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Existing guidelines on the preparation (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE)) and reporting (Animal Research: Reporting of In Vivo Experiments (ARRIVE)) of animal experiments do not provide a clear and standardized approach for refinement during in vivo cancer studies, resulting in the publication of generic methodological sections that poorly reflect the attempts made at accurately monitoring different pathologies. Compliance with the 3Rs guidelines has mainly focused on reduction and replacement; however, refinement has been harder to implement. The Oncology Best-practices: Signs, Endpoints and Refinements for in Vivo Experiments (OBSERVE) guidelines are the result of a European initiative supported by EurOPDX and INFRAFRONTIER, and aim to facilitate the refinement of studies using in vivo cancer models by offering robust and practical recommendations on approaches to research scientists and animal care staff. We listed cancer-specific clinical signs as a reference point and from there developed sets of guidelines for a wide variety of rodent models, including genetically engineered models and patient derived xenografts. In this Consensus Statement, we systematically and comprehensively address refinement and monitoring approaches during the design and execution of murine cancer studies. We elaborate on the appropriate preparation of tumor-initiating biologicals and the refinement of tumor-implantation methods. We describe the clinical signs to monitor associated with tumor growth, the appropriate follow-up of animals tailored to varying clinical signs and humane endpoints, and an overview of severity assessment in relation to clinical signs, implantation method and tumor characteristics. The guidelines provide oncology researchers clear and robust guidance for the refinement of in vivo cancer models.

Background Immigrant studies offer insights into the relative importance of environment and genes in disease etiology. There is considerable variation in testicular cancer incidence worldwide. We investigated testicular cancer risk in first- and second-generation immigrants to Denmark, a high-incidence country, to evaluate the relative influence of genes and environment and the potential timing of action of environmental factor(s). Methods A cohort of 2.1 million men who were born since 1930 and lived in Denmark between 1968 and 2003 was established based on information in the Danish Civil Registration System, which included their immigration histories. Cancer histories were obtained from the Danish Cancer Registry. Testicular cancer risk was estimated as rate ratios (RRs) with 95% confidence intervals (CIs) based on log-linear Poisson regression. Results Overall, 4216 testicular cancer cases occurred during 43 million person-years of follow-up in 2.1 million men. These included 166 cases among 344444 direct immigrants to Denmark and 13 cases among 56189 men born in Denmark to immigrant parents. These first- and second-generation immigrants had RRs of testicular cancer of 0.37 (95% CI = 0.31 to 0.43) and 0.88 (95% CI = 0.51 to 1.53), respectively, compared with men bom in Denmark of parents born in Denmark. The rate in first-generation immigrants was not modified by age at immigration or duration of stay and reflected that in the country of origin. Conclusion The testicular cancer risk in first-generation immigrants was lower than that in native-born Danes and reflected that in the countries of origin, whereas the risk in second-generation immigrants was similar to that in natives of Denmark. Together these findings argue for a substantial influence of environmental factors limited to the period early in life, most probably to the period in utero.

BackgroundBreathlessness is a major cause of suffering and disability globally. The symptom relates to multiple factors including asthma and lung function, which are influenced by hereditary factors. No study has evaluated potential inheritance of breathlessness itself across generations.MethodsWe analysed the association between breathlessness in parents and their offspring in the Respiratory Health in Northern Europe, Spain and Australia generation study. Data on parents and offspring aged ≥18 years across 10 study centres in seven countries included demographics, self-reported breathlessness, asthma, depression, smoking, physical activity level, measured Body Mass Index and spirometry. Data were analysed using multivariable logistic regression accounting for clustering within centres and between siblings.ResultsA total of 1720 parents (mean age at assessment 36 years, 55% mothers) and 2476 offspring (mean 30 years, 55% daughters) were included. Breathlessness was reported by 809 (32.7%) parents and 363 (14.7%) offspring. Factors independently associated with breathlessness in parents and offspring included obesity, current smoking, asthma, depression, lower lung function and female sex. After adjusting for potential confounders, parents with breathlessness were more likely to have offspring with breathlessness, adjusted OR 1.8 (95% CI 1.1 to 2.9). The association was not modified by sex of the parent or offspring.ConclusionParents with breathlessness were more likely to have children who developed breathlessness, after adjusting for asthma, lung function, obesity, smoking, depression and female sex in both generations. The hereditary components of breathlessness need to be further explored.

