Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

A comparative study of cell classifiers for image-based high-throughput screening

BACKGROUND: Millions of cells are present in thousands of images created in high-throughput screening (HTS). Biologists could classify each of these cells into a phenotype by visual inspection. But in the presence of millions of cells this visual classification task becomes infeasible. Biologists train classification models on a few thousand visually classified example cells and iteratively improve the training data by visual inspection of the important misclassified phenotypes. Classification methods differ in performance and performance evaluation time. We present a comparative study of computational performance of gentle boosting, joint boosting CellProfiler Analyst (CPA), support vector machines (linear and radial basis function) and linear discriminant analysis (LDA) on two data sets of HT29 and HeLa cancer cells. RESULTS: For the HT29 data set we find that gentle boosting, SVM (linear) and SVM (RBF) are close in performance but SVM (linear) is faster than gentle boosting and SVM (RBF). For the HT29 data set the average performance difference between SVM (RBF) and SVM (linear) is 0.42 %. For the HeLa data set we find that SVM (RBF) outperforms other classification methods and is on average 1.41 % better in performance than SVM (linear). CONCLUSIONS: Our study proposes SVM (linear) for iterative improvement of the training data and SVM (RBF) for the final classifier to classify all unlabeled cells in the whole data set. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2105-15-342) contains supplementary material, which is available to authorized users

Effect of Addition of Palm Oil Biodiesel in Waste Plastic Oil on Diesel Engine Performance, Emission, and Lubricity.

This research was aimed to examine the diesel engine's performance and emission of secondary fuels (SFs), comprising waste plastic oil (WPO) and palm oil biodiesel (POB), and to analyze their tribological properties. Their compositions were analyzed by gas chromatography-mass spectrometry (GC-MS). Five SFs (10-50% POB in WPO) were prepared by mechanical stirring. The results were compared to blank WPO (WPO100) and Malaysian commercial diesel (B10). WPO90 showed the maximum brake power (BP) and brake torque (BT) among the SFs, and their values were 0.52 and 0.59% higher compared to B10, respectively. The increase in POB ratio (20-50%) showed a negligible difference in BP and BT. WPO70 showed the lowest brake-specific fuel consumption among the SFs. The brake thermal efficiency (BTE) increased with POB composition. The maximum reductions in emission of hydrocarbon (HC, 37.21%) and carbon monoxide (CO, 27.10%) were achieved by WPO50 among the SFs. WPO90 showed the maximum reduction in CO2 emission (6.78%). Increasing the POB composition reduced the CO emissions and increased the CO2 emissions. All SFs showed a higher coefficient of friction (COF) than WPO100. WPO50 showed the minimal increase in COF of 2.45%. WPO90 showed the maximum reduction in wear scar diameter (WSD), by 10.34%, compared to B10. Among the secondary contaminated samples, SAE40-WPO90 showed the lowest COF, with 5.98% reduction compared to SAE40-WPO100. However, with increasing POB content in the secondary contaminated samples, the COF increased. The same trend was also observed in their WSD. Overall, WPO90 is the optimal SF with excellent potential for diesel engines

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Performance studies of the CMS strip tracker before installation

Peer reviewe

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

A Comparison of Performance, Emissions, and Lube Oil Deterioration for Gasoline–Ethanol Fuel

Over the years, due to the surge in energy demand, the use of alternative fuels has emerged as an interesting area of research. In the current work, a comparative study was conducted by employing gasoline, 6% ethanol–gasoline (E6), and 12% ethanol–gasoline (E12) in a spark-ignition engine. Performance, emissions, and lube oil damage tests were conducted at a constant load by varying engine speed. E12 showed improved performance, i.e., 7.82% higher torque and 14.69% improved brake thermal efficiency (BTE) in comparison with neat gasoline. In addition, CO, CO2, HC, and NOx emissions were found to be minimal for E12. Furthermore, lubricating oil properties (kinematic viscosity, flash point, and total base number (TBN)) and wear debris (iron, aluminum, and copper) showed a visibly improved performance with gasoline compared to E6 and E12. The highest decline in kinematic viscosity of 27.87%, compared to fresh oil, was recorded for E12. Thus, the lube oil properties have to be modified according to the chemical properties of the alternative fuel

