Prediction of Inhibitory Activity of Epidermal Growth Factor Receptor Inhibitors Using Grid Search-Projection Pursuit Regression Method

The epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) is an important protein target for anti-tumor drug discovery. To identify potential EGFR inhibitors, we conducted a quantitative structure–activity relationship (QSAR) study on the inhibitory activity of a series of quinazoline derivatives against EGFR tyrosine kinase. Two 2D-QSAR models were developed based on the best multi-linear regression (BMLR) and grid-search assisted projection pursuit regression (GS-PPR) methods. The results demonstrate that the inhibitory activity of quinazoline derivatives is strongly correlated with their polarizability, activation energy, mass distribution, connectivity, and branching information. Although the present investigation focused on EGFR, the approach provides a general avenue in the structure-based drug development of different protein receptor inhibitors

Effect of gastro-esophageal reflux symptoms on the risk of Barrett's esophagus: A systematic review and meta-analysis

Background and Aim Gastro-esophageal reflux (GER) is the main predisposing factor for Barrett's esophagus (BE). A more precise estimate of the association of GER symptoms with the risk of BE would be important to prioritize endoscopic screening. We conducted a systematic review and meta-analysis to examine this issue. Methods MEDLINE, EMBASE, and EMBASE Classic were searched to identify cross-sectional studies that reported the prevalence of BE based on presence of GER symptoms. The prevalence of BE was compared according to presence or absence of GER symptoms using an odds ratio (OR), with a 95% confidence interval (CI). Specificity and sensitivity of GER symptoms for predicting BE was calculated. Results Of 10,463 citations evaluated, 19 studies reported the prevalence of BE in 43,017 subjects. The pooled OR among individuals with weekly GER symptoms compared with those without was 1.67 (95% CI 1.30-2.15) for endoscopically suspected BE, and 2.42 (95% CI 1.59-3.68) for histologically confirmed BE. No significant association was found between weekly GER symptoms and the presence of short segment BE (OR 1.30; 95% CI 0.86-1.97), whereas a strong association was present with long segment BE, with an OR of 6.30 (95% CI 2.26-17.61). Conclusions Gastro-esophageal reflux symptoms are associated with an increased odds of BE, with a further increase when weekly symptoms are present. Overall, GER symptoms showed low sensitivity and specificity for predicting BE; however, a strong association was found between weekly GER symptoms and long segment BE, but not short segment BE, suggesting that it may be worth considering screening individuals with weekly GER symptoms to rule out long segment BE

Standard Bismuth Quadruple Therapy versus Concomitant Therapy for the First-Line Treatment of Helicobacter pylori Infection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

(1) Background: Whether standard bismuth quadruple therapy (BQT) is superior to concomitant therapy for the first-line treatment of Helicobacter (H.) pylori infection is unclear. The aim of this systematic review and meta-analysis was to compare the efficacy of standard BQT versus concomitant therapy for H. pylori eradication in subjects naive to treatment. (2) Methods: Online databases were searched for randomized controlled trials. We pooled risk ratio (RR) of individual studies for dichotomous outcomes using a random-effect model. (3) Results: Six studies with 1810 adults were included. Overall intention-to-treat (ITT) eradication rate was 87.4% with BQT and 85.2% with concomitant therapy (RR 1.01, 95%CI:0.94-1.07). Subgroup analysis of five Asian studies showed a small but significant superiority of BQT over concomitant therapy (87.5% vs. 84.5%; RR 1.04, 95%CI:1.01-1.08). Pooling four studies at low risk of bias yielded a similar result (88.2% vs. 84.5%; RR 1.05, 95%CI:1.01-1.09). There was no difference between the regimens in the frequency of adverse events (RR = 0.97, 95%CI:0.79-1.2). (4) Conclusions: The efficacy of BQT seems to be similar to concomitant therapy, with similar side effect profile. However, BQT showed a small but significant benefit over concomitant therapy in Asian populations and in studies at low risk of bias

The Heterogeneity of Skewness in T2W-Based Radiomics Predicts the Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Our study aimed to investigate whether radiomics on MRI sequences can differentiate responder (R) and non-responder (NR) patients based on the tumour regression grade (TRG) assigned after surgical resection in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT). Eighty-five patients undergoing primary staging with MRI were retrospectively evaluated, and 40 patients were finally selected. The ROIs were manually outlined in the tumour site on T2w sequences in the oblique-axial plane. Based on the TRG, patients were grouped as having either a complete or a partial response (TRG = (0,1), n = 15). NR patients had a minimal or poor nCRT response (TRG = (2,3), n = 25). Eighty-four local first-order radiomic features (RFs) were extracted from tumour ROIs. Only single RFs were investigated. Each feature was selected using univariate analysis guided by a one-tailed Wilcoxon rank-sum. ROC curve analysis was performed, using AUC computation and the Youden index (YI) for sensitivity and specificity. The RF measuring the heterogeneity of local skewness of T2w values from tumour ROIs differentiated Rs and NRs with a p-value ≈ 10−5; AUC = 0.90 (95%CI, 0.73–0.96); and YI = 0.68, corresponding to 80% sensitivity and 88% specificity. In conclusion, higher heterogeneity in skewness maps of the baseline tumour correlated with a greater benefit from nCR