ObjectivesTo investigate the association between occupational noise exposure and stroke incidence in a pooled study of five Scandinavian cohorts (NordSOUND).MethodsWe pooled and harmonised data from five Scandinavian cohorts resulting in 78 389 participants. We obtained job data from national registries or questionnaires and recoded these to match a job-exposure matrix developed in Sweden, which specified the annual average daily noise exposure in five exposure classes (LAeq8h): <70, 70–74, 75–79, 80–84, ≥85 dB(A). We identified residential address history and estimated 1-year average road traffic noise at baseline. Using national patient and mortality registers, we identified 7777 stroke cases with a median follow-up of 20.2 years. Analyses were conducted using Cox proportional hazards models adjusting for individual and area-level potential confounders.ResultsExposure to occupational noise at baseline was not associated with overall stroke in the fully adjusted models. For ischaemic stroke, occupational noise was associated with HRs (95% CI) of 1.08 (0.98 to 1.20), 1.09 (0.97 to 1.24) and 1.06 (0.92 to 1.21) in the 75–79, 80–84 and ≥85 dB(A) exposure groups, compared with <70 dB(A), respectively. In subanalyses using time-varying occupational noise exposure, we observed an indication of higher stroke risk among the most exposed (≥85 dB(A)), particularly when restricting analyses to people exposed to occupational noise within the last year (HR: 1.27; 95% CI: 0.99 to 1.63).ConclusionsWe found no association between occupational noise and risk of overall stroke after adjustment for confounders. However, the non-significantly increased risk of ischaemic stroke warrants further investigation.

Modeling tumor metabolism in vitroremains challenging. Here, we used galactose as an in vitrotool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.

Many of the plant-derived compounds used in chemotherapies are currently produced by semisynthesis, which results in limited supplies at exorbitant market prices. However, the synthetic biology era, which began ca15 years ago, has progressively yielded encouraging advances by using engineered microbes for the practical production of cheaper plant anticancer drugs.

La Direction de l'eau et de l'assainissement du Conseil départemental de Seine-Saint-Denis gère un réseau d'assainissement d'un linéaire de 700 kilomètres. Ce réseau est équipé de 178 stations de mesure cumulant 769 voies de hauteur, vitesse, débit calculé, turbidité et pluviométrie. Afin d'améliorer la qualité des mesures, une expertise des mesures de débit, calculées à partir d'une mesure de hauteur et d'une ou plusieurs mesures de vitesse, a été mise en place.

Herein, we present an ex vivoapproach to study glioblastoma (GBM) cell motility in viable mouse brain slice cultures, closely mimicking in vivofeatures. We detail the preparation and culturing of mouse brain slices followed by tumor cell injection, allowing for the analysis of different aspects of the cellular migration and invasion process. Our assay facilitates testing diverse perturbations including genetic modifications and treatments in a physiological context. Thus, the protocol provides a compromise between in vitroassays and in vivomodels.

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery associated with other adverse outcomes. Recent studies have shown that drainage of pericardial effusion by a posterior pericardial incision reduces the incidence of POAF. An alternative approach is a chest tube placed posteriorly in the pericardium. We evaluated if the use of a posterior pericardial drain was associated with reduced risk of POAF in patients undergoing coronary artery bypass graft (CABG) and/or aortic valve replacement (AVR).

