Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80–90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.American Society for Radiation Oncology (Junior Faculty Career Research Training Award)Harvard University. Joint Center for Radiation Therapy (Foundation Grant)Dana-Farber/Harvard Cancer Center (SPORE Developmental Research Project Award in Lung Cancer Research)National Cancer Institute (U.S.) (Award K08CA172354

Direct Sensing of Endothelial Oxidants by Vascular Endothelial Growth Factor Receptor-2 and c-Src

BACKGROUND: ADPH oxidase-derived reactive oxygen species (ROS) play important roles in redox homeostasis and signal transduction in endothelial cells (ECs). We previously demonstrated that c-Src plays a key role in VEGF-induced, ROS-dependent selective activation of PI3K-Akt but not PLCγ-1-ERK1/2 signaling pathways. The aim of the present study was to understand how VEGFR-2-c-Src signaling axis 'senses' NADPH oxidase-derived ROS levels and couples VEGF activation of c-Src to the redox state of ECs. METHODOLOGY/PRINCIPAL FINDINGS: Using biotinylated probe that detects oxidation of cysteine thiol (cys-OH) in intracellular proteins, we demonstrate that VEGF induced oxidative modification in c-Src and VEGFR-2, and that reduction in ROS levels using siRNA against p47(phox) subunit of Rac1-dependent NADPH oxidase inhibited this phenomenon. Co-immunoprecipitation studies using human coronary artery ECs (HCAEC) showed that VEGF-induced ROS-dependent interaction between VEGFR-2 and c-Src correlated with their thiol oxidation status. Immunofluorescence studies using antibodies against internalized VEGFR-2 and c-Src demonstrated that VEGF-induced subcellular co-localization of these tyrosine kinases were also dependent on NADPH oxidsase-derived ROS. CONCLUSION/SIGNIFICANCE: These results demonstrate that VEGF induces cysteine oxidation in VEGFR-2 and c-Src in an NADPH oxidase-derived ROS-dependent manner, suggesting that VEGFR-2 and c-Src can 'sense' redox levels in ECs. The data also suggest that thiol oxidation status of VEGFR-2 and c-Src correlates with their ability to physically interact with each other and c-Src activation. Taken together, these findings suggest that prior to activating downstream c-Src-PI3K-Akt signaling pathway, VEGFR-2-c-Src axis requires an NADPH oxidase-derived ROS threshold in ECs

Evaluation of the characteristics of non-oxidative biodiesels: A FAME composition, thermogravimetric and IR analysis

This experiment evaluates the effects of non-oxidative biodiesel (low oxygen content biodiesels) characteristics and their engine performances. Biodiesels produced from different feedstocks typically contains 10% to 15% oxygen by weight, which enhances the combustion quality and reduces the emissions of hydrocarbons (HCs) and carbon monoxide (CO). However, it produces a higher amount of nitrogen oxides (NOx) due to an increasing number of combustion products, resulting in a higher cylinder temperature. In addition, lean air-fuel mixtures can contribute to higher NOx emissions because biodiesel is more oxygenated than diesel. In this study, biodiesels produced from different feedstocks by a transesterification process were used to reduce the oxygen content by dipping an iron bar in the biodiesels, which absorbs oxygen and gets oxidized. Then, the oil characteristics, such as the percentage of saturated and unsaturated fatty acids, thermal degradation, stability and existing functional groups, were analyzed using fatty acid methyl ester (FAME) composition analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy analysis of neat biodiesel and non-oxidative biodiesel. Herein, Pongamia and Moringa biodiesels, containing normal and reduced weight percentages of oxygen, were evaluated to improve the quality and stability of biodiesels used in the diesel engine, which will also reduce the NOx emissions. Non-oxidative biodiesels had some positive effect on their properties, which can further reduce the NOx emissions. Herein, non-oxidative Pongamia and Moringa had quite similar characteristics and the former was observed to perform better in the reduction of NOx and other emissions as well

Study of production optimization and effect of hydroxyl gas on a CI engine performance and emission fueled with biodiesel blends

