Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

Inactivation of Listeria monocytogenes, Staphylococcus aureus, and Salmonella enterica under High Hydrostatic Pressure: A Quantitative Analysis of Existing Literature Data

ABSTRACT High hydrostatic pressure processing (HPP) is a mild preservation technique, and its use for processing foods has been widely documented in the literature. However, very few quantitative synthesis studies have been conducted to gather and analyze bacterial inactivation data to identify the mechanisms of HPP-induced bacterial inactivation. The purpose of this study was to conduct a quantitative analysis of three-decimal reduction times (t3δ) from a large set of existing studies to determine the main influencing factors of HPP-induced inactivation of three foodborne pathogens (Listeria monocytogenes, Staphylococcus aureus, and Salmonella enterica) in various foods. Inactivation kinetics data sets from 1995 to 2017 were selected, and t3δ values were first estimated by using the nonlinear Weibull model. Bayesian inference was then used within a metaregression analysis to build and test several models and submodels. The best model (lowest error and most parsimonious) was a hierarchical mixed-effects model including pressure intensity, temperature, study, pH, species, and strain as explicative variables and significant factors. Values for t3δ and ZP associated with inactivation under HPP were estimated for each bacterial pathogen, with their associated variability. Interstudy variability explained most of the variability in t3δ values. Strain variability was also important and exceeded interstudy variability for S. aureus, which prevented the development of an overall model for this pathogen. Meta-analysis is not often used in food microbiology but was a valuable quantitative tool for modeling inactivation of L. monocytogenes and Salmonella in response to HPP treatment. Results of this study could be useful for refining quantitative assessment of the effects of HPP on vegetative foodborne pathogens or for more precisely designing costly and labor-intensive experiments with foodborne pathogens.

To randomize, or not to randomize, that is the question: using data from prior clinical trials to guide future designs

Background Understanding the value of randomization is critical in designing clinical trials. Here, we introduce a simple and interpretable quantitative method to compare randomized designs versus single-arm designs using indication-specific parameters derived from the literature. We demonstrate the approach through application to phase II trials in newly diagnosed glioblastoma (ndGBM). Methods We abstracted data from prior ndGBM trials and derived relevant parameters to compare phase II randomized controlled trials (RCTs) and single-arm designs within a quantitative framework. Parameters included in our model were (i) the variability of the primary endpoint distributions across studies, (ii) potential for incorrectly specifying the single-arm trial’s benchmark, and (iii) the hypothesized effect size. Strengths and weaknesses of RCT and single-arm designs were quantified by various metrics, including power and false positive error rates. Results We applied our method to show that RCTs should be preferred to single-arm trials for evaluating overall survival in ndGBM patients based on parameters estimated from prior trials. More generally, for a given effect size, the utility of randomization compared with single-arm designs is highly dependent on (i) interstudy variability of the outcome distributions and (ii) potential errors in selecting standard of care efficacy estimates for single-arm studies. Conclusions A quantitative framework using historical data is useful in understanding the utility of randomization in designing prospective trials. For typical phase II ndGBM trials using overall survival as the primary endpoint, randomization should be preferred over single-arm designs.

Body mass index and survival from amyotrophic lateral sclerosis

BackgroundSeveral studies have examined the relationship between body mass index (BMI) and survival from amyotrophic lateral sclerosis (ALS). Many indicate that low BMI at diagnosis or during follow-up may be associated with accelerated progression and shortened survival. This study systematically evaluated the relationship between BMI and survival in patients with ALS.MethodsThe PubMed database was searched to identify all available studies reporting time-to-event data. Eight studies with 6,098 patients fulfilled the eligibility criteria. BMI was considered a continuous and ordered variable. Interstudy heterogeneity was assessed by the Cochran Q test and quantified by the I2 metric. Fixed- or random-effects odds ratios summarized pooled effects after taking interstudy variability into account. Significance was set at p < 0.05.ResultsThe ALS survival hazard ratio (HR) decreased approximately by 3% (95% confidence interval [CI]: 2%–5%) for each additional BMI unit when BMI was considered a continuous variable. When BMI was considered a categorical variable, the HRs for “normal” BMI vs “overweight” BMI and “obese” BMI were estimated to be as high as 0.91 (95% CI: 0.79–1.04) and 0.78 (95% CI: 0.60–1.01), respectively. The HR for the comparison of the “normal” BMI vs “underweight” BMI was estimated to be as high as 1.94 (95% CI: 1.42–2.65).ConclusionsBMI is significantly and inversely associated with ALS survival.

Survival in previously treated advanced NSCLC: Pemetrexed versus best supportive care (BSC)

17015 Background: Patients with advanced NSCLC who progress following initial treatment have several approved secondary treatment options including single agent intravenous chemotherapy (docetaxel or pemetrexed) and an oral EGFR tyrosine kinase inhibitor (erlotinib). Docetaxel and erlotinib were shown in randomized trials to have an overall survival (OS) advantage over BSC. On the other hand, pemetrexed was approved based on a randomized trial (JMEI) in which it showed clinically equivalent survival to docetaxel. Investigators felt that it was not ethical to compare pemetrexed to BSC because docetaxel was approved in that setting. However, indirect comparisons of pemetrexed with BSC are possible and are legitimate statistically. Methods: We used summary data from JMEI and TAX317(b) in the analysis. Studies BR21 and ISEL provide relevant data from recent trials with a BSC arm. We based comparisons on the logarithms of these HRs and their variances in proportional hazards models, accounting for interstudy variability. Results: Patients in these studies had similar prognostic characteristics. Docetaxel in TAX317(b) showed a significant survival benefit over BSC (HR = 0.56, 95% CI 0.35–0.88). In JMEI, the pemetrexed over docetaxel HR was 0.99 (95% CI 0.82–1.20). The HR of pemetrexed over BSC for survival was 0.55 (95% CI 0.33–0.90). The similarity of median OS for the placebo (or BSC) arms of studies TAX317(b), BR21 and ISEL supports the above analysis. Conclusions: In comparison with BSC pemetrexed lowers the hazard of mortality in previously treated advanced NSCLC by an estimated 45% (95% CI 10%-67%). [Table: see text] [Table: see text]