Anti-myeloperoxidase nephritogenic autoimmunity induces severe glomerulonephritis. To assess the therapeutic potential of monoclonal antibodies targeting T helper (Th) subset differentiation determining cytokines, we studied a murine model of anti-myeloperoxidase glomerulonephritis. The temporal participation of T helper subsets was determined by quantitating gene expression of CD4+T-cells isolated from nephritic kidneys and cytokine production by lymphocytes from nodes draining myeloperoxidase immunization sites. Th17 cytokines (IL-17A and IL-6) rose rapidly but declined as autoimmunity matured when Th1 cytokines (IL-12 and TNF) predominated. Therefore, T helper subset participation in anti-myeloperoxidase autoimmunity is biphasic, with Th17 early and Th1 late. To confirm the functional relevance of this biphasic pattern, we compared systemic anti-myeloperoxidase autoimmunity in wild type, Th17 deficient and Th1 deficient mice. Early, Th1 deficient mice developed similar autoimmunity and glomerulonephritis to wild type mice. However, Th17 deficient mice had significantly reduced anti-myeloperoxidase autoimmunity. In late autoimmunity, Th1 deficient mice developed reduced autoimmunity and were protected from anti-myeloperoxidase glomerulonephritis. The therapeutic potential of these findings were demonstrated by neutralizing monoclonal antibodies. Targeting IL-23p19 attenuated early Th17 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not late phase disease. Targeting IL-12p35 attenuated late phase Th1 dominated anti-myeloperoxidase autoimmunity and glomerulonephritis but not early autoimmunity or glomerulonephritis. Targeting both T helper subsets with an anti-IL-12p40 monoclonal antibody was effective during both early and late phases of anti-myeloperoxidase glomerulonephritis. Thus, definition of dominant T helper differentiating subsets in anti-myeloperoxidase glomerulonephritis by renal CD4+T-cell cytokine gene expression allows effective proper phase monoclonal antibody treatment of anti-myeloperoxidase glomerulonephritis.

Plusieurs modèles peuvent être utilisés pour représenter les processus hydrologiques en milieu urbain. Ces modèles sont développés suivant différentes approches en fonction de l'objectif de modélisation, de l'échelle spatio-temporelle et de la disponibilité des données hydroclimatiques et spatiales. Dans cet article, nous proposons de développer un outil parcimonieux et généralisable à partir d'une structure de modèle non dédié au contexte urbanisé. Dans un premier temps, nous analysons la structure de départ et la sensibilité des paramètres qu'elle contient à la présence de surfaces urbaines dans le bassin versant. Pour ce faire, un échantillon de 365 bassins versants français et américains a été construit. Le modèle est calé sur deux périodes pour chaque bassin versant, donnant ainsi 730 couples bassin-période pour lesquels la fraction urbaine dans le bassin a été déterminée. L'analyse de la sensibilité des paramètres du modèle hydrologique par rapport à cette fraction ainsi que d'autres indicateurs hydrologiques a été effectuée pour une sélection de 416 couples bassin-période, homogènes en surface. Les résultats montrent que les paramètres du modèle et les indicateurs hydrologiques présentent des différences significatives entre un échantillon de bassins versants fortement urbanisés et un échantillon de bassins versants faiblement urbanisés, traduisant des écoulements plus rapides et plus importants sur les bassins fortement urbanisés.

The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children’s irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors.We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n= 12) or not received (n= 12) TBI.Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture.Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P= 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1(minus 39%, P= 0.01) and CIDEA(minus 36%, P= 0.004) and a clear alteration of pre-adipocyte differentiation.These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.

Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitroinvasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivoand in vivoexperiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo.Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.

ABSTRACTWe aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (≤−5°C) and hot temperatures (≥21°C) compared to optimal temperature were 1.47 (95% CI: 0.72–2.99) and 1.43 (95% CI: 0.67–3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association.

