Eurasanté

Abstract Breast cancer is the most frequent cancer among women causing the greatest number of cancer-related deaths. Cancer heterogeneity is a main obstacle to therapies. Around 96% of the drugs fail from discovery to the clinical trial phase probably because of the current unreliable preclinical models. New models emerge such as companion dogs who develop spontaneous mammary tumors resembling human breast cancer in many clinical and molecular aspects. The present work aimed at developing a robust canine mammary tumor model in the form of tumoroids which recapitulate the tumor diversity and heterogeneity. We conducted a complete characterization of these canine mammary tumoroids through histologic, molecular and proteomic analysis, demonstrating their strong similarity to the primary tumor. We demonstrated that these tumoroids can be used as a drug screening model. In fact, we showed that Paclitaxel, a human chemotherapeutic, could killed canine tumoroids with the same efficacy as human tumoroids with 0.1 to 1 μM of drug needed to kill 50% of the cells. Due to easy tissue availability, canine tumoroids can be produced at larger scale and cryopreserved to constitute a biobank. We have demonstrated that cryopreserved tumoroids keep the same histologic and molecular features (ER, PR and HER2 expression) as fresh tumoroids. Two techniques of cryopreservation were compared demonstrating that tumoroids made from frozen tumor material allowed to maintain a higher molecular diversity. These findings revealed that canine mammary tumoroids can be easily generated at large scale and can represent a more reliable preclinical model to investigate tumorigenesis mechanisms and develop new treatments for both veterinary and human medicine.

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-022-04390-3.

As long as the structuralstudy of molecular mechanisms requiresmultiple molecular dynamics reflecting contrasted bioactive states,the subsequent analysis of molecular interaction networks remainsa bottleneck to be fairly treated and requires a user-friendly 3Dview of key interactions. Structural Interaction Network AnalysisProtocols (SINAPs) is a proprietary python tool developed to (i) quicklysolve key interactions able to distinguish two protein states, eitherfrom two sets of molecular dynamics simulations or from two crystallographicstructures, and (ii) render a user-friendly 3D view of these key interactionsthrough a plugin of UCSF Chimera, one of the most popular open-sourceviewing software for biomolecular systems. Through two case studies,glucose transporter-1 (GLUT-1) and A2A adenosine receptor (A2AR),SINAPs easily pinpointed key interactions observed experimentallyand relevant for their bioactivities. This very effective tool wasthus applied to identify the amino acids involved in the molecularenzymatic mechanisms ruling the activation of an immunomodulator drugcandidate, P28 glutathione-S-transferase (P28GST). SINAPs is freelyavailable at https://github.com/ParImmune/SINAPs.

Rapid, yet sensitive and accurate testing concepts are critical in the control of spreading viral diseases.

CD44+/CD24- phenotype has been used to identify human and canine mammary cancer stem-like cells. In canine mammary tumors, CD44+/CD24- phenotype has been associated with high grade and lymph node infiltration. However, several studies have reported opposing results regarding the clinical significance of phenotypic groups formed by the combination of CD44 and CD24 in both human and canine mammary tumors. So far, no study has investigated the correlation between these phenotypes and survival in dogs. The aim of this study was to investigate the expression and distribution of CD44 and CD24 in canine mammary carcinomas and to correlate them with histological diagnosis and survival in a well-characterized cohort. Immunohistochemistry was performed in 96 mammary carcinomas with antibodies against CD44 and CD24. Expression of CD44+ and CD44+/CD24- phenotype was detected in 75 of 96 (78%) and 63 of 96 (65.6%) carcinomas, respectively. Their expression was associated with tumor type, occurring more often in tubular complex carcinomas than in solid carcinomas. CD44+/CD24- phenotype was associated with a better overall survival ( P = .001). CD24+ expression was detected in 52 of 96 tumors (54%) and CD44-/CD24+ phenotype in 39 of 96 tumors (40.6%). Both were associated with poor clinicopathological parameters (high grade, and emboli). No correlation with overall survival was observed. CD44+/CD24- expression was associated with a better prognosis and occurred at high frequency and high level, indicating that this phenotype is not suitable to detect cancer stem cells in canine mammary carcinomas. Although further studies are needed, our results suggest that CD24 may constitute a valuable marker of poor prognosis for canine mammary carcinomas.

Alzheimer’s disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunction. In the past, specific peroxisome proliferator-activated receptor (PPAR)γ-agonists, such as pioglitazone, have been tested with limited success to improve AD pathology. Here, we investigated the therapeutic efficacy of GFT1803, a novel potent PPAR agonist that activates all the three PPAR isoforms (α/δ/γ) in the APP/PS1 mouse model in comparison to the selective PPARγ-agonist pioglitazone. Both compounds showed similar brain/plasma partitioning ratios, although whole body and brain exposure to GFT1803 was significantly lower as compared to pioglitazone, at doses used in this study. Oral treatment of APP/PS1 mice with GFT1803 decreased microglial activation, amyloid β (Aβ) plaque area, Aβ levels in sodium dodecyl sulfate- and formic acid-soluble fractions in a concentration-dependent manner. With a single exception of Aβ38 and Aβ40 levels, measured by ELISA, these effects were not observed in mice treated with pioglitazone. Both ligands decreased glial fibrillary acidic protein (GFAP) expression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme expression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1 mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) produced both quantitatively superior and qualitatively different therapeutic effects with respect to amyloid plaque burden, insoluble Aβ content, and neuroinflammation at significantly lower whole body and brain exposure rates.

BackgroundSubstantial increases in syphilis have been reported since the early 2000s in northern countries, particularly among men who have sex with men (MSM). The authors aimed to identify risk factors for early syphilis in MSM in Lille, a large urban area of northern France.MethodsA matched case–control study was conducted in MSM aged ≥18 years. Cases were diagnosed with primary, secondary or early latent syphilis between April 2008 and June 2010. Controls sought care in STIs clinics or were followed in an HIV clinic. Controls had no history of and no current syphilis. They were matched to cases for age and HIV status. Multivariate conditional logistic regression models were used to identify risk factors for early syphilis.Results53 patients with early syphilis were enrolled. Average age was 37 years, and 47% were HIV-infected. For analysis, they were matched to 90 controls. Factors associated with syphilis were: low educational attainment (OR=5.38, 95% CI 1.94 to 14.94; p=0.001), receptive oral sex with casual male partners without a condom (OR=4.86, 95% CI 1.63 to 14.48; p=0.005) and anal sex toy use with casual male partners (OR=2.72, 95% CI 1.01 to 7.32; p=0.05). Seeking of sex partners online (OR=5.17, 95% CI 1.33 to 20.11), use of poppers (OR=2.2, 95% CI 1.1 to 4.3) and erectile dysfunction drugs (OR=1.9, 95% CI 1.0 to 13.2) were associated with syphilis only in the univariate analysis.ConclusionsReceptive oral sex without a condom and use of anal sex toys were identified as presenting a major risk of syphilis infection. Although these practices have been shown to present low risk of HIV transmission, the general public is unaware of their impact on transmission of other STIs.