Depletion and environmental impacts of the fossil fuel are the major concerns to think about the alternative energy sources to reduce the load on petroleum fuel. Researchers worldwide are working years to improve the biodiesel fuel economy and emission characteristic. At the same time, they are working on fuel development so that can be used in the IC engine without significant modification in vehicle design. Among different alternative fuels biodiesel as well as hydroxyl gas (HHO, also known as Oxyhydrogen gas) are renewable, recyclable and non-polluting fuel. In this study, HHO gas has been introduced with ordinary diesel (OD) and 20% (v/v) palm biodiesel blended with OD (PB20) for evaluating the engine performance and emission characteristics. Optimum yield of HHO was found using single anode and two cathodes from a solution containing 1% KOH and 100 ml of water producing 2150 cc of HHO gas when electrolysis was carried out for 15 min. Using the HHO generator, about 2% more power and 5% less consumption was observed for biodiesel blended fuel in a single cylinder CI engine at full load variable speed operating conditions. Besides, on an average 20% and 10% reduction of CO and HC emission were observed respectively

Study on stability, fuel properties, engine combustion, performance and emission characteristics of biofuel emulsion

This study reviewed papers related to biofuel emulsion, principally assessing the use of biofuel emulsion. The discussion is focused mainly on three active areas of emulsified biofuel, namely, exploration of various factors affecting the preparation of stable emulsion and its fuel properties, investigation of the effect of water concentration on physicochemical properties of fuel, and observation of the improvement and degradation of combustion, performance, and emission characteristics and the possible methods to enhance these characteristics

Production, characterization, engine performance and emission characteristics of Croton megalocarpus and Ceiba pentandra complementary blends in a single-cylinder diesel engine

Compounding energy demand and environmental issues necessitate suitable alternative or partial replacement of fossil fuels. Among the possible sources, biodiesel from non-edible vegetable oil sources is more economically feasible and possesses characteristics close to those of petroleum diesel. Two potential non-edible biodiesel feedstocks "Croton megalocarpus" and "Ceiba pentandra" were used for biodiesel production through esterification and transesterification process on a laboratory scale. Biodiesel characterization, engine performance and emission characteristics were investigated in an unmodified direct injection, naturally aspirated, single-cylinder diesel engine. 20% (v/v) of each of C. megalocarpus (CM), C. pentandra (CP) and their combined blends (CMB20, CPB20, CMB15CPB05, CMB10CPB10, and CMB05CPB15) were tested under varying engine speeds ranging from 1000 rpm to 2400 rpm at full load conditions. CMB20 and CPB20 reduced the brake power (BP) by 2.63% and 3.70%, brake thermal efficiency (BTE) by 5.97% and 3.72%, carbon monoxide (CO) emission by 1.09% and 2.39%, hydrocarbon (HC) emission by 1.48% and 4.62% and smoke emission by 12.35% and 17.13%, respectively compared to petroleum diesel. On the other hand, CMB20 and CPB20 increased the brake specific fuel consumption (BSFC) by 9.74% and 7.63%, NOX emission by 13.19% and 15.45%, respectively. A mixture of 10% of both biodiesels with diesels (CMB10CPB10) provides better performance and emission characteristics. CMB10CPB10 reduced BP, BTE, CO, HC and smoke by 0.53%, 0.50%, 5.21%, 8.38% and 20.71%, respectively and increased BSFC and NOX by 3.90% and 18.66%, respectively compared to conventional diesel. A combined blend of CM and CP could be a sustainable substitute for fossil diesel in the context of performance and emission

An overview on comparative engine performance and emission characteristics of different techniques involved in diesel engine as dual-fuel engine operation

Abatement of pollutant emissions from transport sector is one of the major concerns throughout the globe. One of the main technical challenges for transportation sector is to reduce pollutant emissions from diesel engine and to meet satisfactory engine performance, simultaneously. Different technical changes have been introduced in diesel engine to apply alternative biofuels to reduce pollutant emissions. Blend, fumigation, and emulsion are three different dual fuel engine operation techniques, which have been introduced in diesel engine for biofuel application. In the blend mode, biofuel and diesel are mixed in desired proportions before injecting into cylinder, whereas in fumigation mode, biofuel is injected into intake manifold to mix with the intake fresh air. Emulsion is a process wherein two immiscible substances are mixed together. This study provides a comprehensive review on these three techniques of biofuel injection and their comparative effects on the engine performance and emissions. From these studies, it is found that the effects on engine performance and emission mostly depend on biofuel properties. Increase in break specific fuel consumption (BSFC) is common in each method due to the lower calorific value of biofuels. Brake thermal efficiency (BTE) decreases in blend and fumigation modes, but increases in emulsion mode. Nitrogen oxides (NOx) emissions decrease in fumigation and emulsion modes, but increase in blend mode. Carbon monoxide (CO) and Hydro carbon (HC) emissions increase in fumigation and emulsion modes, but decrease in blend mode. Particulate Matter (PM) emission decreases in all three modes

