Background: Inhibition of poly-adenosine diphosphate-ribose polymerase (PARP) is an effective therapy against cancers with DNA damage repair (DDR) deficiencies, such as BRCA1 and BRCA2 defects. In preclinical studies, PARP inhibitors demonstrated potential therapeutic value in Ewing sarcoma (ES), but clinical trials with olaparib failed to show significant clinical benefit. A key regulatory event in DNA damage repair is acetylation and deacetylation of histones, controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increased expression of HDACs correlate with more malignant phenotypes in sarcomas and inhibition of HDAC in pre-clinical models of ES inhibits tumor growth. HDAC inhibition combined with PARP inhibition has promising results in vitro, however clinically, combination therapies often require complicated sequential dosing protocols due to different pharmacokinetic profiles and overlapping toxicities, that severely limits clinical utility. Here, we report the efficacy of a novel bifunctional small-molecule compound designed to have both PARP and HDAC inhibition activity. Methods: PARP1 and PARP2 activity was measured using the Trevigen Universal Colorimetric PARP Assay Kit, the BPS Bioscience PARP2 Colorimetric PARP2 Assay Kit, and by PARylation assays. HDAC activity was measured using HeLa cell nuclear extracts and a fluorogenic peptide-based biochemical assay. Cell survival EC50 s were determined using live cell imaging with an Incucyte S3 system and the CellTiter Glo viability assay. DNA damage was detected by western blot, immuno-fluorescence, and comet assays. Results: A representative compound from the kt-3000 series showed potent inhibition of PARP1 and PARP2 with IC50 values in the low nM range, comparable to FDA-approved PARP inhibitors. The compound also showed inhibition of HDAC enzymes with IC50 values in the low μM range, slightly lower than the FDA-approved HDAC inhibitor, vorinostat. Cell survival EC50 values were superior to olaparib in ES cell lines in vitro. Treatment with the kt-3000 compound also resulted in increased DNA damage and S and G2/M cell cycle arrest as compared to olaparib. Conclusion: Our kt-3000 compound shows potent inhibition of PARP1, PARP2, and HDAC, as well as induction of DNA damage and cell cycle arrest. Further development of these bifunctional single molecule inhibitors may offer a novel treatment opportunity for Ewing sarcoma and other solid tumors with limited responses to PARPi monotherapies. Conflict of interest: Board of Directors: J. Bacha and D. Brown are directors of Rakovina Therapeutics. Corporate-sponsored Research: S. Truong, B. Zhai, F. Ghaidi, L. Ramos, J. Joshi are employees of Rakovina Therapeutics. J. Langlands, M. Daugaard and W. Shen are consultants to Rakovina Therapeutics.

Elevated exposure to ambient manganese (Mn) is associated with adverse health outcomes. In Marietta, Ohio, the primary source of ambient Mn exposure is from the longest operating ferromanganese refinery in North America. In this study, the US EPA air dispersion model, AERMOD, was used to estimate ambient air Mn levels near the refinery for the years 2008-2013. Modeled air Mn concentrations for 2009-2010 were compared to concentrations obtained from a stationary air sampler. Census block population data were used to estimate population sizes exposed to an annual average air Mn > 50 ng/m3, the US EPA guideline for chronic exposure, for each year. Associations between modeled air Mn, measured soil Mn, and measured indoor dust Mn in the modeled area were also examined. Median modeled air Mn concentrations ranged from 6.3 to 43 ng/m3 across the years. From 12,000-56,000 individuals, including over 2000 children aged 0-14 years, were exposed to respirable annual average ambient air Mn levels exceeding 50 ng/m3 in five of the six years. For 2009-2010, the median modeled air Mn concentration at the stationary site was 20 ng/m3, compared to 18 ng/m3 measured with the stationary air sampler. All model performance measures for monthly modeled concentrations compared to measured concentrations were within acceptable limits. The study shows that AERMOD modeling of ambient air Mn is a viable method for estimating exposure from refinery emissions and that the Marietta area population was at times exposed to Mn levels that exceeded US EPA guidelines.

While selective laser melting (SLM) offers design freedom of metal parts with much less material consumption, there exist several limitations, including high surface roughness, low-dimensional accuracy, and high tensile residual stresses. To make functional parts with high form accuracy and superior surface integrity, an as-SLM part needs finishing to remove the deposited surface material. The integration of machining and SLM creates a hybrid manufacturing route to overcome the inherited limitations of SLM. However, little study has been done to characterise surface integrity of an as-SLM part followed by machining (e.g. hybrid SLM-milling). In this paper, surface, integrity including surface roughness, microstructure, and microhardness, have been characterised for IN718 samples processed by the hybrid process. It has been found that microhardness varies with the scan direction and the use of coolant in the subsequent milling, and surface integrity can be significantly improved by the hybrid SLM-milling route.

Increasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms.

Human development and sustainability face significant challenges that must be addressed by the science and engineering community. Formulating solutions to overcome the challenges is best approached by engaging as diverse a population of problem solvers as possible and by developing a robust STEM workforce. However, obstacles exist in undergraduate STEM education that prevent many students from completing an intended STEM major. Further, a rapid and significant demographic shift is occurring in America that is leading to become a population considerably more Hispanic. However, Hispanics are appreciably underrepresented in the STEM workforce at this time. An examination of these socioeconomic, cultural and educational issues is presented, along with recommendations from the literature on how to address them and examples of selected efforts to build capacity at a Hispanic-Serving two-year college to contribute to the diversification of the STEM workforce.

Since their introduction in the late 1960s, inferior vena cava (IVC) filters have been commonly used in patients with venous thromboembolic disease to prevent pulmonary embolism (PE), particularly if the patient is not a candidate for anticoagulation therapy. Despite their extensive use, studies

Dianhydrogalactitol (VAL-083) is a unique bi-functional alkylating agent causing N7-guanine-methylation and inter-strand DNA crosslinks. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has shown activity in prior NCI-sponsored clinical trials against various cancers, including glioblastoma (GBM) and medulloblastoma. VAL-083 is also active against GBM cancer stem cells and acts as a radiosensitizer independent of O6-methylguanine-DNA methyltransferase activity (in contrast to e.g. temozolomide and BCNU). Here we report new insights into VAL-083 mechanism of action by showing that VAL-083 induces irreversible cell-cycle arrest and cell death caused by replication-dependent DNA damage. In lung (H2122, H1792, H23, A549) and prostate (PC3, LNCaP) cancer cell lines VAL-083 treatment caused irreversible S/G2 cell-cycle arrest and cell death (IC50 range 3.06-25.7 µM). VAL-083 pulse-treatment led to persistent phosphorylation of DNA double-strand breaks (DSB) sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting persistent DNA lesions. After 10 months in culture with increasing VAL-083 concentrations, H1792 and LNCaP cells survive at concentrations up to 9.4 µM and 7.4 µM, respectively, suggesting that efficient resistance mechanisms are not easily acquired by the cancer cells. Taken together with previous results showing that VAL-083 circumvents cisplatin-resistance and is less dependent on p53 activity than cisplatin, these results suggest a molecular mechanism for VAL-083 that differs from both TMZ, BCNU and cisplatin. They further suggest that irreparable DNA damage induced by VAL-083 is impervious to common strategies employed by cancer cells to escape effects of alkylating drugs used in GBM treatment.

Manganese (Mn) is ubiquitous in the environment and essential for normal growth and development, yet excessive exposure can lead to impairments in neurological function. This study modeled ambient Mn concentrations as an alternative to stationary and personal air sampling to assess exposure for children enrolled in the Communities Actively Researching Exposure Study in Marietta, OH. Ambient air Mn concentration values were modeled using US Environmental Protection Agency’s Air Dispersion Model AERMOD based on emissions from the ferromanganese refinery located in Marietta. Modeled Mn concentrations were compared with Mn concentrations from a nearby stationary air monitor. The Index of Agreement for modeled versus monitored data was 0.34 (48 h levels) and 0.79 (monthly levels). Fractional bias was 0.026 for 48 h levels and −0.019 for monthly levels. The ratio of modeled ambient air Mn to measured ambient air Mn at the annual time scale was 0.94. Modeled values were also time matched to personal air samples for 19 children. The modeled values explained a greater degree of variability in personal exposures compared with time-weighted distance from the emission source. Based on these results modeled Mn concentrations provided a suitable approach for assessing airborne Mn exposure in this cohort.

Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source.