BackgroundCardiovascular disease (CVD) is the main cause of death in most industrialised countries, including those in Europe. The mortality rates due to coronary heart disease (CHD), one of the most serious CVD conditions, have been decreasing in most European countries during the last decades. However, whether the trends over time in CHD mortality rates differ depending on neighbourhood deprivation has rarely been investigated.MethodsFor each year of the study period, 1988–2012, in Sweden, age-standardised mortality rates were calculated for three different types of neighbourhoods, characterised by a Neighbourhood Deprivation Index. Joinpoint regression was used to investigate potential changes in age-standardised mortality rates by neighbourhood deprivation and over time.ResultsOver the study period, age-standardised mortality rates due to CHD were consistently the highest in the deprived neighbourhoods and the lowest in the affluent neighbourhoods. We observed a statistically significant overall decline, ranging from 67% to 59%, in the age-standardised CHD mortality rates for each level of neighbourhood deprivation. Furthermore, the decline for the affluent neighbourhoods was significantly higher compared with the decline in the deprived neighbourhoods.ConclusionAge-standardised CHD mortality rates decreased significantly in Sweden between 1988 and 2012. This decline was more pronounced in the affluent neighbourhoods, which indicates that the improvements in prevention and treatment of CHD have not benefited individuals residing in deprived neighbourhoods to an equal extent. Knowledge of time trends in CHD mortality by level of neighbourhood deprivation may help guide decision-makers in the development of appropriate healthcare policies for deprived neighbourhoods.

Climate change can directly affect human health by varying exposure to non-optimal outdoor temperature. However, evidence on this direct impact at a global scale is limited, mainly due to issues in modelling and projecting complex and highly heterogeneous epidemiological relationships across different populations and climates.

Who would have guessed in the early 2000s that craft beer would be such a huge trend? What started off as just a few local brews sold locally, inched up [...]

WHO WOULD HAVE GUESSED in the early 2000s that craft beer would be such a huge trend? What started off as just a few local brews sold locally, inched up [...]

WHO WOULD HAVE GUESSED JUST OVER 10 YEARS AGO THAT CRAFT BEER would become such a huge trend? What started off as just a few local brews sold locally, inched [...]

L'anthropisation a de multiples impacts sur les réponses hydrologiques des bassins versants. Ces impacts sont difficiles à quantifier à l'échelle spatiale du bassin versant et les résultats de la littérature sur ce sujet sont assez disparates. L'objectif de cette étude est de faire le lien entre la proportion des surfaces urbaines actuelles (considérées comme moins perméables) et l'évolution des réponses hydrologiques des bassins versants. Ceci pose un important problème lié à la relation entre la variabilité du climat et celle de la réponse hydrologique des bassins. Pour ce faire, le modèle hydrologique GR4J a été utilisé. Cette étude est basée sur l'analyse de 104 bassins versants urbains et 68 bassins non-urbains aux États-Unis. Le débit et la pluie journalière des bassins étudiés ont été collectés pour des périodes de 30 à 70 ans selon les bassins. Dans cette méthode, seul le jeu de paramètres du modèle change d'une période de 5 ans à l'autre et la totalité de la chronique de débit est reconstituée à chaque fois, ce qui permet de s'affranchir de la variabilité du climat entre les périodes de 5 ans. Les premiers résultats montrent que les caractéristiques hydrologiques analysées ne présentent pas de tendance significative pour une majorité de bassins versants urbains et que la proportion de bassins avec tendance significative est relativement similaire pour les bassins urbains et non-urbains. Ces résultats doivent être analysés également en fonction de l'évolution historique de l'occupation de sol.

EVERY GOOD MARKETER KNOWS IT: YOU HAVE TO LOCALIZE TO SUCCEED in international waters. Atlanta-based The Coca-Cola Co.'s secret recipe for Coca-Cola can vary by location. McDonald's Corp., Oak Brook, [...]

