Lipid-Induced Peroxidation in the Intestine Is Involved in Glucose Homeostasis Imbalance in Mice

BACKGROUND: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. METHODOLOGY/PRINCIPAL FINDINGS: An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. CONCLUSIONS/SIGNIFICANCE: Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity

Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

La motivation robotique

CAEN-BU Droit Lettres (141182101) / SudocSudocFranceF

Etude d’accessibilité d’un clavier augmenté pour des techniques d’interaction en entré

National audienceWe present SmartCom, a combination of a smartphone and the traditional physical keyboard to enhance command selection by 1) eliminating occlusion, 2) reducing command discoverability time and 3) reducing homing cost. We performed a reachability study to evaluate the feasibility of gestures combining key press and phone touch. The results are promising and none of our participants found SmartCom usage difficult. In the future, we plan to design and evaluate novel interaction techniques for SmartCom.Nous présentons SmartCom, une combinaison d'un smartphone et du clavier physique traditionnel pour améliorer la sélection des commandes en 1) éliminant l'occlusion, 2) réduisant le temps de découverte des commandes et 3) réduisant le coût de l'homing. Nous avons réalisé une étude d'accessibilité pour évaluer la faisabilité de gestes combinant l'appui sur les touches du clavier et le toucher sur le smartphone. Les résultats sont prometteurs et aucun de nos participants n'a trouvé l'utilisation de SmartCom difficile. Prochainement, nous prévoyons de concevoir et évaluer de nouvelles techniques d'interaction pour SmartCom

Influence of aging on SEI and charge transfer resistances and their dependence on current and temperature for a Li-ion NCA+NMC/graphite cell

International audienceModeling the electrical behavior of cells is often complex because several parameters have to be determined simultaneously, which may lead to inconsistencies and inaccuracies. In the present paper, we modeled the surface resistance by using a method based on rules of dependence, already presented in the literature, which makes it possible to separate the contributions of the SEI (Solid Electrolyte Interphase) layer and the charge transfer as a function of the temperature and the current. A physically consistent model is able to provide a better estimate of the surface resistance values at untested operating points. The main contributions of this work are to transpose this method to an NCA+NMC / graphite+SiO cell and to show that the proposed model is easier to recalibrate as the cell ages than interpolation tables. Besides, the proposed experimental protocol reduces the time needed for testing. By testing cells at different states of health, it was observed that the charge transfer resistance increased with both cycling and calendar aging and that the SEI resistance also increased in both cases because of the high temperatures to which the cells were subjected

An Update on the Treatment of Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma (pRCC) is the second-most common subtype of kidney cancer following clear cell renal cell carcinoma (ccRCC), representing 15% of kidney cancers. Despite advances in therapy, including combination strategies with targeted therapies and immune checkpoint inhibitors, progress has lagged behind that of ccRCC. This is in part due to the heterogenous nature of the various subtypes of pRCC. More recently, investigators have turned efforts towards histology and biology-based trials. In this review, we outline some of the distinct biological characteristics of pRCC and discuss the most impactful clinical trials to date. Finally, we look ahead to several highly anticipated ongoing trials in pRCC

An Update on the Treatment of Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma (pRCC) is the second-most common subtype of kidney cancer following clear cell renal cell carcinoma (ccRCC), representing 15% of kidney cancers. Despite advances in therapy, including combination strategies with targeted therapies and immune checkpoint inhibitors, progress has lagged behind that of ccRCC. This is in part due to the heterogenous nature of the various subtypes of pRCC. More recently, investigators have turned efforts towards histology and biology-based trials. In this review, we outline some of the distinct biological characteristics of pRCC and discuss the most impactful clinical trials to date. Finally, we look ahead to several highly anticipated ongoing trials in pRCC

Detection of BRCA1, and BRCA2 Alterations in Matched Tumor Tissue and Circulating Cell-Free DNA in Patients with Prostate Cancer in a Real-World Setting

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious BRCA1 and/or 2 mutations. Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of BRCA mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting. Methods: Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect. Results: The presence or absence of mutations in the BRCA gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0–232) months. BRCA mutation was present in the patient’s original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% [95% CI, 95.3–99.1%]. The adjusted concordance between metastatic samples and cfDNA was 93.5% [95% CI, 86.4–97.3%]. Of the patients who had a BRCA mutation detected in their prostate tissue, there was a 70% probability of detecting a BRCA mutation in the patient’s cfDNA as well. For patients who did not have a detectable BRCA mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%. Conclusion: There is a high level of concordance between tissue and blood for BRCA mutations. Testing cfDNA can provide reliable information on BRCA mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new BRCA mutation later in the disease course is a rare event