Background: Existing guidelines address pharmacotherapy for heart failure (HF), but little is known about the association of lifestyle practices, including alcohol intake, with prognosis. Although excess alcohol use may cause cardiomyopathy/HF, there are putative beneficial effects associated with moderate alcohol intake. Prior studies in this area have been mixed and were limited by analyses of patients with prevalent HF. We hypothesized that moderate alcohol use would be associated with increased survival among older adults with incident HF, with a J-curve relationship between alcohol consumption and survival. Methods: The Cardiovascular Health Study (CHS) is a prospective, observational study of black and white U.S. adults ≥65 years of age. Participants had baseline clinical exams followed by 9 yearly clinic visits, with alcohol use assessed at most visits. Twice-yearly phone calls were used to ascertain clinical events. We identified subjects with incident HF diagnosed within the first 9 years of follow-up. The first post-HF alcohol intake was divided into four categories: long-term abstainers, former drinkers, ≤7 drinks/week (wk), and >7 drinks/wk. Methods: We used multiple linear regression to assess the relationship between categories of alcohol intake and subsequent survival while adjusting for important covariates. After excluding former drinkers, we also assessed alcohol use as a continuous variable, including a quadratic term to test for a J-curve relationship between alcohol use and survival. Sequential methods were used to impute missing data. Survival was calculated as time from HF diagnosis to death or last follow-up (maximum 18 years from CHS study entry). Results: We identified 393 individuals with incident HF. With respect to alcohol use after HF diagnosis. 42.7% were long-term abstainers, 24.4% former drinkers, 28.5% had ≤7 drinks/wk, and 4.3% had >7 drinks/wk. Higher alcohol use was more common among men, whites, those with higher income and higher education, participants without diabetes, and current and former smokers. 15-foot walk time was lowest in the moderate intake group (≤7 drinks/wk). Compared with long-term abstention, consumption of ≤7 drinks/wk was associated with significantly longer survival after HF diagnosis (an additional 180 days, 95% CI 51–760 days). A significant J-curve relationship was observed between alcohol intake and survival, with 10 drinks/wk associated with peak projected survival after adjusting for other factors (additional 401 days of life compared with long-term abstainers). Conclusion: Among older adults, moderate alcohol use after HF diagnosis was associated with longer subsequent survival. The present observational study cannot distinguish between a beneficial effect directly attributable to moderate alcohol use versus its association with other prognostic factors. Further efforts to determine optimal alcohol intake in adults with HF and whether this differs by age, gender, and etiology of HF are needed.

Amongst alternative fuels for diesel-engine application, biodiesel is very attractive because it is biodegradable, an environmentally-friendly and sustainable source that can meet future energy demands. However, there are few published studies of the impact of biodiesel fuel and its blends on fuel injection pumps (FIPs). This study will investigate the influence of biodiesels derived from waste cooking oils with incremental blends of B10, B20, B30, B40 and B100. The FIP in this study is a rotary type attached to a four-cylinder, four-stroke direct injection, turbocharged diesel engine. Vibration and pressure measurements were made on the FIP. The results show the peak pressure close to the pump increases slightly the higher the proportion of biodiesel because of increased viscosity, density and bulk modulus of the fuel. Low frequency vibration increased as the proportion of biodiesel increased. These results demonstrate an increase in dynamic load on the pump components. However, high frequency vibration levels are lowest for the blends B10, B20 and B30, which may be helpful for improving the service life of the delivery.

This report aims to evaluate the usefulness of self-sampling as an approach for future national surveillance of emerging respiratory infections by comparing virological data from two parallel surveillance schemes in England. Nasal swabs were obtained via self-administered sampling from consenting adults (≥?16 years-old) with influenza symptoms who had contacted the National Pandemic Flu Service (NPFS) health line during the 2009 influenza pandemic. Equivalent samples submitted by sentinel general practitioners participating in the national influenza surveillance scheme run jointly by the Royal College of General Practitioners (RCGP) and Health Protection Agency were also obtained. When comparable samples were analysed there was no significant difference in results obtained from self-sampling and clinician-led sampling schemes. These results demonstrate that self-sampling can be applied in a responsive and flexible manner, to supplement sentinel clinician-based sampling, to achieve a wide spread and geographically representative way of assessing community transmission of a known organism.

Blood and oral fluid (OF) samples were collected from 103 suspected measles cases between February and November 2010 during a nationwide measles outbreak in Zimbabwe. Siemens measles IgM enzyme immunoassay (EIA) on serum, Microimmune measles IgM capture EIA on OF, real-time haemagglutinin (H) gene PCR and nested nucleocapsid (N) gene PCR on OF were performed, confirming 75 measles cases. These samples were then used to evaluate a newly developed point of care test (POCT) for measles and determine its potential for identifying measles cases in outbreaks. After performing POCTs on OF samples, nucleic acid was extracted from the used test strips and the measles H and N genes amplified by RT-PCR. The sensitivity, specificity, positive and negative predictive values of the POCT for IgM in OF was 75·0% [95% confidence interval (CI) 63·4-84·5], 96·2% (95% CI 80·4-99·9), 98·2% (95% CI 90·3-100) and 58·1% (95% CI 42·1-73·0), respectively. The N gene sequences showed high level of agreement between original OF and corresponding POCT strips. Measles genotype B3 was identified in all cases. We conclude that the measles POCT has the potential to be used, at the point of contact, in outbreak situations and provide molecular characterization of the virus at a later date.