Data-driven prioritization and preclinical evaluation of therapeutic targets in glioblastoma

Background: Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM. Methods: mRNA expression data of patient-derived GBM (n = 1279) and normal brain tissue (n = 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo. Results: We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including EGFR and VEGFA, have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes, RRM2, MAPK9 (JNK2, SAPK1a), and XIAP play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth. Conclusions: The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration

The Lipid Profile and Mortality Risk in Elderly Type 2 Diabetic Patients: A Ten-Year Follow-Up Study (ZODIAC-13)

BACKGROUND:The precise relationship between the lipid profile and mortality in elderly patients with type 2 diabetes mellitus (T2DM) remains unclear. The aim of this study was to investigate the relationship between the lipid profile over time, and mortality in elderly patients with T2DM. METHODS AND FINDINGS:In 1998, 881 primary care patients with T2DM aged 60 years and older participated in the ZODIAC study, a prospective observational study. The cohort was divided into two age categories: 60-75 years and older than 75 years. Updated means of all lipid profile indices were calculated after a median follow-up time of 9.8 years. These values were used as time dependent covariates in a Cox proportional hazard model. The cholesterol-HDL ratio and LDL-cholesterol were positively related to both all-cause and cardiovascular mortality in the low age group. In contrast, except for the triglyceride level, none of the other lipid profile indices were related to all-cause mortality in patients aged over 75 years. The mortality risk decreased by 17% (95%CI: 5% to 27%) for each 1 mmol/L higher serum level of triglycerides. The relationships between the various lipid profile indices and cardiovascular mortality were not significant. However, the results were different after stratification for diabetes duration. In the subgroup of elderly patients with a diabetes duration of 8 years and longer, higher lipids were predictive of increased cardiovascular mortality. The main limitation of this study is its observational design, which prevents us drawing conclusions about causality. CONCLUSION:Although the lipid profile was not predictive in the overall group of elderly patients, higher lipids were related to increased cardiovascular mortality in patients with diabetes of long duration. In order to make valid recommendations concerning lipid-lowering treatment, a randomized controlled trial or a meta-analysis concerning this specific population is mandatory

Analysis of variance for testing method of cement in determination of strength

AbstractThe statistical tools such as descriptive statistics, full factorial design and analysis of source of variation were used to identify the potential factors that impact the validity of testing method for determining the strength of cement. The results showed that personal error impacted both accuracy and precision of test greatly. Experimental time associated with temperature fluctuation resulted in strength variation but did not impact the precision of test in all curing ages. Different compactions did not impact the precision of test but resulted in the strength variation on 3 d and 28 d significantly. Different methods for the initial moist air curing significantly impacted the precision of testing method and resulted in the strength variation of cement on 1 d

Addition of sulphonylurea to metformin does not relevantly change body weight:a prospective observational cohort study (ZODIAC-39)

Aim: To investigate changes in body weight trajectories after the addition of individual sulphonylureas (SUs) to metformin in patients with type 2 diabetes. Materials and methods: We conducted a retrospective observational cohort study, in a primary care setting in the Netherlands. Patients aged >= 18 years with type 2 diabetes who were included in the ZODIAC cohort between 1998 and 2012 and who received metformin monotherapy at inclusion (n = 29 195), and had used metformin as monotherapy for at least 1 year before receiving dual therapy through the addition of an SU for at least 1 year were eligible for inclusion. The primary outcome was within-drug yearly change in body weight after receiving add-on therapy with individual SUs during 5 years of follow-up. The secondary outcome was within-drug yearly change in glycated haemoglobin (HbA1c). Annual changes in weight and HbA1c were estimated with linear mixed models, adjusted for age, gender and diabetes duration. Results: A total of 2958 patients were included. No significant weight changes were observed within and between any of the individual SUs after treatment intensification (p = 0.24). In addition, no significant difference in weight between the add-on therapy combinations was observed (p = 0.26). The average HbA1c the year before intensification was 7.2% (55 mmol/mol) and dropped below 7.0% (53 mmol/mol) the year after. Conclusions: In patients with type 2 diabetes treated in primary care, strict glycaemic control can be maintained with SUs used as add-on therapy to metformin, without the offset of relevant weight changes

Within-class differences in cancer risk for sulfonylurea treatments in patients with type 2 diabetes (ZODIAC-55) - a study protocol

