Quasi-Monte Carlo simulation of discrete-time Markov chains on multidimensional state spaces

International audienc

Randomized quasi-Monte Carlo simulation of Markov chains with an ordered state space

International audienc

Quasi-Monte Carlo simulation of discrete-time Markov chains on multidimensional state spaces

International audienc

Selective Hypoxia-Cytotoxin 7-Fluoro-2-Aminophenazine 5,10-Dioxide: Toward Candidate-to-Drug Stage in the Drug-Development Pipeline

7-Fluoro-2-aminophenazine 5,10-dioxide, 1, has displayed in vitro bioreductive selective cytotoxicity, which could acts towards tumors containing hypoxic regions. In this work, we describe some preclinical studies of compound 1 confirming its in vivo antitumor activity. The synthesis of compound 1 was scaled up to 3 g improving the micro-scale yield. Some drug-like properties for compound 1 were theoretically-predicted and others, i.e. aqueous-solubility and toxicity -mutagenicity, in vivo chromosomal-aberrations and ip acute LD50-, were experimentally confirmed. Antitumoral activity was studied in mice bearing hypoxic 4T1-breast-tumor by assessing evolution of the tumor sizes, animal-survival and bio-chemical/hematological. Compound 1 in vivo efficacy, with the absence of systemic toxicity, was confirmed. Results highlight the potential of 7-fluoro-2-aminophenazine 5,10-dioxide as promissory therapeutic agentfor solid tumors.Fil: Dávila, Belén. Universidad de la República; UruguayFil: Sánchez, C.. Universidad de la República; UruguayFil: Fernandez, M.. Universidad de la República; UruguayFil: Cerecetto, H.. Universidad de la República; UruguayFil: Lecot, N.. Universidad de la República; UruguayFil: Cabral, P.. Universidad de la República; UruguayFil: Glisoni, Romina Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Nanobiotecnología. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Nanobiotecnología; ArgentinaFil: González, M.. Universidad de la República; Urugua

Polymerase-chain-reaction-based semi-quantification of hepatitis D viraemia in patients treated with high doses of alpha 2b interferon

To study the antiviral efficacy of high doses of alpha 2b interferon (alpha 2b-IFN) for chronic hepatitis D treatment, we used polymerase-chain-reaction(PCR)-based semi-quantitative detection of HDV RNA. The semi-quantification method used was based on the appearance of a positive amplification signal as a function of the number of PCR cycles. By amplifying dilutions (10(-1)-10(-8)) of an HDV-positive woodchuck liver RNA, we confirmed that exponential amplification efficacy occurred at between 20 and 30 cycles. Positive signals were observed from dilution 10(-2) (gel electrophoresis after 20 cycles of PCR) to dilution 10(-7) (hybridization after 30 cycles of PCR). To characterize the HDV RNA level in sera of 8 patients treated with alpha 2b-IFN (10 MU/3 times a week) for 1 year, we extracted RNA from serum samples taken every 6 months. All samples were amplified in parallel for 20 and 30 PCR cycles. Analysis of HDV cDNA after ethidium bromide/agarose gel electrophoresis and after molecular hybridization (100 times more sensitive than gel analysis), enabled us to grade the signals observed from negative to positive as 1+, 2+, 3+ and 4+, with all results being positive. Three types of evolution of HDV viraemia were evidenced among the 8 treated patients. HDV replication continued to occur at a high level at the 6th and 12th month in 2 patient sera. For 2 other patients, an HDV RNA decrease or disappearance was evidenced in the serum at the 6th month; however, viral replication recurred at a higher level at the 12th month.(ABSTRACT TRUNCATED AT 250 WORDS

High CD8⁺ tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy

Aims: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. Methods and results: The prognostic significance of OAC-associated CD3+, CD4+, CD8+, forkhead box protein 3 (FoxP3+) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). Conclusion: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.</p