The Hairless Rat: A Relevant Animal Model to Predict In Vivo Percutaneous Absorption in Humans?

Percutaneous absorption of 4 radiolabeled molecules was compared in the hairless rat (back) and in different anatomic sites in human (arm, abdomen, postauricular, forehead). The conditions under which these 4 compounds were administered (area treated, dose, vehicle, contact time, etc.) were similar in both species. The results showed that, in humans and rats, there exists the same rank order in total absorption: benzoic acid sodium salt < caffeine < benzoic acid < acetylsalicylic acid. In both species there was a factor of 3 between the most and the least absorbed molecule. Although skin permeability varied significantly with the physicochemical nature of the compound administered, it also depended on the anatomic site involved. Independent of the molecule studied, the rank order of permeability of the sites tested in humans appeared as follows: arm ≤ abdomen < postwar < forehead. There was a factor of 3 between the most and the least permeable sites. For each molecule and each anatomic site, the ratios of total percutaneous absorption human/hairless rat (back) were determined. For a given anatomic site and whatever the molecule tested, these ratios were constant. It thus appears that when conditions are carefully controlled, it may be possible, by measurements on animals, to predict the absorption of a compound in humans. Further experimentation with chemicals of varied physicochemical properties will be required for validation of the model

Numerical Modeling of Microstructure Formation during Solidification and Heat Treatments of Ni-base superalloys

International audienceNumerical models have been developed for the simulation of microstructure formation in Ni-base alloys. The first step consists of a calculation of the segregation of solutal species in the primary solidified g-phase and formation/dissolution of the interdendritic g'-phase. Finally, local compositions of solutal species are used to calculate the nucleation, growth and coarsening of g'-precipitates with a precipitation model

Investigation of passive and active silica-tin oxide nanostructured optical fibers fabricated by " inverse dip-coating " and " powder in tube " method based on the chemical sol-gel process and laser emission

International audienceThis paper presents a study of original nanostructured optical fibers based on the SiO 2-SnO 2-(Yb 3+) system. Two different processes have been developed and compared: the sol-gel chemical method associated to the " inverse dip-coating " (IDC) and the " powder in tube " (PIT) process. The microstructural and optical properties of the fibers are studied according to the concentration of SnO 2. X-Ray Diffraction as well as Transmission Electron Microscopy studies show that SnO 2 crystallizes into the cassiterite phase as nanoparticles with a diameter ranging from 4 to 50 nm as a function of tin oxide concentration. A comparative study highlights a better conservation of SnO 2 into the fiber core with the PIT approach according to the refractive index profile and X-Ray analysis measurement. The attenuation evaluated by the classic cutback method gives respectively values higher than 3 dB/m and 0.2 dB/m in the visible (VIS) and infrared (IR) range for the PIT fiber whereas background losses reach 0.5 dB/m in the VIS range for IDC fibers. The introduction of ytterbium ions into the core of PIT fibers, directly in the first chemical step, leads to a laser emission (between 1050 and 1100 nm) according to the fiber length under 850 nm wavelength pumping. Luminescence studies have demonstrated the influence of the tin oxide nanostructure on the rare earth optical properties especially by the modification of the absorption (850 to 1000 nm) and emission (950 to 1100 nm) by discretization of the bands, as well as on the IR emission lifetime evaluated to 10 µs

Colorectal neuroendocrine carcinomas and adenocarcinomas share oncogenic pathways. A clinico-pathologic study of 12 cases