Influence of poly(methyl acrylate) additive on cold flow properties of coconut biodiesel blends and exhaust gas emissions

Biodiesel comprises fatty acid esters and is used as an alternative fuel for diesel engines. However, biodiesel has poor cold flow properties (i.e., CP, CFPP and PP) than mineral diesel fuel. This study aims to reduce the PP, CFPP and CP of coconut biodiesel (CB) blends using poly(methyl acrylate) (PMA) additives and investigate their effects on single-cylinder four-stroke diesel engine performance and exhaust gas emission. DSC and TGA were used to observe crystal behavior and thermal stability of the biodiesel fuel blends. Engine performance and emission were analyzed by Dynomax-2000 software and gas analyzer, respectively. Results showed that 20% of CB blended with diesel and 0.03 wt% of PMA showed significant improvement in the PP, CFPP and CP. Other properties of B20 with additives met the requirements of ASTM D6751. The BSFC of B20 with PMA was reduced by 3.247%, whereas the BTE was increased by 2.16%, compared with those of B20. Burning B20 with PMA increased the NO emission by 2.15%, whereas HC, CO and smoke emissions were 19.81%, 13.35% and 3.93% lower than those of B20, respectively. Therefore, CB20 blend with 0.03 wt% PMA can be used as an alternative fuel in cold regions without compromising fuel quality

Analysis of thermal stability and lubrication characteristics of: Millettia pinnata oil

Lubricants are mostly used to reduce the friction and wear between sliding and metal contact surfaces, allowing them to move smoothly over each other. Nowadays, due to the increase in oil prices and reduction of oil reserves, it is necessary to replace mineral oil, which will also protect the environment from hazards caused by these oils. It is essential to find an alternative oil for the replacement of mineral-oil-based lubricants, and vegetable oil already meets the necessary requirements. Vegetable-oil-based biolubricants are non-toxic, biodegradable, renewable and have a good lubricating performance compared to mineral-oil-based lubricants. This study analyzes the thermal stability and lubricating characteristics of different types of vegetable oil. The friction and wear characteristics of the oils were investigated using a four-ball tester, according to ASTM method 4172. Millettia pinnata oil has good oxidation stability due to the presence of higher percentages of oleic acid in its fatty acid composition. Millettia pinnata oil also shows a higher kinematic viscosity. Rice bran oil shows a higher viscosity index than other oils, and it is better for boundary lubrication. In thermogravimetric analysis, it was found that Millettia pinnata oil remains thermally stable at 391 °C. Millettia pinnata oil showed a lower coefficient of friction and rice bran oil showed a lower wear scar diameter compared to other vegetable oils and lube oils. A lower wear scar surface area was found with rice bran oil compared to other vegetable and commercial oils. Therefore, due to a better lubricating performance, Millettia pinnata oil has great potential to be used as a lubricating oil in industrial and automotive applications

Evaluating combustion, performance and emission characteristics of Millettia pinnata and Croton megalocarpus biodiesel blends in a diesel engine

Biodiesel from non-edible vegetable oil is considered as a monetarily doable source among the conceivable sources. It can be used as a replacement of the fossil diesel without any modification of engine design. In this study, “Millettia pinnata" (MP) which is known as Karanja and “Croton megalocarpus” (CM), non-edible biodiesel feedstock sources used for biodiesel production. 20% (v/v) of each M. pinnata (MP20) and C. megalocarpus (CM20) and their combined blends were evaluated in a single-cylinder diesel engine with variable load and speed condition in the context of performance, combustion and emission characteristics. For speed test condition, MP20 and CM20 reduced the brake power by 3.70% and 0.53%, brake thermal efficiency by 3.36% and 1.41%, carbon dioxide emission by 18.46% and 6.20%, hydrocarbon emission by 9.00% and 2.89% respectively compared to neat diesel but increased the brake specific fuel consumption by 7.63% and 4.64%, NOX emission by 17.15% and 8.16%, respectively. Beyond diesel, a mixture of 5% MP and 15% CM biodiesel with 80% diesel (MP5CM15) provides higher in-cylinder peak pressure (77.44 bar), better heat release rate (39.26 J/°CA), shorter ignition delay and combustion duration. Thus MP5CM15 found to be a substitutable alternative to neat diesel except for NOX emission