topdown approach known as Life Cycle Assessment (LCA). Impacts are most of the time assessed within the “biodiversity loss” damage ...category indicator. However, LCA methods do not cover the 5 drivers of biodiversity loss as identified by (Millenium Ecosystem Assessment, 2005) (MEA): only land occupation and transformation, pollution, and climate change are covered, while species overexploitation and invasive species are not. Besides, ecologists work on the ground to measure concrete impacts from given practices on biodiversity in specific areas for some parts of the value chain of the product (e.g. production of agricultural biomaterial).
The Product Biodiversity Footprint (PBF) approach aims at bridging the gap between LCA and ecology. Its objective is to allow comparison of variants of a given product to support eco-design, addressing the five drivers of MEA. The methodology combines LCA and ecology current knowledge and organizes them towards practical indicators and representations for business decision.
PBF has been tested in three business case studies. The one for L’Oréal presented herewith shows that the integration of ecological data enables to refine and complement LCA results. This method at product level is, to our knowledge, the first to address the five MEA drivers on biodiversity along the value chain, with a combination of quantitative and semi-quantitative indicators. Stemming from an LCA global framework and approach, ecology knowledge adds refinements that enable to distinguish between different anthropogenic practices and better informed decision making.
•Product Biodiversity Footprint method combines Life Cycle Assessment and Ecology.•The methodology is developed for decision making in product design.•Ecology knowledge enhances impact evaluation of various practices on biodiversity.
IntroductionNon-invasive testing for ischemia to diagnose coronary artery disease(CAD) are frequently inconclusive(25%).HypothesisTo assess the prognostic value of stress CMR in patients with a first ...inconclusive stress test.MethodsBetween 2008 and 2018, consecutive patients with inconclusive stress test, defined by stress echocardiography or nuclear testing with uncertain conclusion, prospectively referred for stress CMR with dipyridamole were followed for major adverse cardiovascular events(MACE)cardiac death or myocardial infarction. An unsupervised clustering analysis was performed.ResultsOf 1502 patients (62±12yrs, 59%men), 1397 completed the follow-up (median 5.5±2.3yrs). Three clusters were identifiedCluster 1 (n=524) had the highest prevalence of previous PCI, the highest presence of a myocardial scar defined, the lowest LVEF (35±7%) and the highest LV dilatation. Cluster 2 (n=406) had the highest previous CABG prevalence, preserved LVEF, absence of LV dilatation, and presence of myocardial scar. This cluster comprised predominantly male patients, with the highest rate of hypertension. Cluster 3 (n=572) had the lowest rate of previous PCI/CABG, the lowest rate of myocardial scar, predominantly female, the highest atrial fibrillation rate and body mass index. Survival analysis found significant differences across clusters for the occurrence of MACE (p=0.02). Inducible ischemia was associated with MACE occurrence in each cluster (C1, HR 2.28; 95%CI1.31-3.99; p=0.0028; C2, HR 3.37; 95%CI1.97-5.75; p<0.0001; C3, HR 2.73; 95%CI1.67-4.46; p<0.0001). In multivariable analysis, inducible ischemia predicted MACE in each cluster (p<0.001 for all).ConclusionsCluster analysis identified 3 different phenotypes with distinct clinical and prognostic profiles. Within these clusters, stress CMR has an additional prognostic value to predict MACE..
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