OBJECTIVE: Neuroendocrine carcinomas (NECs) are rare neoplasms with an increasing incidence. Oncogenetic pathways of colorectal NEC are still poorly understood, and no treatment standards are available for these rare tumors. METHODS: We analyzed retrospectively the clinical records and histology of 12 patients with colorectal NEC. KRAS and BRAF mutations were investigated after the dissection of exoendocrine and neuroendocrine components. ALK alterations and EML4-ALK transcripts were detected by in-situ hybridization and determination of fusion transcripts, respectively. RESULTS: At the time of diagnosis, the mean age of the patients was 60 years (40-79) and 10 patients had synchronous metastases. A transient response occurred in two patients and one patient treated with cisplatin-etoposide or fluoropyrimidine-oxaliplatin, respectively. Tumor progression-related death occurred in 11 of 12 patients. Ten tumors contained an exocrine component, accounting for 5-70% of the tumor, and the other two contained an amphicrine component. BRAF/KRAS mutations were found in six of 10 tumors, corresponding to BRAF(V600E) (n=2) or KRAS(G12D) (n=2), KRAS(G12V) or KRAS(G13D). DNA was obtained from both exocrine and endocrine components in seven cases, and the BRAF/KRAS status was identical in all cases. Split of the ALK locus was detected in a minority of tumor cells in two of eight cases, but EML4-ALK transcripts were absent. CONCLUSION: The association of an exocrine component in all cases and the similar profile of BRAF/KRAS mutations indicate that colorectal NEC may correspond to a high-grade transformation of colorectal carcinoma. New chemotherapy regimens using targeted therapies should be assessed in these tumors

Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo.

peer reviewedaudience: researcherVitamin C is known for its antioxidant potential and activity in the collagen biosynthetic pathway. Photoprotective properties of topically applied vitamin C have also been demonstrated, placing this molecule as a potential candidate for use in the prevention and treatment of skin ageing. A topically applied cream containing 5% vitamin C and its excipient were tested on healthy female volunteers presenting with photoaged skin on their low-neck and arms in view to evaluate efficacy and safety of such treatment. A double-blind, randomized trial was performed over a 6-month period, comparing the action of the vitamin C cream vs. excipient on photoaged skin. Clinical assessments included evaluation at the beginning and after 3 and 6 months of daily treatment. They were performed by the investigator and compared with the volunteer self assessment. Skin relief parameters were determined on silicone rubber replicas performed at the same time-points. Cutaneous biopsies were obtained at the end of the trial and investigated using immunohistochemistry and electron microscopy. Clinical examination by a dermatologist as well as self-assessment by the volunteers disclosed a significant improvement, in terms of the 'global score', on the vitamin C-treated side compared with the control. A highly significant increase in the density of skin microrelief and a decrease of the deep furrows were demonstrated. Ultrastructural evidence of the elastic tissue repair was also obtained and well corroborated the favorable results of the clinical and skin surface examinations. Topical application of 5% vitamin C cream was an effective and well-tolerated treatment. It led to a clinically apparent improvement of the photodamaged skin and induced modifications of skin relief and ultrastructure, suggesting a positive influence of topical vitamin C on parameters characteristic for sun-induced skin ageing

Phase II study of irinotecan with bolus and high dose infusional 5-FU and folinic acid (modified de Gramont) for first or second line treatment of advanced or metastatic colorectal cancer

We investigated the activity of irinotecan given with a more convenient modified bimonthly de Gramont regimen of bolus and infusional 5-fluorouracil [IrMdG] in advanced or metastatic colorectal cancer in the first and second line setting. Irinotecan 180 mg m−2 was infused over 90 min. L-folinic acid 175 mg or d,l folinic acid 350 mg was given over 2 h followed by a bolus of 5-fluorouracil (400 mg m−2) and a 46 h continuous infusion of 5-fluorouracil (2.4–2.8 g m−2). Forty-six previously untreated patients (Group A) and 36 who had received 5-fluorouracil for metastatic disease (Group B) were recruited. Seventy-eight patients were evaluable for response. A partial response was seen in 13 out of 43 (30% [95%CI 28.1–31.9%]) in Group A and 8/35 (23% [95% CI 17.9–28.1%]) in Group B. 40% (95%CI 38.1–41.9%) of Group A and 26% (95% CI 20.9–31.1%) of Group B patients achieved disease stabilisation. The median progression free survival from the start of this treatment was 7 months (95% CI 4.4–9.6 months) in Group A and 5 months (95% CI 2.8–7.2 months) in Group B. Median overall survival was 14 months (95% CI 9.0–18.9) in Group A and 11 months (95% CI 5.9–16.1) in Group B. Grade 3–4 toxicity in both treatment groups were similar; leucopenia 17% and diarrhoea 7–8%. Grade 3–4 mucositis was not seen and severe alopecia affected only three patients. IrMdG is an active and well-tolerated regimen for both the first and second line treatment of advanced colorectal cancer

