Duquesne University

About: Duquesne University is a education organization based out in Pittsburgh, Pennsylvania, United States. It is known for research contribution in the topics: Population & Health care. The organization has 3615 authors who have published 7169 publications receiving 180066 citations. The organization is also known as: Duquesne University of the Holy Spirit.

Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines.

Abstract: Classical and nonclassical isosteric C8−N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The syntheses of the analogues were accomplished by reductive amination of the appropriate anilines with 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine (28) followed by saponification of the ethyl esters, for the classical analogue 6. The N9-methyl analogues were obtained from the N9−H precursors by reductive methylation. In general, the nonclassical compounds 7−17 were similar in potency to TMP against Toxoplasma gondii DHFR, with selectivity ratios greater than 38 and 21 for 11 and 16, respectively. These compounds were poor inhibitors of Pneumocystis carinii DHFR and rat liver DHFR. The nonclassical analogues were also inactive against TS. The classical analogue 6 was a marginal inhibitor of isolated human TS (IC50 = 46 μM) and of human DHFR (IC50 = 10 μM)...

Effects of Putative Hydroxylated Thalidomide Metabolites on Blood Vessel Density in the Chorioallantoic Membrane (CAM) Assay and on Tumor and Endothelial Cell Proliferation

Abstract: Angiogenesis, in particular anti-angiogenesis, is an area of particular therapeutic interest in cancer treatment. Several anti-angiogenic agents are in the final stages of clinical trials. One of these agents, thalidomide, best known for its teratogenic potential, is showing promise against several tumor types. Thalidomide has been shown previously to require bio-activation to exert its anti-angiogenic effect in isolated blood vessels and endothelial cells. In this work, we confirmed these findings using the in utero chicken embryo chorioallantoic membrane (CAM) system. In particular, the anti-angiogenic effect of thalidomide is significantly enhanced by activation by human but not by rat liver microsomes. We also showed in the CAM assay that hydroxylation of thalidomide at either the 1'- or 5-position retained anti-angiogenic activity whereas its hydroxylation at the 4-position led to an inactive compound. We further demonstrated that thalidomide shows weak anti-proliferative activity against MDA-MB-231 human breast cancer cells in culture. Thalidomide showed slightly more anti-proliferative activity, however, against the SH-SY5Y human neuroblastoma and human umbilical vein endothelial cell (HUVEC) types. Furthermore, incubation of thalidomide with human liver microsomes added no additional anti-proliferative effect in these cell types versus thalidomide given alone. Finally, we report that none of the thalidomide metabolites tested had any anti-proliferative effect against the breast or neuroblastoma cells, but do possess appreciable anti-proliferative activity against the endothelial cells. In summary, this work suggests that hydroxylated thalidomide analogs based on putative metabolites of the drug possess significant anti-angiogenic activity and that exploring further derivatives of these as potential anti-angiogenic agents warrants further merit.

Characterization of mixed‐function oxidase systems of the nestling herring gull and its implications for bioeffects monitoring

Abstract: The hepatic mixed-function oxidase system was characterized in embryonic and nestling herring gulls (Larus argentatus). The activity of aminopyrine N-demethylase decreased significantly with the age of the nestlings. No consistent changes in 7-ethyoxyresorufin O-deethylase, benzo[a]pyrene 3-hydroxylase or cytochrome P450 levels with age were found. Levels of organochlorines were determined in individual livers for the 21-d-old nestlings. Correlations among organochlorine residue levels were good, and the activities of aminopyrine N-demethylase and benzo[a]pyrene 3-hydroxylase correlated with each other and with cytochrome P450 levels. No correlations were found with 7-ethoxyresorufin O-deethylase activity, and none of the enzyme levels correlated with the organochlorine residue levels. However, cytochrome P450 levels correlated with both hexachlorobenzene and oxychlordane levels. The implications for the use of the mixed-function oxidase system for environmental monitoring of exposure to organochlorines and polynuclear aromatic hydrocarbons are discussed.

Droplet-based high-throughput cultivation for accurate screening of antibiotic resistant gut microbes

Abstract: Traditional cultivation approaches in microbiology are labor-intensive, low-throughput, and yield biased sampling of environmental microbes due to ecological and evolutionary factors. New strategies are needed for ample representation of rare taxa and slow-growers that are often outcompeted by fast-growers in cultivation experiments. Here we describe a microfluidic platform that anaerobically isolates and cultivates microbial cells in millions of picoliter droplets and automatically sorts them based on colony density to enhance slow-growing organisms. We applied our strategy to a fecal microbiota transplant (FMT) donor stool using multiple growth media, and found significant increase in taxonomic richness and larger representation of rare and clinically relevant taxa among droplet-grown cells compared to conventional plates. Furthermore, screening the FMT donor stool for antibiotic resistance revealed 21 populations that evaded detection in plate-based assessment of antibiotic resistance. Our method improves cultivation-based surveys of diverse microbiomes to gain deeper insights into microbial functioning and lifestyles.

Adherence to Behavioral Interventions for Stress Incontinence: Rates, Barriers, and Predictors

Abstract: Background First-line conservative treatment for stress urinary incontinence (SUI) in women is behavioral intervention, including pelvic-floor muscle (PFM) exercise and bladder control strategies Objective The purposes of this study were: (1) to describe adherence and barriers to exercise and bladder control strategy adherence and (2) to identify predictors of exercise adherence Design This study was a planned secondary analysis of data from a multisite, randomized trial comparing intravaginal continence pessary, multicomponent behavioral therapy, and combined therapy in women with stress-predominant urinary incontinence (UI) Methods Data were analyzed from the groups who received behavioral intervention alone (n=146) or combined with continence pessary therapy (n=150) Adherence was measured during supervised treatment and at 3, 6, and 12 months post-randomization Barriers to adherence were surveyed during treatment and at the 3-month time point Regression analyses were performed to identify predictors of exercise adherence during supervised treatment and at the 3- and 12-month time points Results During supervised treatment, ≥86% of the women exercised ≥5 days a week, and ≥80% performed at least 30 contractions on days they exercised At 3, 6, and 12 months post-randomization, 95%, 88%, and 80% of women, respectively, indicated they were still performing PFM exercises During supervised treatment and at 3 months post-randomization, ≥87% of the women reported using learned bladder control strategies to prevent SUI In addition, the majority endorsed at least one barrier to PFM exercise, most commonly “trouble remembering to do exercises” Predictors of exercise adherence changed over time During supervised intervention, less frequent baseline UI and higher baseline 36-Item Short-Form Health Survey (SF-36) mental scores predicted exercise adherence At 3 months post-randomization, women who dropped out of the study had weaker PFMs at baseline At 12 months post-randomization, only “trouble remembering” was associated with exercise adherence Limitations Adherence and barrier questionnaires were not validated Conclusions Adherence to PFM exercises and bladder control strategies for SUI can be high and sustained over time However, behavioral interventions to help women link exercise to environmental and behavioral cues may only be beneficial over the short term