Most of previous assessments of hydrologic model performance are fragmented, based on small number of catchments, different methods or time periods and do not link the results to landscape or climate characteristics. This study uses large‐sample hydrology to identify major catchment controls on daily runoff simulations. It is based on a conceptual lumped hydrological model (GR6J), a collection of 29 catchment characteristics, a multinational set of 1103 catchments located in Austria, France, and Germany and four runoff model efficiency criteria. Two analyses are conducted to assess how features and criteria are linked: (i) a one‐dimensional analysis based on the Kruskal‐Wallis test and (ii) a multidimensional analysis based on regression trees and investigating the interplay between features. The catchment features most affecting model performance are the flashiness of precipitation and streamflow (computed as the ratio of absolute day‐to‐day fluctuations by the total amount in a year), the seasonality of evaporation, the catchment area, and the catchment aridity. Nonflashy, nonseasonal, large, and nonarid catchments show the best performance for all the tested criteria. We argue that this higher performance is due to fewer nonlinear responses (higher correlation between precipitation and streamflow) and lower input and output variability for such catchments. Finally, we show that, compared to national sets, multinational sets increase results transferability because they explore a wider range of hydroclimatic conditions. The article uses large sample hydrology to identify catchment controls on daily runoff simulations from the GR6J lumped modelNonflashy, nonseasonal, large, and nonarid catchments show the best performance for four uncorrelated efficiency criteriaThe study underline the value of multinational dataset to increase results robustness

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8–related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8–related MCD.

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l’Enfant et de l’Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2–47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73–15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63–10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47–7.13), allogeneic graft (OR=4.34, 95% CI: 2.07–9.12 for alternative donors and OR=2.53, 95% CI: 1.2–5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09–5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

The peripheral nervous system plays an important role in cancer progression. Studies in multiple cancer types have shown that higher intratumoral nerve density is associated with poor outcomes. Peripheral nerves have been shown to directly regulate tumor cell properties, such as growth and metastasis, as well as affect the local environment by modulating angiogenesis and the immune system. In this Review, we discuss the identity of nerves in organs in the periphery where solid tumors grow, the known mechanisms by which nerve density increases in tumors, and the effects these nerves have on cancer progression. We also discuss the strengths and weaknesses of current in vitro and in vivo models used to study nerve–cancer interactions. Increased understanding of the mechanisms by which nerves impact tumor progression and the development of new approaches to study nerve–cancer interactions will facilitate the discovery of novel treatment strategies to treat cancer by targeting nerves.

Neurovascular disease such as symptomatic stroke, silent brain infarcts and vascular cognitive impairment are common complications of sickle cell disease (SCD) that can have devastating consequences on quality of life, employment, and social functioning. Early recognition of neurovascular disease is a prerequisite for the timely optimization of medical care and to connect patients to adaptive resources. While cognitive impairment has been well described in children, currently available data are limited in adults. As a result, guidance on the optimal cognitive screening strategies in adults is scarce. We conducted a systematic review to identify the different screening tools that have been evaluated in SCD. A meta-analysis was performed to estimate the prevalence of suspected cognitive impairment in this population. In this qualitative synthesis, we present 8 studies that evaluated 6 different screening tools. Patient characteristics that impacted on cognitive screening performance included age, education level, and a prior history of stroke. We report a pooled prevalence of 38% [14-62%] of suspected cognitive impairment. We discuss the relative benefits and limitations of the different screening tools to help clinicians select an adapted approach tailored to their specific patients’ needs. Further studies are needed to establish and validate cognitive screening strategies in patients with diverse cultural and educational backgrounds.

The prediction of damage and crack propagation plays an increasingly important role in the design of current vehicles and espeeially for those to come, In order to accurately prediet the damge and failure evolution occurring in crash simulations, a realistic material description is required. The damage variable must consider the mierostruetural characteristics of the material. For this purpose, the shape and orientation of the microstructural cavities are taken into account in the developed finite element model so as to improve prediction of damage and fracture occurrence. The growth, nucleation and coalescence phases are considered to describe the evolution of the microvoid volume fraction. This model has been implemented into the finite element code, PAM-SOLIDTMAn identification procedure for the matenal parameters is developed using an inverse method. This procedure is based on the correlation between experimental measurements obtained from tensile tests and numerical simulations. The identification was carried out automatically by using an optimiser coupled with the finite element code for an anisotropie aluminium material obtained from an extruded tube member. The use of the damage model is illustrated by several bending of extruded notehless aluminium tubes and then with a notched aluminium tubes.

