Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing

BACKGROUND: Epidermal homeostasis involves the monitoring of continuous proliferative and differentiative processes as keratinocytes migrate from the basal layer to the skin surface. Recently, differentiation of epidermal stem cells was shown to be promoted by the Notch pathway. This pathway is characterised by cell-cell interactions between transmembrane proteins and was first implicated in lateral inhibition, patterning and cell binary choices during embryogenesis. METHODS: By in situ hybridisation, we investigated the in vivo expression of related genes, namely; Notch 1–3, Delta 1, Jagged 1, Lunatic Fringe, Radical Fringe and Manic Fringe during keratinocyte proliferation and differentiation in humans in basal cell carcinoma, psoriasis and in wound healing experiments, compared with normal adult skin. RESULTS: We show that the highest level of transcription of these genes is in the basal cell layer of non-lesional skin. Conversely, when keratinocytes were hyperproliferating, as in basal cell carcinoma, psoriasis, and during the first step of re-epithelialisation, expression was weak or non-existent. Furthermore, normal levels of transcripts were rescued in psoriatic plaques when treated by phototherapy, as well as in newly regenerated stratified epidermis following wound healing. CONCLUSION: The Notch signalling involved in the differentiation programme of normal adult human epidermis is altered under experimental conditions and pathologies which modify this programme

A reliability assessment of physical vulnerability of reinforced concrete walls loaded by snow avalanches

Snow avalanches are a threat to many kinds of elements (human beings, communication axes, structures, etc.) in mountain regions. For risk evaluation, the vulnerability assessment of civil engineering structures such as buildings and dwellings exposed to avalanches still needs to be improved. This paper presents an approach to determine the fragility curves associated with reinforced concrete (RC) structures loaded by typical avalanche pressures and provides quantitative results for different geometrical configurations. First, several mechanical limit states of the RC wall are defined using classical engineering approaches (Eurocode 2), and the pressure of structure collapse is calculated from the usual yield line theory. Next, the fragility curve is evaluated as a function of avalanche loading using a Monte Carlo approach, and sensitivity studies (Sobol indices) are conducted to estimate the respective weight of the RC wall model inputs. Finally, fragility curves and relevant indicators such a their mean and fragility range are proposed for the different structure boundary conditions analyzed. The influence of the input distributions on the fragility curves is investigated. This shows the wider fragility range and/or the slight shift in the median that has to be considered when a possible slight change in mean/standard deviation/inter-variable correlation and/or the non-Gaussian nature of the input distributions is accounted for

Avalanche risk evaluation and protective dam optimal design using extreme value statistics

International audienceIn snow avalanche long-term forecasting, existing risk-based methods remain difficult to use in a real engineering context. In this work, we expand a quasi analytical decisional model to obtain simple formulae to quantify risk and to perform the optimal design of an avalanche dam in a quick and efficient way. Specifically, the exponential runout model is replaced by the Generalized Pareto distribution (GPD), which has theoretical justifications that promote its use for modelling the different possible runout tail behaviours. Regarding the defence structure/flow interaction, a simple law based on kinetic energy dissipation is compared with a law based on the volume stored upstream of the dam, whose flexibility allows us to cope with various types of snow. We show how a detailed sensitivity study can be conducted, leading to intervals and bounds for risk estimates and optimal design values. Application to a typical case study from the French Alps, highlights potential operational difficulties and how they can be tackled. For instance, the highest sensitivity to the runout tail type and interaction law is found at abscissas of legal importance for hazard zoning (return periods of 10-1000 a), a crucial result for practical purposes

Assessing fragility of a reinforced concrete element to snow avalanches using a non-linear dynamic mass-spring model

This paper presents an assessment of the fragility of a reinforced concrete (RC) element subjected to avalanche loads, and more generally to dynamic pressure fields applied orthogonally to a wall, within a reliability framework. In order to obtain accurate numerical results with supportable computation times, a light and efficient Single-Degree-of-Freedom (SDOF) model describing the mechanical response of the RC element is proposed. The model represents its dynamic mechanical response up to failure. Material non-linearity is taken into account by a moment–curvature approach, which describes the overall bending response. The SDOF model is validated under quasi-static and dynamic loading conditions by comparing its results to alternative approaches based on finite element analysis and the yield line theory. Following this, the deterministic SDOF model is embedded within a reliability framework to evaluate the failure probability as a function of the maximal avalanche pressure reached during the loading. Several reliability methods are implemented and compared, suggesting that non-parametric methods provide significant results at a moderate level of computational burden. The sensitivity to material properties, such as tensile and compressive strengths, steel reinforcement ratio, and wall geometry is investigated. The effect of the avalanche loading rate is also underlined and discussed. Finally, the obtained fragility curves are compared with respect to the few proposals available in the snow avalanche engineering field. This approach is systematic and will prove useful in refining formal and practical risk assessments. It could be applied to other similar natural hazards, which induce dynamic pressure fields onto the element at risk (e.g., mudflows, floods) and where potential inertial effects are expected and for which fragility curves are also lacking.</p

