A risk signature-based on metastasis-associated genes to predict survival of patients with osteosarcoma

Osteosarcoma (OS) is the most common primary solid malignant bone tumor, and its metastasis is a prominent cause of high mortality in patients. In this study, a prognosis risk signature was constructed based on metastasis-associated genes. Four microarrays datasets with clinical information were downloaded from Gene Expression Omnibus, and 256 metastasis-associated genes were identified by limma package. Further, a protein-protein interaction network was constructed, and survival analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments data matrix, identifying 19 genes correlated with prognosis. Six genes were selected by the least absolute shrinkage and selection operator regression for multivariate cox analysis. Finally, a three-gene (MYC, CPE, and LY86) risk signature was constructed, and datasets GSE21257 and GSE16091 were used to validate the prediction efficiency of the signature. The survival times of low- and high-risk groups were significantly different in the training set and validation set. Additionally, gene set enrichment analysis revealed that the genes in the signature may affect the cell cycle, gap junctions, and interleukin-6 production. Therefore, the three-gene survival risk signature could potentially predict the prognosis of patients with OS. Further, proteins encoded by CPE and LY86 may provide novel insights into the prediction of OS prognosis and therapeutic targets.     

ROC-guided survival trees and ensembles

Tree-based methods are popular nonparametric tools in studying time-to-event outcomes. In this article, we introduce a novel framework for survival trees and ensembles, where the trees partition the dynamic survivor population and can handle time-dependent covariates. Using the idea of randomized tests, we develop generalized time-dependent receiver operating characteristic (ROC) curves for evaluating the performance of survival trees. The tree-building algorithm is guided by decision-theoretic criteria based on ROC, targeting specifically for prediction accuracy. To address the instability issue of a single tree, we propose a novel ensemble procedure based on averaging martingale estimating equations, which is different from existing methods that average the predicted survival or cumulative hazard functions from individual trees. Extensive simulation studies are conducted to examine the performance of the proposed methods. We apply the methods to a study on AIDS for illustration.     

Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case–control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA + AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR = 1.20, 95%CI: 1.03–1.40, P = 0.021; MI: RR = 1.32, 95%CI: 1.11–1.57, P = 0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR = 0.92, 95%CI: 0.73–1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84–1.03, P = 0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.     

Enhancing the egg's natural defence against bacterial penetration by increasing cuticle deposition

The cuticle is a proteinaceous layer covering the avian egg and is believed to form a defence to microorganism ingress. In birds that lay eggs in challenging environments, the cuticle is thicker, suggesting evolutionary pressure; however, in poultry, selection pressure for this trait has been removed because of artificial incubation. This study aimed to quantify cuticle deposition and to estimate its genetic parameters and its role on trans‐shell penetration of bacteria. Additionally, cuticle proteins were characterised to establish whether alleles for these genes explained variation in deposition. A novel and reliable quantification was achieved using the difference in reflectance of the egg at 650 nm before and after staining with a specific dye. The heritability of this novel measurement was moderate (0.27), and bacteria penetration was dependent on the natural variation in cuticle deposition. Eggs with the best cuticle were never penetrated by bacteria (P < 0.001). The cuticle proteome consisted of six major proteins. A significant association was found between alleles of one of these protein genes, ovocleidin‐116 (MEPE), and cuticle deposition (P = 0.015) and also between alleles of estrogen receptor 1 (ESR1) gene and cuticle deposition (P = 0.008). With the heritability observed, genetic selection should be possible to increase cuticle deposition in commercial poultry, so reducing trans‐generational transmission of microorganisms and reversing the lack of selection pressure for this trait during recent domestication.     

Phlebotominae of epidemiological importance in cutaneous leishmaniasis in northwestern Argentina: risk maps and ecological niche models

In Argentina, 58.2% out of the 8126 Cutaneous Leishmaniasis (CL) incident cases accumulated from 1954 to 2006 were reported in the provinces of Salta and Jujuy. The aim of this study was to develop an exploratory risk map and a potential distribution map of the vector, in order to offer recommendations for CL prevention. A total of 12 079 Phlebotominae (Diptera: Psychodidae) belonging to the species Lutzomyia neivai (Pinto), Lu. migonei (França), Lu. cortelezzii (Brèthes), Lu. shannoni (Dyar), Lu. quinquefer (Dyar) and Brumptomyia spp. (França & Parrot) were captured. Potential distribution models were created for two species, Lu. neivai (incriminated vector of Leishmania braziliensis) and Lu. migonei, associated with domestic animals in Argentina and that in turn could be involved as a link between zoonotic transmission cycles and anthropozoonotic. The Maximum Entropy Modeling System (MaxEnt) was used. The Jackknife test was performed, and the ‘rainfall of the driest month’ was the variable that best generalized the models. Accuracy was evaluated by the area under the curve (AUC) and validated by the Cohen's kappa index. This approximation provides a new analytical resource of high potential for the prevention of the disease, in order to allocate resources properly and to develop the most suitable strategies for action.     

Genes alternations with exposure time of environmental factors

A theoretical model discussing the environmental factors (EFs) effect of exposure time on genes, which leads to human diseases, is presented using multi-logistic model. The advantages and limitations of this model are discussed in terms of its usefulness for simulating genetic samples. It has been shown that EFs affect genes with the same degree both at high exposure level, low exposure time and at low exposure level, high exposure time.     