A Mediterranean Diet Mix Has Chemopreventive Effects in a Murine Model of Colorectal Cancer Modulating Apoptosis and the Gut Microbiota

Objectives: Unhealthy dietary patterns have been associated with colorectal cancer (CRC) onset while Mediterranean Diet (MD) has been proposed for CRC prevention. This study evaluated the effect of a Mediterranean Diet Mix (MD-MIX) on colonic tumors development in A/J mice fed a low-fat (LFD) or a high-fat western diet (HFWD), and injected with the procarcinogen azoxymethane (AOM).Materials and Methods: Forty A/J male mice were randomly assigned into four feeding arms (10 mice/arm; LFD, LFD-MD-MIX, HFWD, HFWD-MD-MIX) to be treated with AOM. Ten mice were exposed to the diets alone (Healthy LFD and Healthy HFWD) to be used as control. Tumor incidence and multiplicity were evaluated at sacrifice. Mucosal fatty acid content and urinary phenolic compounds were assayed by mass spectrometry. Apoptosis was evaluated by TUNEL assay and gene expression markers. Cell proliferation was evaluated by Ki67 immunohistochemistry. Microbiota composition was assessed at different time points by 16S RNA sequencing.Results: A tumor incidence of 100% was obtained in AOM-treated mice. The MD-MIX supplementation was able to reduce the number of colonic lesions in both LFD and HFWD-fed mice and to induce apoptosis, in particular in the LFD-MD-MIX arm. Moreover, a preventive effect on low-grade dysplasia and macroscopical lesions (>1 mm) development was found in HFWD-fed mice together with a regulation of the AOM-driven intestinal dysbiosis.Conclusions: MD-MIX was able to counteract CRC development in mice under different dietary backgrounds through the regulation of apoptosis and gut microbiota

Vulnerable workers in insecure jobs A meta-synthesis of qualitative findings

Job insecurity is a widespread workplace stressor that has been extensively investigated using quantitative (primarily correlational) approaches. However, scholars have also used qualitative methods to understand it. Using a critical organizational psychology framework, this meta-synthesis aimed to investigate vulnerable employees’ perceptions of job insecurity. Qualitative evidence suggested that there are meaningful differences across three categories of vulnerable employees (i.e., women, immigrants, and employees working for organizations with certain characteristics). Specifically, males perceived job insecurity as threatening their identity, while females were more concerned with deteriorating working conditions (i.e., qualitative job insecurity). Managers highlighted specific threats to their job as a function of certain organization’s characteristics and highlighted individual coping strategies, while rank-and-file employees were more concerned with powerlessness. Immigrants noted how job insecurity trickles down to their life outside of their jobs as well as the intersections of job insecurity and the legal system. Qualitative studies also investigated individual actions that participants used to attain security and corporate strategies that enhanced job insecurity. Taken together, these results challenge two neoliberal assumptions, namely (a) corporations enact strategies that increase job insecurity only as a reaction to financial exigency and (b) employment relations are overall harmonious

Analyzing workplace accident underreporting a systematic review, a Monte Carlo simulation, and a real data application

This dissertation is made up of three studies considering the most appropriate measurement and analysis of workplace accident underreporting. A systematic review (Study 1) highlighted a heterogeneous set of choices in terms of measurement and analytical strategies. Multi-item recognition-based scales seem to perform better compared to recall measures. Likewise, scholars used several analytical strategies when estimating count models. However, some of those might be inappropriate as they might lead to biased estimates. The Monte Carlo simulation (Study 2) showed that General Linear Model (GLM) with a negative binomial and Poisson distributions and Linear Model (LM) with raw outcomes returned similar parameter estimates (i.e., average marginal effects) in large samples, whereas the LM with log-transformed outcomes and GLM with binary outcomes yielded biased estimates. Analyses on a real dataset (Study 3) added two pieces of evidence: standard errors and model fit. LM with raw outcomes, GLM with a Poisson distribution, and GLM with a negative binomial distribution returned comparable standard errors in large samples, but standard errors in the LM with log-transformed outcomes and GLM with binary outcomes were underestimated. Compared with the GLM with negative binomial, LM with raw outcomes and GLM with a Poisson distribution showed worse fit to the data, likely capturing severe violations of distributional assumptions. Overall, these results suggest that LM with raw outcomes, GLM with negative binomial and Poisson distributions are equivalent in medium samples (N > 500). Six best practice recommendations are also discussed

A Memetic Algorithm for Protein Structure Prediction in a 3D-Lattice HP Model

Abstract. This paper presents a memetic algorithm with self-adaptive local search, applied to protein structure prediction in an HP, cubiclattice model. Besides describing in detail how the algorithm works, we report experimental results that justify important implementation choices, such as the introduction of speciation mechanisms and the extensive application of local search. Test runs on 48-mer chains show that the proposed algorithm has promising search capabilities.