SUV420-mediated heterochromatin changes in pediatric brain cancers

Silencing mechanisms play a role in genomic stability by maintaining condensed, non-active regions of the genome. SUV420 enzymes contain a SET domain conferring methyltransferase activity toward histones. The Histone H4 lysine 20 trimethylation (H4K20me3) mark maintained by SUV420H2 is associated with heterochromatin formation and gene silencing, whereas the dimethylated mark (H4K20me2) is associated with DNA repair. In studies of epigenetic factors in large patient cohorts with ependymoma, it was found that SUV420H2 expression was lost or diminished in patients with reciprocal increases in prognostic markers such as hTERT. To better understand the normal function of Suv4-20H1/H2 enzyme in neural progenitors, and pathological changes in cancers, a variety of differentiation paradigms were used. The NT2D1 neurally restricted cell line, and BGO1V and H9 human embryonic stem cells (ESCs), and differentiated progeny, were used alongside tumors to better understand enzyme targets and functional outcomes (e.g.,lineage, differentiation, regional chromatin modifications). Lineage stages were verified with stage-specific markers by immunofluorescence and qPCR. Suv4-20 H1 and H2 were present in ESCs and neural progenitors and decreased thereafter. RNAi knockdown of SUV420 enzymes led to decreased H4K20 methylation in cancer cells. DNA methylation microarrays and ChIP-PCR suggest 1) that SUV420 is not regulated by DNA methylation in ependymomas; 2) that active chromatin marks such as H3K4 dimethylation are enriched near the transcriptional start site in the SUV420H2 gene, and 3) that hTERT is hyper-methylated at specific CpG islands and histones in a tumor sub-group-specific manner. This data supports the hypothesis that Suv4-20H2 is highly active in progenitor cells and functionally lost in some brain cancers. These studies begin to elucidate coincident mechanisms of gene silencing active in neural progenitors that may be altered in a subset of pediatric brain cancers

A Comprehensive Hepatitis C Viral Kinetic Model Explaining Cure

International audienceWe propose a model that characterizes and links the complexity and diversity of clinically observed hepatitis C viral kinetics to sustained virologic response (SVR)--the primary clinical end point of hepatitis C treatment, defined as an undetectable viral load at 24 weeks after completion of treatment)--in patients with chronic hepatitis C (CHC) who have received treatment with peginterferon α-2a ± ribavirin. The new attributes of our hepatitis C viral kinetic model are (i) the implementation of a cure/viral eradication boundary, (ii) employment of all hepatitis C virus (HCV) RNA measurements, including those below the lower limit of quantification (LLOQ), and (iii) implementation of a population modeling approach. The model demonstrated excellent positive (99.3%) and negative (97.1%) predictive values for SVR as well as high sensitivity (96.6%) and specificity (99.4%). The proposed viral kinetic model provides a framework for mechanistic exploration of treatment outcome and permits evaluation of alternative CHC treatment options with the ultimate aim of developing and testing hypotheses for personalizing treatments in this disease

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Adaptive Bayesian compound designs for dose finding studies

We consider the problem of how to efficiently and safely design dose finding studies. Both current and novel utility functions are explored using Bayesian adaptive design methodology for the estimation of a maximum tolerated dose (MTD). In particular, we explore widely adopted approaches such as the continual reassessment method and minimizing the variance of the estimate of an MTD. New utility functions are constructed in the Bayesian framework and are evaluated against current approaches. To reduce computing time, importance sampling is implemented to re-weight posterior samples thus avoiding the need to draw samples using Markov chain Monte Carlo techniques. Further, as such studies are generally first-in-man, the safety of patients is paramount. We therefore explore methods for the incorporation of safety considerations into utility functions to ensure that only safe and well-predicted doses are administered. The amalgamation of Bayesian methodology, adaptive design and compound utility functions is termed adaptive Bayesian compound design (ABCD). The performance of this amalgamation of methodology is investigated via the simulation of dose finding studies. The paper concludes with a discussion of results and extensions that could be included into our approach

Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies

Aims: To characterize the population pharmacokinetics of BYL719 in adult cancer patients and assess the time course of tumor response in relation to drug exposure and dosing schedule Methods: Plasma samples and longitudinal tumor size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modeling was employed to develop the population pharmacokinetic and pharmacodynamic model. Goodness of model fit was assessed according to graphical and statistical criteria. Results: Pharmacokinetics was best described by a one-compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 L/h (BSV 26%) and 108 L (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 hours (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumor growth was modeled using a turnover model characterized by a zero order growth rate of 0.581 cm.week-1 and a first order death rate of 0.0123 week-1. BYL719 inhibited tumor growth with an IC50 of 100 ng/ml (BSV 154%). Model-based predictions showed potential for additional anti-tumor activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily. Conclusions: The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719

Time-dependent clearance of mycophenolic acid in renal transplant recipients

Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects. One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation. The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL. By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofeti