Characterization of the tumor vasculature in mouse melanoma models. Roles of siRNA-loaded lipid nanocapsules

A significant increase of reported cutaneous melanoma cases have been observed within the past four decades. Despite numerous therapeutic strategies available and ongoing works on novel therapeutics, the vital prognosis for the diagnosed patients are still poor due to low response rate of the tumors to these treatments. For this reason, the application of interfering RNA (RNAi) as a therapeutic agent allowing reestablishment of physiological process of cellular death seems to be a promising altern ative strategy. The use of nanoparticles enables to i) improve the pharmacokinetic of RNAi, ii) potentialize its efficiency and iii) avoid side effects is essential to improve tumor targeting. Therefore, the structure and density of vascularization in a tumor-site is a crucial factor for determining efficacy of nanovectors. This allows the passive targeting which is due to enhanced permeability and retention (EPR) effect. [...

Mechanisms underlying the vasorelaxant effect induced by Anacardium occidentale L. leaf fraction in rat small resistance mesenteric arteries

Anacardium occidentale L. (A. occidentale), belonging to Anacardiaceae family, has been documented as traditional plant for the treatment of diabetes and hypertension [1]. Four extracts of A. occidentale were used for this study, namely AOL1 (from cyclohexane), AOL2 (from CH2Cl2), AOL3 (from EtOAc) and AOL4 (from MeOH). The most potent antiradical reactivity was observed in AOL4 with 2023 TE/g of extract compared to chlorogenic acid (2976 TE/g of compound) as positive standard. In the other hand, our data showed a significant inhibitory effect of EtOAc and MeOH extracts on BSA glycoxidation measured in terms of advanced glycation end products (AGEs). In isolated mesenteric artery rings precontracted with phenylephrine [2], AOL1, AOL2, AOL3, and AOL4 induced a concentration-dependant relaxation respectively with IC50 values of 120µg/ml, 100µg/ml, 70µg/ml and 70µg/ml. Exposure of Eahy cells to high glucose for 7 days significantly (p<0.05) decreased, cell viability (22%), the level of antioxidant gluthatione and expression of protein kinase C. Incubation with low concentrations (7µg/ml, 12.5µg/ml) of AOL3 and AOL4 for 7 days significantly (p<0.05) attenuated high glucose-induced dysfunction of EAhy cells. Preliminary phytochemical investigations of AOL3 and AOL4 by HPLC-DAD analyses suggested the presence of flavonoids and biflavonoids as major compounds in both extracts. Anacardium occidentale leaf extract induces a vasodilatation in mesenteric arteries precontracted with phenylephrine. Ethyl-acetate and methanol extracts improved high glucose-mediated endothelial dysfunction and thus may be potential new therapeutic agents for diabetic cardiovascular complications

Melanoma tumour vasculature heterogeneity: from mice models to human

Tumour angiogenesis is defined by an anarchic vasculature and irregularities in alignment of endothelial cells. These structural abnormalities could explain the variability in distribution of nanomedicines in various tumour models. Then, the main goal of this study was to compare and to characterize the tumour vascular structure in different mouse models of melanoma tumours (B16F10 and SK-Mel-28) and in human melanomas from different patients. Tumours were obtained by subcutaneous injection of 106 B16F10 and 3.106 SK-Mel-28 melanoma cells in C57BL/6 and nude mice, respectively. Tumour growth was evaluated weekly, while vasculature was analysed through fluorescent labelling via CD31 and desmin. Significant differences in tumour growth and mice survival were evidenced between the two melanoma models. A fast evolution of tumours was observed for B16F10 melanoma, reaching a tumour size of 100 mm3 in 7 days compared to SK-Mel-28 which needed 21 days to reach the same volumes. Important differences in vascularization were exposed between the melanoma models, characterized by a significant enhancement of vascular density and a significant lumen size for mice melanoma models compared to human. Immunostaining revealed irregularities in endothelium structure for both melanoma models, but structural differences of vasculature were observed, characterized by a stronger expression of desmin in SK-Mel-28 tumours. While human melanoma mainly develops capillaries, structural irregularities are also observed on the samples of this tumour model. Our study revealed an impact of cell type and tumour progression on the structural vasculature of melanoma, which could impact the distribution of drugs in the tumour environment