MenaINV, an actin-regulatory protein known to promote metastasis, has roles in driving cross-talk between extracellular matrix, growth factor cues, and their downstream pathways during tumor cell invasion. MenaINVis a shared component of the signaling pathway driving both EGF chemotaxis and fibronectin haptotaxis.

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has been proposed to increase the cell dose. We report a prospective randomized study, designed to compare single- vs double-UCB transplantation in children and young adults with acute leukemia in remission or myelodysplasia. Eligible patients had at least two 4-6 HLA-identical UCBs with >3 × 107 nucleated cells/kg for the first and >1.5 × 107 for the second. The primary end point was the 2-year cumulative incidence of transplantation strategy failure, a composite end point including transplant-related mortality (TRM), engraftment failure, and autologous recovery. Randomized patients who did not proceed to transplantation due to refractory disease were considered transplantation failures. A total of 151 patients were randomized and included in the intent-to-treat analysis; 137 were transplanted. Double-UCB transplantation did not decrease transplantation strategy failure (23.4% ± 4.9% vs 14.9% ± 4.2%). Two-year posttransplant survival, disease-free survival, and TRM were 68.8% ± 6.0%, 67.6% ± 6.0%, and 5.9% ± 2.9% after single-unit transplantation compared with 74.8% ± 5.5%, 68.1% ± 6.0%, and 11.6% ± 3.9% after double-unit transplantation. The final relapse risk did not significantly differ, but relapses were delayed after double-unit transplantation. Overall incidences of graft-versus-host disease (GVHD) were similar, but chronic GVHD was more frequently extensive after double-UCB transplantation (31.9% ± 5.7% vs 14.7% ± 4.3%, P = .02). In an exploratory subgroup analysis, we found a significantly lower relapse risk after double-unit transplantation in patients receiving total body irradiation without antithymocyte globulin (ATG), whereas the relapse risk was similar in the group treated with busulfan, cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell dose remains the standard of care and leads to low TRM. Double-unit transplantation should be reserved for patients who lack such units. This trial was registered at www.clinicaltrials.gov as #NCT01067300.

L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, 13C–glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.

Cet article traite de la fatigue thermique subie par les outillages de mise en forme. Pour appréhender le problème d’endommagement des outillages, il est nécessaire de bien connaître les conditions de transfert de chaleur et d’évaluer les contraintes thermo-mécaniques subies par l’outillage. La prévision de la durée de vie et l’évolution de la plasticité cyclique qui précède la fissuration est difficile car certains matériaux ont tendance à s’écrouir alors que d’autres ont tendance à s’adoucir. Nous proposons le recours à des expériences de fatigue thermo-mécanique (TMF) pour appréhender cette prévision. Par un exemple emblématique, nous montrons comment il est possible d’aborder le problème. Le cas considéré est la fonderie gravité en coquille d’acier. Nous mettons en évidence l’influence de paramètres process sur le transfert de chaleur et sur les contraintes thermo-mécaniques subies par le moule pendant un cycle de coulée. Les paramètres retenus sont la température initiale du moule et la nature du poteyage. Des essais de fatigue thermo-mécanique ont été menés et les résultats sur 1000 cycles sont exposés.