Selenium and selenium-antagonistic elements in nutritional cancer prevention

Selenium is an essential trace element with antioxidative, antimutagenic, antiviral and anticarcinogenic properties. There is increasing evidence that the dietary selenium intakes are sub-optimal in the populations of many countries and that human cancer mortalities would significantly decline if additional selenium was made available either through supplementation or the fortification of certain foods. An important property of selenium is its interaction with other elements that may be present in foods, the water, the workplace and the environment, e.g. As, Cu, Ni, Co, Cr, Mn, Zn, Cd, Sn, Pb, Hg, Bi, Mo, Ag, Au, etc. The sequestration of elements by selenium represents an efficient natural detoxification mechanism for some of these elements but also results in the physiological inactivation of selenium. Animal experiments confirm that the chronic exposure to low levels of these elements abolishes the cancer-protective effect of selenium. Human cancer is likewise significantly determined by the interactions of selenium with other elements, as evidenced by epidemiological, ecological and case-control studies. Cadmium, for example, is a key risk-increasing element for prostate cancer; for breast cancer, Cd, Cr, Zn are mainly contributing; for bronchial cancer (in smelter workers), Cd, As, Cr, Sb, Co, La, all these elements are in a reciprocal relationship with Se. While selenium remains the key cancer-protective trace element, the interpretation of its mode of action necessitates consideration of the effects of selenium antagonistic elements.     

Working on Sundays–Effects on Safety,Health, and Work-life Balance

Several attributes of the work schedule can increase the risk of occupational injuries and accidents, health impairments, and reduced social participation. Although previous studies mainly focused on the effects of shiftwork and long working hours on employee health and safety, there is little evidence of a potential negative impact of working Sundays on the incidence of occupational accidents, health impairments, and work-life balance. A representative sample of employed workers in 31 member and associated states of the European Union (n?=?23,934) served as the database for a cross-sectional analysis. The sample was collected via face-to-face interviews in the year 2005. The association of the risks of occupational accidents, health impairments, and decreases in work-life balance with working Sundays was calculated using logistic regression models, controlling for potential confounders, such as shiftwork, workload, and demographic characteristics. The results indicated that working one or more Sundays/month was associated with increase both in the risk of reporting one or more health impairments (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.06–1.29) and poorer work-life balance (OR: 1.15, 95% CI: 1.02–1.28). These effects remained after controlling for potentially confounding factors, such as other work schedule attributes, intensity of physical and mental workload, and individual characteristics. Furthermore, working Sundays was also related to increased risk of occupational accidents within the last year (OR: 1.34, 95% CI: 1.03–1.73). Controlling again for individual, workload, and working-time characteristics, a significant association with accident risk, however, remained only in work sectors with low a priori risk of occupational accidents (OR: 1.40, 95% CI: 1.02–1.91), although the increased risk could be observed for both medium and high a priori risk sectors working Sundays (without controlling for additional confounders). The results thus indicate that the detrimental effects of working Sundays on safety, health, and social well-being should be taken into account when designing work schedules. The potential hazards to employees' safety, health, and work-life balance, in particular, should be considered in discussions concerning extending work on Sundays in certain sectors, e.g., retail. (Author correspondence: awirtz@hsph.harvard.edu)     

Cardiovascular Risk of Resistant Hypertension: Dependence on Treatment-Time Regimen of Blood Pressure–Lowering Medications

In resistant hypertension, ingesting one or more blood pressure (BP)-lowering medications at bedtime is associated with significant reduction of sleep-time BP, a sensitive prognostic marker of cardiovascular disease (CVD) risk. This randomized trial investigated if bedtime therapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional, morning-time therapy with all medications. We conducted a prospective, open-label, blinded-endpoint trial on 776 patients (387 men/389 women) with resistant hypertension, 61.6?±?11.2 (mean?±?SD) yrs of age. Patients were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. BP was measured by ambulatory monitoring for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required. After a median follow-up of 5.4 yrs (range, .5–8.5 yrs), participants ingesting ≥1 hypertension medications at bedtime showed a significantly lower hazard ratio (HR) of total CVD events (adjusted by age, sex, and diabetes) than those ingesting all medications upon awakening (.38 [95% CI: .27–.55]; number of events 102 vs. 41; p?<?.001). The difference between groups in the adjusted HR of major CVD events (a composite of CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also statistically significant (.35 [95% CI: .18–.68]; number of events 32 vs. 12; p?=?.002). At the last evaluation, patients treated with the bedtime versus awakening-time-treatment regimen showed significantly lower sleep-time systolic/diastolic BP mean values (121.6/65.4 vs. 113.0/61.1?mm Hg; p?<?.001) and higher prevalence of controlled ambulatory BP (61% vs. 46%; p?<?.001). The progressive decrease in the sleep-time systolic BP mean during follow-up was the most significant predictor of event-free survival (15% risk reduction per 5?mm Hg decreased asleep systolic BP mean). Among patients with resistant hypertension, ingestion of at least one hypertension medication at bedtime, compared with all medications upon waking, resulted in improved ambulatory BP control and fewer hard and soft CVD events. (Author correspondence: rhermida@uvigo.es)