Estimation of dynamical model parameters taking into account undetectable marker values

BACKGROUND: Mathematical models are widely used for studying the dynamic of infectious agents such as hepatitis C virus (HCV). Most often, model parameters are estimated using standard least-square procedures for each individual. Hierarchical models have been proposed in such applications. However, another issue is the left-censoring (undetectable values) of plasma viral load due to the lack of sensitivity of assays used for quantification. A method is proposed to take into account left-censored values for estimating parameters of non linear mixed models and its impact is demonstrated through a simulation study and an actual clinical trial of anti-HCV drugs. METHODS: The method consists in a full likelihood approach distinguishing the contribution of observed and left-censored measurements assuming a lognormal distribution of the outcome. Parameters of analytical solution of system of differential equations taking into account left-censoring are estimated using standard software. RESULTS: A simulation study with only 14% of measurements being left-censored showed that model parameters were largely biased (from -55% to +133% according to the parameter) with the exception of the estimate of initial outcome value when left-censored viral load values are replaced by the value of the threshold. When left-censoring was taken into account, the relative bias on fixed effects was equal or less than 2%. Then, parameters were estimated using the 100 measurements of HCV RNA available (with 12% of left-censored values) during the first 4 weeks following treatment initiation in the 17 patients included in the trial. Differences between estimates according to the method used were clinically significant, particularly on the death rate of infected cells. With the crude approach the estimate was 0.13 day(-1 )(95% confidence interval [CI]: 0.11; 0.17) compared to 0.19 day(-1 )(CI: 0.14; 0.26) when taking into account left-censoring. The relative differences between estimates of individual treatment efficacy according to the method used varied from 0.001% to 37%. CONCLUSION: We proposed a method that gives unbiased estimates if the assumed distribution is correct (e.g. lognormal) and that is easy to use with standard software

The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth

<p>Abstract</p> <p>Background</p> <p>Human clear cell renal cell carcinoma (CRCC) remains resistant to therapies. Recent advances in Hypoxia Inducible Factors (HIF) molecular network led to targeted therapies, but unfortunately with only limited clinical significance. Elucidating the molecular processes involved in kidney tumorigenesis and resistance is central to the development of improved therapies, not only for kidney cancer but for many, if not all, cancer types. The oncogenic PI3K/Akt, NF-kB and MAPK pathways are critical for tumorigenesis. The sonic hedgehog (SHH) signaling pathway is crucial to normal development.</p> <p>Results</p> <p>By quantitative RT-PCR and immunoblot, we report that the SHH signaling pathway is constitutively reactivated in tumors independently of the von Hippel-Lindau (VHL) tumor suppressor gene expression which is inactivated in the majority of CRCC. The inhibition of the SHH signaling pathway by the specific inhibitor cyclopamine abolished CRCC cell growth as assessed by cell counting, BrdU incorporation studies, fluorescence-activated cell sorting and β-galactosidase staining. Importantly, inhibition of the SHH pathway induced tumor regression in nude mice through inhibition of cell proliferation and neo-vascularization, and induction of apoptosis but not senescence assessed by in vivo studies, immunoblot and immunohistochemistry. Gli1, cyclin D1, Pax2, Lim1, VEGF, and TGF-β were exclusively expressed in tumors and were shown to be regulated by SHH, as evidenced by immunoblot after SHH inhibition. Using specific inhibitors and immunoblot, the activation of the oncogenic PI3K/Akt, NF-kB and MAPK pathways was decreased by SHH inhibition.</p> <p>Conclusions</p> <p>These findings support targeting SHH for the treatment of CRCC and pave the way for innovative and additional investigations in a broad range of cancers.</p

Diagnostic de cancer du rein par analyse des microsatellites urinaires.

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Evaluation de la concordance inter-observateurs du grade de Fuhrman. (Analyse anatomopathologique multicentrique et analyse de survie d'une série de 241 patients présentant un carcinome à cellules rénales localisé avec un suivi médian de plus de 15 ans.)

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

A prospective survey of surgical approaches in clinically localized renal cell carcinoma - A preliminary attempt at surgical quality control

We analyzed the inter-institutional variability of factors related to the performance and outcome of surgery for localized renal cell carcinoma (RCC). Data were prospectively collected from 41 urologists that performed 168 radical nephrectomies for RCC. The participants reported on the surgeon, the incision, the stage, the need for blood transfusion, the duration of surgery and the gastrointestinal decompression. The timing of the start of oral intake, pain control, the time of discharge from the hospital and the early complications of surgery were also investigated. One third of the urologists perform routine lymphadenectomy and one fourth adrenalectomy. The flank incision was the most popular, followed by Chevron and midline abdominal incisions. There are differences in the approach to radical nephrectomy in Europe and this has an impact on the quality of life of the patients and on health economics. There is an urgent need to assess surgical quality for localized RCC

The ERANOS Code and data system for fast reactor neutronic analyses

International audienceThe main modelling options of ERANOS 2.0, the latest version of the ERANOS fast reactor analysis code and data system, are described. These include the ECCO cell and lattice code (Collision Probability Method in many groups using the subgroup method), the BISTRO 2-D S n transport code, the TGV/VARIANT 3-D Nodal Variational Transport code, and a special procedure for creating equivalent homogeneous cross sections for control rods. The recommended "reference" core calculation route is presented. A summary of the ERANOS extensive validation is provided. It is concluded that ERANOS 2.0 can predict the main characteristics of conventional as well as advanced liquid-metal-cooled fast reactors with an excellent accuracy, and that it can also be used for modelling advanced fast reactor cores, source-driven sub-critical media and gas-cooled fast reactors