Effect of diesel-palm biodiesel fuel with plastic pyrolysis oil and waste cooking biodiesel on tribological characteristics of lubricating oil

Engine oil's lubricity and tribological properties are changed when it is diluted with unburned fuels. SAE40 lubricating oil (LO) samples were contaminated with known percentage (5%) of fuels (commercial diesel (B10), diesel-palm biodiesel (PB) blend (B30a), and diesel–PB–plastic pyrolysis oil (PPO)–waste cooking biodiesel (WCB) blends (B20, B30b, and B40)). Utilizing four-ball tester, the influence of each of these fuels on wear and frictional properties of LO was measured, and wear type on worn surfaces was examined. LO diluted by B10 had a high coefficient of friction (COF) (11.52%) with severe abrasive and adhesive wear than mineral lubricant followed by B30a (3.00%). LO mixed with quaternary fuels had a lower COF, wear scar diameter (WSD) and polishing wear. When compared to SAE40–B30a, SAE40–B30b had fewer frictional properties with adhesive wear. When compared to SAE–40 mineral lubricant, SAE40–B20 had the smallest increase in COF value (1.90%), followed by SAE40–B30b (2.17%), and SAE40–B40 (2.63%). While the WSD values for all tested samples are reduced by 3.12, 5.68, 6.33, 11.11, and 17.33%, respectively, when compared to pure lubricant for SAE40–B10, SAE40–B20, SAE40–B30a, SAE40–B30b, and SAE4–B40. PPO and WCB in B10 are found to reduce lubricant degradation when compared to diesel-PB blend and commercial diesel

Honey, a Gift from Nature to Health and Beauty: A Review

Benefits of honey are contributed by the composition of its elements such as glucose, fructose, glucose oxidase, vitamins and phenolic compounds. For health, honey can be used to treat wounds due to the antibacterial activity conferred by the hydrogen peroxide produced by glucose oxidase in honey. Anti-inflammatory, anti-oxidant, deodorizing and tissue regeneration activities in honey also help in the wound healing process. It can also be an alternative sweetener for diabetic patients to ensure compliance to a healthy diet. Moreover, honey exerts several effects such as lowering low density lipids and increasing high density lipids, thus reducing risk of atherosclerosis. In terms of beauty, honey can be used on skin and hair. It moisturizes skin through its natural humectant properties contributed by high contents of fructose and glucose. Honey treats acne on the skin due to its antibacterial activity, anti-inflammatory action and tissue repair. The hair can benefit from honey in such a way that the hair has abundance, and becomes easier to comb. However, there have not been as many studies regarding the use of honey in skin in comparison to its use for health. Therefore, future studies on honey could research its use, action and benefits in both cosmetics and dermatology

Hybrid Fuzzy Logic Scheme for Efficient Channel Utilization in Cognitive Radio Networks

© 2013 IEEE. The proliferation of mobile devices and the heterogeneous environment of wireless communications have increased the need for additional spectrum for data transmission. It is not possible to altogether allocate a new band to all networks, which is why fully efficient use of the already available spectrum is the demand of the day. Cognitive radio (CR) technology is a promising solution for efficient spectrum utilization, where CR devices, or secondary users (SUs), can opportunistically exploit white spaces available in the licensed channels. SUs have to immediately vacate the licensed channel and switch to another available channel when they detect the arrival of the incumbent primary user. However, performance for the SU severely degrades if successive channel switching happens. Moreover, taking the channel-switching decisions based on crisp logic is not a suitable approach in the brain-empowered CR networks (CRNs) where sensing information is not only imprecise and inaccurate but also involves a major uncertainty factor. In this paper, we propose a fuzzy logic-based decision support system (FLB-DSS) that jointly deals with channel selection and channel switching to enhance the overall throughput of CRNs. The proposed scheme reduces the SU channel switching rate and makes channel selection more adaptable. The performance of the proposed scheme is evaluated using a Matlab simulator, and a comprehensive comparison study with a baseline scheme is presented. The simulation results are promising in terms of the throughput and the number of handoffs and making our proposed FLB-DSS a good candidate mechanism for SUs while making judicious decisions in the CR environment