Quality of life effects of androgen deprivation therapy in a prostate cancer cohort in New Zealand: Can we minimize effects using a stratification based on the aldo-keto reductase family 1, member C3 rs12529 gene polymorphism?

Background: Androgen deprivation therapy (ADT) is an effective palliation treatment in men with advanced prostate cancer (PC). However, ADT has well documented side effects that could alter the patient’s health-related quality of life (HRQoL). The current study aims to test whether a genetic stratification could provide better knowledge for optimising ADT options to minimize HRQoL effects. Methods: A cohort of 206 PC survivors (75 treated with and 131 without ADT) was recruited with written consent to collect patient characteristics, clinical data and HRQoL data related to PC management. The primary outcomes were the percentage scores under each HRQoL subscale assessed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires (QLQ-C30 and PR25) and the Depression Anxiety Stress Scales developed by the University of Melbourne, Australia. Genotyping of these men was carried out for the aldo-keto reductase family 1, member C3 (AKR1C3) rs12529 single nucleotide polymorphism (SNP). Analysis of HRQoL scores were carried out against ADT duration and in association with the AKR1C3 rs12529 SNP using the generalised linear model. P-values <0 · 05 were considered significant, and were further tested for restriction with Bonferroni correction. Results: Increase in hormone treatment-related effects were recorded with long-term ADT compared to no ADT. The C and G allele frequencies of the AKR1C3rs12529 SNP were 53·4 % and 46·6 % respectively. Hormone treatmentrelated symptoms showed an increase with ADT when associated with the AKR1C3 rs12529 G allele. Meanwhile, decreasing trends on cancer-specific symptoms and increased sexual interest were recorded with no ADT when associated with the AKR1C3 rs12529 G allele and reverse trends with the C allele. As higher incidence of cancerspecific symptoms relate to cancer retention it is possible that associated with the C allele there could be higher incidence of unresolved cancers under no ADT options

Measuring 3D indoor air velocity via an inexpensive low-power ultrasonic anemometer

The ability to inexpensively monitor indoor air speed and direction on a continuous basis would transform the control of environmental quality and energy use in buildings. Air motion transports energy, ventilation air, and pollutants around building interiors and their occupants, and measured feedback about it could be used in numerous ways to improve building operation. However indoor air movement is rarely monitored because of the expense and fragility of sensors. This paper describes a unique anemometer developed by the authors, that measures 3-dimensional air velocity for indoor environmental applications, leveraging new microelectromechanical systems (MEMS) technology for ultrasonic range-finding. The anemometer uses a tetrahedral arrangement of four transceivers, the smallest number able to capture a 3-dimensional flow, that provides greater measurement redundancy than in existing anemometry. We describe the theory, hardware, and software of the anemometer, including algorithms that detect and eliminate shielding errors caused by the wakes from anemometer support struts. The anemometer has a resolution and starting threshold of 0.01 m/s, an absolute air speed error of 0.05 m/s at a given orientation with minimal filtering, 3.1° angle- and 0.11 m/s velocity errors over 360° azimuthal rotation, and 3.5° angle- and 0.07 m/s velocity errors over 135° vertical declination. It includes radio connection to internet and is able to operate standalone for multiple years on a standard battery. The anemometer also measures temperature and has a compass and tilt sensor so that flow direction is globally referenced regardless of anemometer orientation. The retail cost of parts is $100 USD, and all parts snap together for ease of assembly

Identifying Significant Environmental Features Using Feature Recognition

The Department of Environmental Analysis at the Kentucky Transportation Cabinet has expressed an interest in feature-recognition capability because it may help analysts identify environmentally sensitive features in the landscape, including those relating to historic preservation, archaeology, endangered species habitat, and geology. LIDAR Analyst and Feature Analyst are a pair of geoprocessing software packages that have been developed by Textron Systems. Using this software, users can use LIDAR data to identify finely-scaled user-specified features. The software’s automated feature extraction saves time that might otherwise be spent manually analyzing images and digitizing features. This report explores the capabilities and accuracy of this software by using LIDAR data to identify sinkholes throughout a small area in Kentucky. This report also discusses an alternative LIDAR-based geoprocessing methodology developed by the Kentucky Geological Society. The method relies on ArcGIS and Python scripting to identify sinkholes. The feasibility and applicability of these methodologies are compared, the workflow for each method is outlined, and the capabilities and limitations of each are noted. Sample results—the identification of sinkholes—from each methodology are presented. The research team found the batch processing capability built into LIDAR and Feature Analyst adequate and beneficial for smaller projects, such as projects that prioritize the extraction of buildings, trees, and forest regions

SAR refinement of antileishmanial N2,N4-disubstituted quinazoline-2,4-diamines

Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N2,N4-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N4-(furan-2-ylmethyl)-N2-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N2,N4-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N2 and N4 exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N2 or N4 generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N4-benzyl-N2-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N2-benzyl-N4-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N2 or N4 may provide clues for the design of safe and effective antileishmanial quinazolines

Leukocyte Pyruvate Kinase Expression is Reduced in Normal Human Pregnancy but not in Pre-eclampsia

Citation Xu Y, Madsen-Bouterse SA, Romero R, Hassan S, Mittal P, Elfline M, Zhu A, Petty HR. Leukocyte pyruvate kinase expression is reduced in normal human pregnancy but not in pre-eclampsia. Am J Reprod Immunol 2010; 64: 137–151Emerging evidence suggests that metabolism influences immune cell signaling and immunoregulation. To examine the immunoregulatory role of glycolysis in pregnancy, we evaluated the properties of pyruvate kinase in leukocytes from non-pregnant women and those with normal pregnancy and pre-eclampsia.We evaluated pyruvate kinase expression in lymphocytes and neutrophils from non-pregnant, pregnant, and pre-eclampsia patients using fluorescence microscopy and flow cytometry. Leukocyte pyruvate kinase activity and pyruvate concentrations were also evaluated. To study pyruvate’s effect on signaling, we labeled Jurkat T cells with Ca 2+ dyes and measured cell responses in the presence of agents influencing intracellular pyruvate.The expression of pyruvate kinase is reduced in lymphocytes and neutrophils from normal pregnant women in comparison with those of non-pregnant women and pre-eclampsia patients. Similarly, the activity of pyruvate kinase and the intracellular pyruvate concentration are reduced in leukocytes of normal pregnant women in comparison with non-pregnant women and women with pre-eclampsia. Using Jurkat cells as a model of leukocyte signaling, we have shown that perturbations of intracellular pyruvate influence Ca 2+ signals.Normal pregnancy is characterized by reduced pyruvate kinase expression within lymphocytes and neutrophils. We speculate that reduced pyruvate kinase expression modifies immune cell responses due to reduced pyruvate concentrations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79222/1/j.1600-0897.2010.00881.x.pd

Bioluminescence imaging reveals inhibition of tumor cell proliferation by Alzheimer's amyloid β protein

Background: Cancer and Alzheimer's disease (AD) are two seemingly distinct diseases and rarely occur simultaneously in patients. To explore molecular determinants differentiating pathogenic routes towards AD or cancer, we investigate the role of amyloid β protein (Aβ) on multiple tumor cell lines that are stably expressing luciferase (human glioblastoma U87; human breast adenocarcinoma MDA-MB231; and mouse melanoma B16F). Results: Quantification of the photons emitted from the MDA-MB231 or B16F cells revealed a significant inhibition of cell proliferation by the conditioning media (CM) derived from amyloid precursor protein (APP) over-expressing cells. The inhibition of U87 cells was observed only after the media was conditioned for longer than 2 days with APP over-expressing cells. Conclusion: Our results suggest that Aβ plays an inhibitory role in tumor cell proliferation; this effect could depend on the type of tumor cells and amount of Aβ

Oral Morphine Versus Ibuprofen Administered at Home for Postoperative Orthopedic Pain in Children: a Randomized Controlled Trial

BACKGROUND: Oral morphine for postoperative pain after minor pediatric surgery, while increasingly popular, is not supported by evidence. We evaluated whether oral morphine was superior to ibuprofen for at-home management of children\u27s postoperative pain. METHODS: We conducted a randomized superiority trial comparing oral morphine (0.5 mg/kg) with ibuprofen (10 mg/kg) in children 5 to 17 years of age who had undergone minor outpatient orthopedic surgery (June 2013 to September 2016). Participants took up to 8 doses of the intervention drug every 6 hours as needed for pain at home. The primary outcome was pain, according to the Faces Pain Scale - Revised, for the first dose. Secondary outcomes included additional analgesic requirements, adverse effects, unplanned health care visits and pain scores for doses 2 to 8. RESULTS: We analyzed data for 77 participants in each of the morphine and ibuprofen groups. Both interventions decreased pain scores with no difference in efficacy. The median difference in pain score before and after the first dose of medication was 1 (interquartile range 0-1) for both morphine and ibuprofen ( INTERPRETATION: Morphine was not superior to ibuprofen, and both drugs decreased pain with no apparent difference in efficacy. Morphine was associated with significantly more adverse effects, which suggests that ibuprofen is a better first-line option after minor surgery. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01686802

Photoenzymatic Hydrogenation of Heteroaromatic Olefins using ‘Ene’-Reductases with Photoredox Catalysts

Flavin‐dependent ‘ene’‐reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic paradigms