The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation

Measuring Productivity and Quality in Model-Based Design

Copyright © 2004 SAE International Accurate measurements of productivity and quality are essential for balancing workload, creating predictable schedules and budgets, and controlling quality. Traditional software development processes include well-established methods for measuring productivity and quality. These include Lines of Code (LOC). With the introduction of Model-Based Design, organizations require a different measure of the software development process

Immigrant Business in Suburban America: How and Why Ethnic Economy Workers in the Suburbs Are Struggling To Get By

Immigrants are moving into U.S. suburbs at the same time that suburban areas are suffering from growing poverty, an aging infrastructure, and increasing anti-immigrant sentiment. These trends provide a unique context for immigrant entrepreneurship. Immigrant entrepreneurs are often part of ethnic economies, such as Chinatowns and Little Italies, and many scholars presume that successful ethnic economies derive from co-ethnic consumer demand and low-wage labor found in tightly-bound, densely populated urban ethnic neighborhoods. This dissertation examines how ethnic economies manage to form in suburban areas, many of which are more spread out and ethnically heterogeneous than urban ethnic neighborhoods. What effect are ethnic economies having on suburban areas? What effect are suburban areas having on ethnic economies? Drawing on techniques from population research, spatial statistics, and data science, my dissertation answers these questions, demonstrating that suburban ethnic economy workers are struggling to recreate the successes they found in urban ethnic neighborhoods due to various challenges unique to suburban areas. Using nationally representative U.S. Census data across two decades, I first show that suburban ethnic economy workers earn incomes no better than their counterparts in central cities. This finding stands in contrast to several prominent case studies that suggest that suburban ethnic economies are wealthier than those found in cities. The finding also supports the theory that the differences between immigrant adaptation in cities and suburbs are diminishing. I then use U.S. Census microdata from before and after the Great Recession to show that unemployment rates grew most quickly in suburban areas characterized by the niching of ethnic minorities into ethnic economies. The geographic isolation of many suburban ethnic economies from co-ethnic social capital likely renders them particularly vulnerable to economic downturns. Finally, using data from Yelp.com, I assess how the rise of ethnic chain restaurants is affecting suburban ethnic economy growth. Ethnic restaurants are often independently owned and operated by entrepreneurs who take part in ethnic economies. In many cases, chain and non-chain ethnic restaurants are equally likely to locate in suburban ethnic communities, suggesting that chains are cutting into a market that traditionally belonged to independent ethnic entrepreneurs. In sum, as suburban ethnic economies continue to grow, the trajectories of suburban ethnic businesses and workers are likely diverging from those found in urban areas. New theories and policy initiatives are necessary to successfully integrate ethnic firms and their employees into suburban economies and communities

Epxoide hydrolase -polymorphism and role in toxicology

Abstract Microsomal epoxide hydrolase is a critical biotransformation enzyme that catalyzes the conversion of a broad array of xenobiotic epoxide substrates to more polar diol metabolites. The gene has been shown previously to exhibit polymorphism, including variation in the coding region leading to amino acid substitutions at positions 113 (Y/H) and 139 (H/R). To better evaluate the phenotype associated with the structural region genetic polymorphisms associated with mEH, we performed enzymatic analyses using purified mEH proteins that were expressed using a baculovirus system, or with microsomal preparations obtained from liver tissues that were derived from individuals with homozygous mEH allelic status. Benzo[a]pyrene-4,5-oxide and cis-stilbene oxide were employed as substrates for the enzymatic determinations. Results obtained with the purified enzymes suggested that the reaction velocity catalyzed by the wild type (Y113/H139) protein was approximately two-fold greater than the corresponding velocities for the variant forms of the enzyme. However, when reaction rates were analyzed using human liver microsomal preparations, the maximal velocities generated among the variant mEH proteins were not statistically different. Collectively, these results indicate that the structural differences coded by the mEH genetic variants may have only modest impact on the enzyme's specific activity in vivo

Evaluation of pharmaceutical excipients as cosolvents in 4-methyl umbelliferone glucuronidation in human liver microsomes: An application for compounds with low solubility

Introduction: In order to minimize the potential inhibitory effects of organic solvents on metabolic activity, standard incubation procedures for carrying out microsomal assays involve the use of less than 1% w/v organic solvents. Often, solvents needed to dissolve the substrate add-up nearly to this concentration. This presents a practical limitation for poorly soluble xenobiotics, which cannot be incubated at concentrations high enough to obtain a Vmax, and therefore subsequent values for Km and Clint cannot be calculated. Our goal was to study the application of a variety of pharmaceutical excipients to aid the solubilization of compounds in vitro in glucuronidation incubations, without affecting the reaction kinetics. Methods: In vitro glucuronidation incubations were carried out in human liver microsomes with 4-methylumbelliferone (4-MU) and the kinetics of 4-MU glucuronidation in the presence of excipients were compared to that in control incubations without any excipients. In addition, IC75 values were calculated for each excipient. Results and Summary: We observed that HPBCD may be employed in in vitro glucuronidation incubations up to 0.5% w/v without affecting the Clint of 4-MU. Although NMP and DMA showed low IC75 values approximately 0.1% w/v each, neither excipients altered the Clint of 4-MUG formation. Our studies point toward a possible application of pharmaceutical excipients to carry out in vitro glucuronidation of substrates with poor aqueous solubility, in order to estimate Clint and subsequently scaled organ clearance values

Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

Background M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.Methods In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.Results In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).Conclusions There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration number NCT03306420

Airspace Technology Demonstration 2 (ATD-2): Simulation and Modeling Used in Surface Analysis

This presentation describes how the fast-time simualtion and modeling techniques are used in the development of ATD-2 system, especially for surface traffic data anlaysis. This presentation will answer the following questions: What analytical results are most important to communicate to Industry from ATD-2 simulation? What fast-time simulations are currently in the works, including EOBT quality impact study and benefits/costs assessment of ATD-2

Identification of a novel N-carbamoyl glucuronide: In vitro, In vivo and mechanistic studies

1-[4-Aminomethyl-4-(3-chloro-phenyl )-cyclohexyl]-tetrahydro-pyrimidin-2-one, 1, was developed as an inhibitor of dipeptidyl peptidase-4 enzyme (DPP-4). Biotransformation studies with 1 revealed the presence of an N-carbamoyl glucuronide metabolite (M1) in rat bile and urine. N-carbamoyl glucuronides are rarely observed, and little is understood regarding the mechanism of N-carbamoyl glucuronidation. The objectives of the current investigation were to elucidate the structure of the novel N-carbamoyl glucuronide, to investigate the mechanism of N-carbamoyl glucuronide formation in vitro using stable labeled CO2, UGT reaction phenotyping, and to assess whether M1 was formed to the same extent in vitro across species – mouse, rat, hamster, dog, monkey and human. Structure elucidation was carried out on a Thermo LTQ-Orbitrap® with accurate mass measurement and MSn capabilities. 13C-labeled carbon dioxide (13CO2) was used for identification of the mechanism of N-carbamoyl glucuronidation. Mechanistic studies with 13C-labeled CO2 in rat liver microsomes revealed that CO2 from the bicarbonate buffer (in equilibrium with exogenous CO2) may be responsible for the formation of M1. M1 was formed in vitro in liver microsomes from multiple species – mainly rat and hamster, followed by similar formation in dog, monkey, mouse, human. M1 could be detected in UGT1A1, UGT1A3 and UGT2B7 Supersomes® in a CO2 rich environment. In conclusion our study demonstrates that formation of M1 was observed in microsomal incubations across various species and strongly suggests the incorporation of CO2 from the bicarbonate buffer, in equilibrium with exogenous CO2 into the carbamoyl moiety of the formed N-carbamoyl glucuronide

Modeling Deicing Operations in Departure Scheduling Using Fast Time Simulation

In winter snow conditions, aircraft need inspection for deicing service before takeoff. Deicing service is a procedure to remove frost, ice, slush, or snow from aircraft for safe operation. Deicing operations vary by airport in many ways. Some airports have designated deicing zones, whereas some use a closed runway or terminal area to perform the procedure. Nonetheless, deicing operations add extra workloads to controllers, and cause increased taxi traffic on the ground. NASA and Korea Aerospace Research Institute (KARI) have been collaborating to model deicing operations at Incheon International Airport (ICN). This paper describes the deicing model and the study of deicing operations in departure scheduling using fast time simulations. The deicing model uses a heuristic algorithm for deicing zone assignment. In the fast time simulations, the model uses probability distributions derived from actual operation data to model deicing request and deicing zone time. It is envisioned that such a deicing model can be useful in airport surface scheduling to provide decision support and improve traffic management performance in winter snow operations