In vivo comparison of the proangiogenic properties of chlordecone and three of its dechlorinated derivatives formed by in situ chemical reduction

In situ chemical reduction (ISCR) has been identified as a possible way for the remediation of soils contaminated by chlordecone (CLD). Evidences provided by the literature indicate an association between the development of prostate cancer and CLD exposure (Multigner et al. 2010). In a previous in vitro study, we demonstrated that the two main dechlorinated CLD derivatives formed by ISCR, CLD-1Cl, and CLD-3Cl have lower cytotoxicity and proangiogenic properties than CLD itself (Legeay et al. 2017). By contrast, nothing is known on the in vivo proangiogenic effect of these dechlorinated derivatives. Based on in vitro data, the aims of this study were therefore to evaluate the in vivo influence of CLD and three of its dechlorinated metabolites in the control of neovascularization in a mice model of prostate cancer. The proangiogenic effect of CLD and three of its dechlorinated derivatives, CLD-1Cl, CLD-3Cl, and CLD-4Cl, was evaluated on a murine model of human prostate tumor (PC-3) treated, at two exposure levels: 33 μg/kg and 1.7 μg/kg respectively reflecting acute and chronic toxic exposure in human. The results of serum measurements show that, for the same ingested dose, the three metabolite concentrations were significantly lower than that of CLD. Dechlorination of CLD lead therefore to molecules that are biologically absorbed or metabolized, or both, faster than the parent molecule. Prostate tumor growth was lower in the groups treated by the three metabolites compared to the one treated by CLD. The vascularization measured on the tumor sections was inversely proportional to the rate of dechlorination, the treatment with CLD-4Cl showing no difference with control animals treated with only the vehicle oil used for all substances tested. We can therefore conclude that the proangiogenic effect of CLD is significantly decreased following the ISCR-resulting dechlorination. Further investigations are needed to elucidate the molecular mechanisms by which dechlorination of CLD reduces proangiogenic effects in prostate tumor

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

G-load effects and efficient acoustic parameters for robust speaker recognition

International audienc

ISCR-induced chlordecone dechlorination leads to derivatives with lower pro-angiogenic properties in vitro and in vivo on a prostate cancer model

International audienc

Mechanisms underlying the vasorelaxant effect induced by Anacardium occidentale L. leaf fraction in rat small resistance mesenteric arteries

International audienceAnacardium occidentale L. (A. occidentale), belonging to Anacardiaceae family, has been documented as traditional plant for the treatment of diabetes and hypertension [1]. Four extracts of A. occidentale were used for this study, namely AOL1 (from cyclohexane), AOL2 (from CH2Cl2), AOL3 (from EtOAc) and AOL4 (from MeOH). The most potent antiradical reactivity was observed in AOL4 with 2023 TE/g of extract compared to chlorogenic acid (2976 TE/g of compound) as positive standard. In the other hand, our data showed a significant inhibitory effect of EtOAc and MeOH extracts on BSA glycoxidation measured in terms of advanced glycation end products (AGEs). In isolated mesenteric artery rings precontracted with phenylephrine [2], AOL1, AOL2, AOL3, and AOL4 induced a concentration-dependant relaxation respectively with IC50 values of 120µg/ml, 100µg/ml, 70µg/ml and 70µg/ml. Exposure of Eahy cells to high glucose for 7 days significantly (p&lt;0.05) decreased, cell viability (22%), the level of antioxidant gluthatione and expression of protein kinase C. Incubation with low concentrations (7µg/ml, 12.5µg/ml) of AOL3 and AOL4 for 7 days significantly (p&lt;0.05) attenuated high glucose-induced dysfunction of EAhy cells. Preliminary phytochemical investigations of AOL3 and AOL4 by HPLC-DAD analyses suggested the presence of flavonoids and biflavonoids as major compounds in both extracts. Anacardium occidentale leaf extract induces a vasodilatation in mesenteric arteries precontracted with phenylephrine. Ethyl-acetate and methanol extracts improved high glucose-mediated endothelial dysfunction and thus may be potential new therapeutic agents for diabetic cardiovascular complications.</p