Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Organisation sptatiale de la variabilité génétique et phénotypique à l'échelle du paysage (le cas du chamois et du chevreuil, en milieu de montagne)

Natural populations are spatially heterogeneous, structured at different scales and ecological traits, such as demographic or genetic component. Many factors can be involved in the spatial substructure of populations: intrinsic factors like intraspecific competition but also environmental factors, such as landscape barriers. Firstly, we studied the spatial organisation of genetic variability in two ungulates, Roe deer and Chamois, in order to identify the spatial scale at which populations are substructured and the ecological factors involved in these spatial patterns. Our results suggest that populations of roe deer and chamois are spatially subdivided and constituted of several sub-units. Our findings indicate the presence of constraints acting on individual movements and gene flow. Landscape fragmentation, habitat heterogeneity and social organisation seem to be the main factors involved in these spatial patterns. Coupled to genetic analyses, the spatial distribution of roe deer body mass in correlation with landscape variables has been investigated. Our results reveal a high spatial heterogeneity of individual body mass, due to pronounced spatial habitat variability in the Bauges massif. Our study highlights first the importance of detecting genetic spatial pattern of populations and the scale at which they are spatially substructured and second the necessity of determining which factors can influence these patterns, especially in wildlife managementLes populations naturelles sont des entités spatialement hétérogènes, structurées à différentes échelles et à divers niveaux tels que démographiques ou génétiques. De nombreux facteurs peuvent être impliqués dans la structuration spatiale des populations, des facteurs intrinsèques à la population, comme la compétition intraspécifique mais également des facteurs d ordre environnemental, tel que la présence de barrières paysagères. Dans un premier temps, nous avons étudié l organisation spatiale de la variabilité génétique chez deux ongulés, le Chevreuil et le Chamois, dans le but d identifier les échelles de structuration des populations et les facteurs à l origine de ces patrons spatiaux. Les résultats suggèrent que chez les deux espèces, les populations sont subdivisées dans l espace et constituées ainsi de plusieurs sous-unités, indiquant qu il existerait au sein du massif des Bauges des contraintes s exerçant sur les mouvements et les flux de gènes. Les principaux facteurs à l origine de ces contraintes seraient la fragmentation du paysage, l hétérogénéité de l habitat mais également l organisation social. En complément des analyses génétiques, la distribution spatiale de la masse corporelle et sa mise en relation avec les variables paysagères ont été appréhendées chez le Chevreuil. Les résultats indiquent qu à l échelle du massif, il existe une forte hétérogénéité spatiale de la masse corporelle qui semble en partie liée à la variabilité de l habitat. L ensemble de ces résultats souligne l importance d identifier les échelles de structuration des populations et les facteurs impliqués, notamment dans le domaine de la gestion de la faune sauvageLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV2R). Most of these mutations lead to intracellular retention of the hV2R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV2Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV2R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV2R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV2R agonist pharmacochaperones promising therapeutic candidates for cNDI

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

International audienceOxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V-1a and V-2 vasopressin receptor subtypes (V-1a-R and V-2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure affinity and structure efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

International audienc

COvid-19 and high-dose VITamin D supplementation TRIAL in high-risk older patients (COVIT-TRIAL): study protocol for a randomized controlled trial

International audienceAbstract Background With the lack of effective therapy, chemoprevention, and vaccination against SARS-CoV-2, focusing on the immediate repurposing of existing drugs gives hope of curbing the COVID-19 pandemic. A recent unbiased genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns. Growing pre-clinical and epidemiological observational data support this assumption. We hypothesized that vitamin D supplementation may improve the prognosis of COVID-19. The aim of this trial is to compare the effect of a single oral high dose of cholecalciferol versus a single oral standard dose on all-cause 14-day mortality rate in COVID-19 older adults at higher risk of worsening. Methods The COVIT-TRIAL study is an open-label, multicenter, randomized controlled superiority trial. Patients aged ≥ 65 years with COVID-19 (diagnosed within the preceding 3 days with RT-PCR and/or chest CT scan) and at least one worsening risk factor at the time of inclusion (i.e., age ≥ 75 years, or SpO2 ≤ 94% in room air, or PaO2/FiO2 ≤ 300 mmHg), having no contraindications to vitamin D supplementation, and having received no vitamin D supplementation > 800 IU/day during the preceding month are recruited. Participants are randomized either to high-dose cholecalciferol (two 200,000 IU drinking vials at once on the day of inclusion) or to standard-dose cholecalciferol (one 50,000 IU drinking vial on the day of inclusion). Two hundred sixty participants are recruited and followed up for 28 days. The primary outcome measure is all-cause mortality within 14 days of inclusion. Secondary outcomes are the score changes on the World Health Organization Ordinal Scale for Clinical Improvement (OSCI) scale for COVID-19, and the between-group comparison of safety. These outcomes are assessed at baseline, day 14, and day 28, together with the serum concentrations of 25(OH)D, creatinine, calcium, and albumin at baseline and day 7. Discussion COVIT-TRIAL is to our knowledge the first randomized controlled trial testing the effect of vitamin D supplementation on the prognosis of COVID-19 in high-risk older patients. High-dose vitamin D supplementation may be an effective, well-tolerated, and easily and immediately accessible treatment for COVID-19, the incidence of which increases dramatically and for which there are currently no scientifically validated treatments. Trial registration ClinicalTrials.gov NCT04344041 . Registered on 14 April 2020 Trial status Recruiting. Recruitment is expected to be completed in April 2021

Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

International audienc

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup