Structural Requirements for Dihydrobenzoxazepinone Anthelmintics:Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Studies of near-surface phenomena and erosion mechanisms in metallic alloys using single- and multi-particle impacts

An experimental study of the effects of material properties on erosion mechanisms was conducted by subjecting targets to single as well as multiple impacts of spherical particles at various velocities. A mechanical properties microprobe was used to monitor the hardening due to the impacts. Initial studies on several engineering alloys showed that work hardening was associated with single impacts, and the results suggested that the capacity to distribute the impact energy over large volumes improved a material's erosion resistance. Studies also showed that the alloys work hardened significantly under multiple-particle impacts. Single-particle impact studies were found to correlate well with results from low-velocity, multiple-particle erosion experiments. (VC

Exposure of Ceramics and Ceramic Matrix Composites in Simulated and Actual Combustor Environments

A high-temperature, high-pressure, tube furnace has been used to evaluate the long term stability of different monolithic ceramic and ceramic matrix composite materials in a simulated combustor environment. All of the tests have been run at 150 psia, 1204 degrees C, and 15% steam in incremental 500 h runs. The major advantage of this system is the high sample throughput; >20 samples can be exposed in each tube at the same time under similar exposure conditions. Microstructural evaluations of the samples were conducted after each 500 h exposure to characterize the extent of surface damage, to calculate surface recession rates, and to determine degradation mechanisms for the different materials. The validity of this exposure rig for simulating real combustor environments was established by comparing materials exposed in the test rig and combustor liner materials exposed for similar times in an actual gas turbine combustor under commercial operating conditions

Comparison study of dicyandiamide-cured epoxy bonded steel joints and polyamidoamine-cured epoxy bonded steel joints

There are instances where efficiency and safety may be compromised as a result of deteriorating fluid transport systems. Thus, it is worth evaluating other methods that can repair the damage for a temporary period without shutting down the operation. The objective was to evaluate the durability of an epoxy-bonded steel in aqueous environments that would represent such a repair. EPON® 828 was chosen as the epoxy resin, and dicyandiamide and polyamidoamine were two types of curing agents evaluated in this study. The epoxy-bonded steel joints were exposed in either distilled water or 3.4% NaCl solution for various times. The mechanical strength of the bonded joints was evaluated using a three-point flexure test. The interfacial shear strength of unaged samples ranged from 0.93 to 0.32 MPa. It was found that the interfacial shear strength decreased with aging time for both epoxy-bonded systems. Scanning electron microscopy (SEM), optical microscopy, and X-ray photoelectron spectroscopy (XPS) were used to determine the locus of failure of the bonded joints. It was concluded that failure occurred cohesively within the oxide layer if oxides were present on the substrate surface prior to the bonding procedure