Background: Patients with type 2 diabetes (T2D) are at increased risk for developing cancer. As approximately 8% of the world's population is living with T2D, even a slight increase in cancer risk could result in an enormous impact on the number of persons developing cancer. In addition, several glucose lowering drug classes for treating patients with T2D have been associated with a difference in risk of cancer overall, and especially for obesity related cancers. In what way and to what degree cancer risk is modified by the use of different sulfonylureas (SU) is unclear. The primary aim of this study will be to evaluate within-class SU differences in obesity related cancer risk. Secondary aims will be to investigate within-class SU differences in risk for all cancers combined and site-specific cancers separately (i.e. breast, colorectal, prostate, bladder and lung cancer) and to account for duration-response relationships between individual SU use and cancer risk. Methods: Patients will be selected from a Dutch primary care cohort of patients with T2D linked with the Dutch Cancer Registration (ZODIAC-NCR). Within this cohort study annually collected clinical data (e.g. blood pressure, weight, HbA1c) and nationwide data on cancer incidence are available. Time-dependent cox proportional hazard analyses will be performed to evaluate SU cancer risk, adjusted for potential confounders. Discussion: This study will be the first prospective cohort study investigating within-class SU differences in cancer risk and could contribute to improved decision making regarding the individual drugs within the class of SUs, and possibly improve quality of life and result in an increased cost-effectiveness of healthcare in patients with T2D

Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation

A key step in heart development is the coordinated development of the atrioventricular canal (AVC), the constriction between the atria and ventricles that electrically and physically separates the chambers, and the development of the atrioventricular valves that ensure unidirectional blood flow. Using knock-out and inducible overexpression mouse models, we provide evidence that the developmentally important T-box factors Tbx2 and Tbx3, in a functionally redundant manner, maintain the AVC myocardium phenotype during the process of chamber differentiation. Expression profiling and ChIP-sequencing analysis of Tbx3 revealed that it directly interacts with and represses chamber myocardial genes, and induces the atrioventricular pacemaker-like phenotype by activating relevant genes. Moreover, mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa. Tbx2 and Tbx3 trigger development of the cushions through a regulatory feed-forward loop with Bmp2, thus providing a mechanism for the co-localization and coordination of these important processes in heart development

Effects of three frequencies of self-monitored blood glucose on HbA1c and quality of life in patients with type 2 diabetes with once daily insulin and stable control: a randomized trial

Abstract Objective The optimal frequency of self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes (T2DM) with stable glycemic control is unknown. This study investigated effects of 3 frequencies of SMBG on glycemic control and quality of life after 9 months in patients using one long-acting insulin injection a day. In an open-label, multi-center, primary-care, parallel (1:1:1) randomized trial in the Netherlands including patients with T2DM, HbA1c ≤ 58 mmol/mol (≤ 7.5%), stable glycemic control, treated with one insulin injection daily, three frequencies of 4-point glucose measurements (before meals and bedtime) were weekly (n = 22), every 2 weeks (n = 16) and monthly (n = 20) were compared. Results A total of 58 patients with T2DM were included by 38 general practitioners, which was lower then anticipated. There were no significant between group differences in HbA1c (mmol/mol); group C compared to A and B; − 2.7 (95% CI − 6.4, 1.0) and − 1.0 (95% CI − 4.9, 3.0) and quality of life. Baring in mind the lower than anticipated inclusion rate, there were no significant differences in HbA1c and quality of life between three different frequencies of SMBG in patients with stable glycemic control using one long-acting insulin injection. Trial registration NCT01460459, registered 10-2011, recruitment between 05-2011 and 12-201

Efficacy of device-guided breathing for hypertension in blinded, randomized, active-controlled trials: A meta-analysis of individual patient data

IMPORTANCE: Device-guided breathing (DGB) is recommended by the American Heart Association for its blood pressure-lowering effects. Most previous studies that showed beneficial effects on blood pressure had low methodological quality and only investigated short-term blood pressure effects. OBJECTIVE: To assess the efficacy of DGB on blood pressure in a meta-analysis of individual patient data from blinded, randomized controlled trials with an active control group. DATA SOURCES: MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane Library. STUDY SELECTION: Included were randomized studies of at least 4 weeks' duration, with a single- or double-blind design and an active control group. Bias was assessed with the Cochrane risk of bias tool, and analyses were performed with linear mixed models. DATA EXTRACTION AND SYNTHESIS: Articles were searched in MEDLINE (using PubMed), EMBASE, and the Cochrane Library. MAIN OUTCOMES AND MEASURES: Office blood pressure. RESULTS: From the 15 selected abstracts, 5 studies were suitable for inclusion. Individual patient data from 2 of 5 studies were not provided. The effect of DGB on office systolic blood pressure compared with music therapy or a sham device was 2.2 mm Hg (95% CI, -2.7 to 7.0) in favor of the control group; DGB did not significantly lower office diastolic blood pressure (0.2 mm Hg [95% CI, -2.8 to 3.1] in favor of DGB). CONCLUSIONS AND RELEVANCE: All trials included in the analysis had a short follow-up period; therefore, no recommendations could be made regarding hypertension treatment. Treatment with DGB did not significantly lower office blood pressure compared with a sham procedure or music therapy