The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma - a substudy of the SORAMIC trial.

Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations.Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS).Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1-23.3). Patients received sorafenib for a median of 51 weeks (IQR 27-62) and blood samples were drawn after a median of 25 weeks (IQR 10-42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166-4526) and 360 ng/ml (IQR 190-593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p = .003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p = .442) or M2 trough levels (428 vs 283 ng/ml, p = .159). Trough levels of sorafenib or M2 showed no significant association with OS.Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment

Association of polymorphisms in survivin gene with the risk of hepatocellular carcinoma in Chinese han population: a case control study

<p>Abstract</p> <p>Background</p> <p>Survivin, one of the strongest apoptosis inhibitors, plays a critical role in the development and progression of hepatocellular carcinoma (HCC). By comparison, relatively little is known about the effect of <it>survivin </it>gene polymorphisms on HCC susceptibility. Our study aimed to investigate the association of <it>survivin </it>gene polymorphisms with the risk of HCC in Chinese han population.</p> <p>Methods</p> <p>A case-control study was conducted in Chinese han population consisting of 178 HCC cases and 196 cancer-free controls. Information on demographic data and related risk factors was collected for all subjects. Polymorphisms of the <it>survivin </it>gene, including three loci of rs8073069, rs9904341 and rs1042489, were selected and genotyped by a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. Association analysis of genotypes/alleles and haplotypes from these loci with the risk of HCC was conducted under different genetic models.</p> <p>Results</p> <p>Using univariate analysis of rs8073069, rs9904341 and rs1042489 under different genetic models, no statistically significant difference was found in genotype or allele distribution of HCC cases relative to the controls (<it>P </it>> 0.05). Linkage disequilibrium (LD) analysis showed that these loci were in LD. Multivariate logistic regression indicated that with no G-C-T haplotype as reference, the haplotype of G-C-T from these loci was associated with a lower risk for HCC under the recessive model (<it>OR = </it>0.46, 95% confidence interval (<it>CI</it>): 0.24~0.90, <it>P </it>= 0.023). Both HBsAg+ and the medical history of viral hepatitis type B were risk factors for HCC. However, no statistically significant haplotype-environment interaction existed.</p> <p>Conclusions</p> <p>No association between rs8073069, rs9904341 or rs1042489 in <it>survivin </it>gene and the risk of HCC is found in Chinese han population, but rs8073069G-rs9904341C- rs1042489T is perhaps a protective haplotype for HCC.</p

HIV-1 Polymerase Inhibition by Nucleoside Analogs: Cellular- and Kinetic Parameters of Efficacy, Susceptibility and Resistance Selection

Nucleoside analogs (NAs) are used to treat numerous viral infections and cancer. They compete with endogenous nucleotides (dNTP/NTP) for incorporation into nascent DNA/RNA and inhibit replication by preventing subsequent primer extension. To date, an integrated mathematical model that could allow the analysis of their mechanism of action, of the various resistance mechanisms, and their effect on viral fitness is still lacking. We present the first mechanistic mathematical model of polymerase inhibition by NAs that takes into account the reversibility of polymerase inhibition. Analytical solutions for the model point out the cellular- and kinetic aspects of inhibition. Our model correctly predicts for HIV-1 that resistance against nucleoside analog reverse transcriptase inhibitors (NRTIs) can be conferred by decreasing their incorporation rate, increasing their excision rate, or decreasing their affinity for the polymerase enzyme. For all analyzed NRTIs and their combinations, model-predicted macroscopic parameters (efficacy, fitness and toxicity) were consistent with observations. NRTI efficacy was found to greatly vary between distinct target cells. Surprisingly, target cells with low dNTP/NTP levels may not confer hyper-susceptibility to inhibition, whereas cells with high dNTP/NTP contents are likely to confer natural resistance. Our model also allows quantification of the selective advantage of mutations by integrating their effects on viral fitness and drug susceptibility. For zidovudine triphosphate (AZT-TP), we predict that this selective advantage, as well as the minimal concentration required to select thymidine-associated mutations (TAMs) are highly cell-dependent. The developed model allows studying various resistance mechanisms, inherent fitness effects, selection forces and epistasis based on microscopic kinetic data. It can readily be embedded in extended models of the complete HIV-1 reverse transcription process, or analogous processes in other viruses and help to guide drug development and improve our understanding of the mechanisms of resistance development during treatment

Correlated electronic decay in expanding clusters triggered by intense XUV pulses from a Free-Electron-Laser

Irradiation of nanoscale clusters and large molecules with intense laser pulses transforms them into highly-excited non- equilibrium states. The dynamics of intense laser-cluster interaction is encoded in electron kinetic energy spectra, which contain signatures of direct photoelectron emission as well as emission of thermalized nanoplasma electrons. In this work we report on a so far not observed spectrally narrow bound state signature in the electron kinetic energy spectra from mixed Xe core - Ar shell clusters ionized by intense extreme-ultraviolet (XUV) pulses from a free-electron-laser. This signature is attributed to the correlated electronic decay (CED) process, in which an excited atom relaxes and the excess energy is used to ionize the same or another excited atom or a nanoplasma electron. By applying the terahertz field streaking principle we demonstrate that CED-electrons are emitted at least a few picoseconds after the ionizing XUV pulse has ended. Following the recent finding of CED in clusters ionized by intense near-infrared laser pulses, our observation of CED in the XUV range suggests that this process is of general relevance for the relaxation dynamics in laser produced nanoplasmas

Studying and simulating the three-dimensional arrangement of droplets

We present some work in progress on the development of a probabilistic chemical compiler, being able to make a plan of how to create a three-dimensional agglomeration of artificial hierarchical cellular constructs. These programmable discrete units cover a wide variety of technical innovations, like a portable biochemical laboratory being able to produce macromolecular medicine on demand, and of scientific investigations, like contributions to questions regarding the origin of life. This paper focuses on one speci c issue of developing such a compiler, namely the problem of simulating the experimentally observed spatial transition from an originally one-dimensional lineup of droplets into a three-dimensional, almost spherical arrangement, in which the droplets form a network via bilayers connecting them and in which they are contained within some outer hull. The network created by the bilayers allows the droplets to communicate with each other and to exchange chemicals contained within them, thus enabling a complex successive biochemical reaction scheme