Surface of hot work tools is damaged by complex thermomechanical-wear-reactive environment interactions. A thermomechanical fatigue (TMF) experiment using tubular specimens is developed. Tests are carried out under out-of-phase thermomechanical cycle. The mechanical strain is minimum (εm min) at upper temperature (Tmax) and it is maximum (εm max) at lower temperature (Tmin) of thermal cycle. The behaviour, the damage and the fatigue life of two tempered martensitic steels X38CrMoV5 (AISI H11) and 55NiCrMoV8 (47 HRC) are assessed. The effect of Tminand Tmaxis examined. Softening is observed for both steels. For a given mechanical strain amplitude (Δεm= εm max– Em min), a drastic dependence on Tmaxis demonstrated, while Tminhas less important effect. X38CrMoV5 has a better TMF life. Ductile fatigue striations are observed on the fracture surface of X38CrMoV5 specimens. The fracture surface of 55NiCrMoV8 specimens is covered by oxidation, making difficult to reveal the fatigue striations. Both oxide cracking and spalling are observed on the external surface of specimens. A phenomenological power law uniaxial model, based on the mechanical strain amplitude and Tmin, Δεm= K(Tmax).[math], is proposed to predict the life under non-isothermal fatigue sollicitations. The life of some thermal fatigue tests is predicted within a factor of two to three. The capability of the model to predict the critical regions of an industrial hot work tool is reported. Key words : Thermomechanical fatigue, thermal fatigue, tool steels, crack initiation, crack propagation, high temperature fatigue.

The actin-binding protein Mena regulates RTK signaling after growth factor stimulation in tumor cells by a novel mechanism. The alternatively spliced MenaINV isoform disrupts this attenuation to drive sensitivity to growth factors, resistance to targeted inhibitors, and ultimately tumor invasion and metastasis.

Les trois modes de dégradation principaux des outillages de frappe à froid sont l’usure, la fissuration de fatigue et la ruine par fatigue de contact (écaillage de l’outil). Nous ne tiendrons pas compte dans cette étude de la rupture par surcharge, qui relève d’un défaut de conception ou d’un accident. L’usure, qui est un mode de dégradation souvent plus lent (comparativement aux deux autres modes), est étudiée par l’intermédiaire du test de grippage. Une méthodologie d’étude est ensuite mise en place pour traiter les deux autres cas. Cette méthodologie utilise le test de compression translation. Ce test permet de reproduire les conditions de fonctionnent du procédé de mise en forme étudié. Il est ici modifié de manière à prendre en compte le facteur tenue dans le temps de l’outil. Tous les paramètres caractéristiques du procédé sont reproduits de telle sorte que les faciès de déformations de la pièce et de l’échantillon sont identiques. Le niveau de dégradation de l’outil est donc recherché non pas sur l’outil mais sur la pièce. Cette démarche s’inscrit dans le cadre d’un contrôle sans démontage de l’outillage. Un exemple est traité.

Pour l’industrie de la frappe à froid, la lubrification des opérations de mise en forme est en grande partie assurée par des revêtements lubrifiants. Il s’agit dans bien des cas de couches phosphatées savonnées. Les paramètres influant sur les performances de ces revêtements sont nombreux et il est nécessaire de disposer de moyens de contrôle garantissant le bon fonctionnement du processus de traitement.

Les procédés d'obtention des revêtements de surface utilisés en mise en forme à froid sont assez bien maîtrisés mais la connaissance des caractéristiques mécaniques de ces revêtements est encore partielle. Les revêtements de surface sont la plupart du temps caractérisés par leurs propriétés tribologiques et leur comportement mécanique est négligé. Le L.A.M.I.H. a montré récemment l'influence de ces revêtements sur la géométrie, l'état de contrainte et de déformation au voisinage de la zone de contact. De plus, les régimes de lubrification dépendent de l'état de contrainte et de plastification de cette zone, et les cissions de frottement en présence peuvent ainsi être mieux connues. L'identification des lois surfaciques dépend alors de la caractérisation du comportement volumique de la surface. Les auteurs proposent donc une méthode d'identification de la loi de comportement du revêtement basée sur une procédure inverse. Une série d'indentations sous charge croissante couplée à une analyse par éléments finis permet d'identifier le comportement du revêtement et du substrat d'accrochage. Les courbes obtenues en compression montrent que le revêtement perd de son influence au profit du substrat avec l'augmentation de la charge. Elles corrèlent les résultats des essais d'étirage grippage.