Circulating microRNAs found dysregulated in ex-exposed asbestos workers and pleural mesothelioma patients as potential new biomarkers

Malignant pleural mesothelioma (MPM), a fatal cancer, is an occupational disease mostly affecting workers ex-exposed to asbestos fibers. The asbestos, a cancerogenic mineral of different chemical composition, was widely employed in western Countries in industrial manufactures of different types. MPM may arise after a long latency period, up to five decades. MPM is resistant to conventional chemo- and radio-therapies. Altogether, these data indicate that the identification of new and specific markers are of a paramount importance for an early diagnosis and treatment of MPM. In recent years, microRNAs expression was found dysregulated in patients, both in cancer cells and sera, affected by tumors of different histotypes, including MPM. Cell and circulanting microRNAs, found to be dysregulated in this neoplasia, were proposed as new biomarkers. It has been reported that circulating microRNAs are stable in biological fluids and could be employed as potential MPM biomarkers. In this investigation, circulating microRNAs (miR) from serum samples of MPM patients and workers ex-exposed to asbestos fibers (WEA) and healthy subjects (HS) were comparatively analyzed by microarray and RT-qPCR technologies. Our results allowed (i) to select MiR-3665, an endogenous stable microRNA, as the internal control to quantify in our analyses circulating miRNAs; to detect (ii) miR-197-3p, miR-1281 and miR 32-3p up-regulated in MPM compared to HS; (iii) miR-197-3p and miR-32-3p up-regulated in MPM compared to WEA; (iv) miR-1281 up-regulated in both MPM and WEA compared to HS. In conclusion, three circulating up-regulated microRNAs, i.e. miR-197-3p, miR-1281 and miR-32-3p are proposed as potential new MPM biomarker

Placoid scales in bioluminescent sharks: Scaling their evolution using morphology and elemental composition

Elasmobranchs are characterised by the presence of placoid scales on their skin. These scales, structurally homologous to gnathostome teeth, are thought to have various ecological functions related to drag reduction, predator defense or abrasion reduction. Some scales, particularly those present in the ventral area, are also thought to be functionally involved in the transmission of bioluminescent light in deep-sea environments. In the deep parts of the oceans, elasmobranchs are mainly represented by squaliform sharks. This study compares ventral placoid scale morphology and elemental composition of more than thirty deep-sea squaliform species. Scanning Electron Microscopy and Energy Dispersive X-ray spectrometry, associated with morphometric and elemental composition measurements were used to characterise differences among species. A maximum likelihood molecular phylogeny was computed for 43 shark species incuding all known families of Squaliformes. Character mapping was based on this phylogeny to estimate ancestral character states among the squaliform lineages. Our results highlight a conserved and stereotypical elemental composition of the external layer among the examined species. Phosphorus-calcium proportion ratios (Ca/P) slightly vary from 1.8-1.9, and fluorine is typically found in the placoid scale. By contrast, there is striking variation in shape in ventral placoid scales among the investigated families. Character-mapping reconstructions indicated that the shield-shaped placoid scale morphotype is likely to be ancestral among squaliform taxa. The skin surface occupied by scales appears to be reduced in luminous clades which reflects a relationship between scale coverage and the ability to emit light. In luminous species, the placoid scale morphotypes are restricted to pavement, bristle- and spine-shaped except for the only luminescent somniosid, Zameus squamulosus, and the dalatiid Mollisquama mississippiensis. These results, deriving from an unprecedented sampling, show extensive morphological diversity in placoid scale shape but little variation in elemental composition among Squaliformes.publishedVersio

Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data.

International audienceThis study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mg/kg/day as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coefficient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts

Influence on Busilvex pharmacokinetics of clonazepam compared to previous phenytoin historical data.

International audienceThis study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mg/kg/day as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coefficient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts

Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients with liver dysfunction (LD): Pharmacokinetic results

2523 Background: VFL is a novel microtubule inhibitor of the vinca alkaloid class that has shown high antitumour activity in several in vivo tumour models and in clinical trials. VFL is mainly eliminated through metabolism and bile excretion. Therefore this trial was designed to determine if LD could increase exposure and toxicity of VFL and require a dose-adjustment. Methods: This trial had a sequential design with the objective of determining the maximal tolerated dose (MTD) and the recommended dose (RD) in three groups of LD based on clinical and biological criteria: mild (PT &gt; 70% and UNL &lt; serum bilirubin = 1.5xUNL), moderate (Child-Pugh A) and severe (Child-Pugh B). VFL and 4-O-deacetylvinflunine (DVFL), its only active metabolite, were quantified in whole blood during cycle 1. PK parameters (AUCinf, Cltot) were estimated using a non-compartmental analysis and were compared using a one-way ANOVA with group factor either between groups or between groups and a control group of 49 patients without LD enrolled in phase I trials). Results: Three VFL doses were investigated: The inter-individual variability (CV) in AUCinf was approximately 30% for all groups. Even if AUCinf increased between mild and moderate groups, no difference was demonstrated between moderate and severe LD groups. All individual values were within the range of control values. Cltot were also similar between groups and the control group. Statistical analysis did not evidence any significant difference between groups. No difference was observed in blood concentrations of DVFL compared to the control group. No relationship between dose limiting toxicity and blood exposure was evidenced. Conclusions: The results showed that vinflunine and DVFL pharmacokinetic parameters do not appear to be affected by the degree of LD. However, the dose of VFL has to be adjusted to the level of LD for safety reasons. [Table: see text] No significant financial relationships to disclose. </jats:p