Sustainable computational science: the ReScience initiative

Computer science o ers a large set of tools for prototyping, writing, running, testing, validating, sharing and reproducing results, however computational science lags behind. In the best case, authors may provide their source code as a compressed archive and they may feel con dent their research is reproducible. But this is not exactly true. Jonathan Buckheit and David Donoho proposed more than two decades ago that an article about computational results is advertising, not scholarship. e actual scholarship is the full so ware environment, code, and data that produced the result. is implies new work ows, in particular in peer-reviews. Existing journals have been slow to adapt: source codes are rarely requested, hardly ever actually executed to check that they produce the results advertised in the article. ReScience is a peer-reviewed journal that targets computational research and encourages the explicit replication of already published research, promoting new and open-source implementations in order to ensure that the original research can be replicated from its description. To achieve this goal, the whole publishing chain is radically di erent from other traditional scienti c journals. ReScience resides on GitHub where each new implementation of a computational study is made available together with comments, explanations, and so ware tests

Palaeogenomics of Upper Palaeolithic to Neolithic European hunter-gatherers

Modern humans have populated Europe for more than 45,000 years1,2. Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period3. Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe4, but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants

Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer

We assessed the potential benefits of including systematic 18fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting tumour recurrence in a prospective randomised trial. Patients (N=130) who had undergone curative therapy were randomised to undergo either conventional (Con) or FDG-PET procedures during follow-up. The two groups were matched at baseline. Recurrence was confirmed histologically. ‘Intention-to-treat' analysis revealed a recurrence in 46 patients (25 in the FDG-PET group, and 21 in the Con group; P=0.50), whereas per protocol analysis revealed a recurrence in 44 out of 125 patients (23 and 21, respectively; P=0.60). In another three cases, PET revealed unexpected tumours (one gastric GIST, two primary pulmonary cancers). Three false-positive cases of FDG-PET led to no beneficial procedures (two laparoscopies and one liver MRI that were normal). We failed to identify peritoneal carcinomatosis in two of the patients undergoing FDG-PET. The overall time in detecting a recurrence from the baseline was not significantly different in the two groups. However, recurrences were detected after a shorter time (12.1 vs 15.4 months; P=0.01) in the PET group, in which recurrences were also more frequently (10 vs two patients) cured by surgery (R0). Regular FDG-PET monitoring in the follow up of colorectal cancer patients may permit the earlier detection of recurrence, and influence therapy strategies

Palaeogenomics of Upper Palaeolithic to Neolithic European hunter-gatherers

Modern humans have populated Europe for more than 45,000 years. Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period. Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe, but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants.Open access funding provided by Max Planck Society. This project has received funding by the European Research Council under the European Union’s Horizon 2020 research and innovation programme under grant agreements no. 803147-RESOLUTION (to S.T.), no. 771234-PALEoRIDER (to W.H.), no. 864358 (to K.M.), no. 724703 and no. 101019659 (to K.H.). K.H. is also supported by the Deutsche Forschungsgemeinschaft (DFG FOR 2237). E.A. has received funding from the Van de Kamp fonds. PACEA co-authors of this research benefited from the scientific framework of the University of Bordeaux’s IdEx Investments for the Future programme/GPR Human Past. A.G.-O. is supported by a Ramón y Cajal fellowship (RYC-2017-22558). L. Sineo, M.L. and D.C. have received funding from the Italian Ministry of University and Research (MUR) PRIN 2017 grants 20177PJ9XF and 20174BTC4R_002. H. Rougier received support from the College of Social and Behavioral Sciences of CSUN and the CSUN Competition for RSCA Awards. C.L.S. and T. Saupe received support from the European Union through the European Regional Development Fund (project no. 2014-2020.4.01.16-0030) and C.L.S. received support from the Estonian Research Council grant PUT (PRG243). S. Shnaider received support from the Russian Science Foundation (no. 19-78-10053).Peer reviewe