The effect of health care expenditures on survival in locally advanced and metastatic Non Small Cell Lung Cancer

Context: The significant survival benefit of chemotherapy over best supportive care for locally advanced and metastatic NSCLC has been amply demonstrated in the literature. However, there is no clear evidence of the impact of the type of chemotherapy or of a superiority of combination chemotherapy over single-agent chemotherapy.Objective: The present study empirically examines, in real-life practise and using multiple proxies, the impact of health care expenditures on overall survival in locally advanced and metastatic NSCLC in order to guide medical decision-making.Methods: Disease characteristics, the resources used, the costs of treatment and survival data were retrospectively collected from the records of 175 patients treated between 2000 and 2004 at Léon Bérard Regional Cancer Center (Lyon, France). Survival data were modelled using multivariate Cox models and controlled for endogeneity with the instrumental variable method.Results: The median survival for the whole cohort was 289 days. The average total cost of treatment reached €35,160. Survival was significantly shorter for patients with stage IV disease, poor performance status, and past or concomitant cardiovascular disease and/or diabetes, for current smokers, and for patients with adenocarcinoma compared to large cell carcinoma. Survival duration was not significantly associated with the total cost of treatment per day of hospitalisation, the number of chemotherapy drugs administered, nor inpatient length of stay.Conclusion: Higher care expenditures do not appear to improve survival for patients with locally advanced or metastatic NSCLC. Hence, maintaining patient quality of life and tailoring therapy to stage, histology and comorbidities appears to be the less bad choice.Cost; NSCLC; Oncology; Survival

Both Retinoic Acid Receptors α (RARα) and γ (RARγ) Are Able to Initiate Mouse Upper-Lip Skin Glandular Metaplasia

Embryonic mouse upper-lip skin explants treated with 16.7 μM all-trans retinoic acid (tRA) give rise to a glandular metaplasia of hair vibrissa follicles; however, at this concentration, tRA can activate not only the three retinoic acid receptors (RARα, β, and γ), but also the retinoid X receptors (RXRα, β, and γ) as a consequence of its isomerization to 9-cis retinoic acid. We therefore studied the respective roles of the RXR and RAR by treating RARα–/–, β–/–, and γ–/– skin explants with tRA and wild-type explants with synthetic retinoids specific for RXR or for each of the RAR. The null mutation of the RARα, RARβ, and RARγ genes did not prevent tRA-induced hair glandular metaplasia, but RARγ inactivation dramatically reduced its ratio. As demonstrated by treating explants with a RAR- or a RXR-specific panagonist (CD367 and Ro25–7386, respectively), RAR are primarily responsible for this metaplasia. The use of two retinoids (Ro40–6055, 8 × 10–3μM, or CD437, 7.7 × 10–2μM) that are believed to act, respectively, as a RARα- or a RARγ-specific agonist showed that both these receptors can initiate a metaplasia. In contrast, BMS453, a RARβ-specific agonist, was unable to give rise to any metaplasia. Nevertheless, the highest degrees and ratios of metaplasia were only obtained after treatment with the CD367 RAR panagonist, or with either Ro40–6055 or CD437 at a concentration sufficient to allow the activation of the three RAR, suggesting that RARβ activation is required for a metaplasia of all vibrissæ

The effect of health care expenditures on survival in locally advanced and metastatic Non Small Cell Lung Cancer

Working Paper GATE 2009-03Context: The significant survival benefit of chemotherapy over best supportive care for locally advanced and metastatic NSCLC has been amply demonstrated in the literature. However, there is no clear evidence of the impact of the type of chemotherapy or of a superiority of combination chemotherapy over single-agent chemotherapy.Objective: The present study empirically examines, in real-life practise and using multiple proxies, the impact of health care expenditures on overall survival in locally advanced and metastatic NSCLC in order to guide medical decision-making.Methods: Disease characteristics, the resources used, the costs of treatment and survival data were retrospectively collected from the records of 175 patients treated between 2000 and 2004 at Léon Bérard Regional Cancer Center (Lyon, France). Survival data were modelled using multivariate Cox models and controlled for endogeneity with the instrumental variable method.Results: The median survival for the whole cohort was 289 days. The average total cost of treatment reached €35,160. Survival was significantly shorter for patients with stage IV disease, poor performance status, and past or concomitant cardiovascular disease and/or diabetes, for current smokers, and for patients with adenocarcinoma compared to large cell carcinoma. Survival duration was not significantly associated with the total cost of treatment per day of hospitalisation, the number of chemotherapy drugs administered, nor inpatient length of stay.Conclusion: Higher care expenditures do not appear to improve survival for patients with locally advanced or metastatic NSCLC. Hence, maintaining patient quality of life and tailoring therapy to stage, histology and comorbidities appears to be the less bad choice

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

International audiencePurpose: Germline mutations in genes encoding mitochon-drial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1 H-MRS in all Sdhb À/À-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1 H-MRS results led to the identification of an unsus-pected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1 H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)