Duganmccullough3676

Bladder cancer is one of the major tumors for men in the world, in which therapy the combination of cisplatin and gemcitabine is still fist-line applied to treat with advanced or metastatic bladder cancer. In our early study, we developed a potential Pt(II) agent, DN604, which has anti-tumor effect as potent as cisplatin toward bladder cancers. Herein, we aim at investigating the combinatory application of DN604 with gemcitabine for bladder cancer treatment. In vitro studies proved that the combined treatment of DN604 and gemcitabine could limit cell proliferation by elevating the incidence of DNA damage induced apoptosis. Notably, further researches showed that the DN604-gemcitabine treatment suppressed cell autophagy to inhibit cell motility upon the ROS dependent p38 MAPK signaling pathway, explicating its better anti-tumor activity than single drug treatment or the cisplatin-gemcitabine treatment. In vivo tests confirmed that the DN604-gemcitabine treatment has superior anti-tumor activity with low toxicity to cisplatin or its combination with gemcitabine treatments. DN604 plus gemcitabine, is of great significance for the treatment with human bladder cancer. Our study has provided a potential combination treatment option.Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 μM, IC50 = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. Androgen Receptor signaling pathway Antagonists 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10-50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.The effects of democracy on living conditions among the poor are disputed. Previous studies have addressed this question by estimating the average effect of democracy on early-life mortality across all countries. We revisit this debate using a research design that distinguishes between the aggregated effects of democracy across all countries and their individual effects within countries. Using Interrupted Time Series methodology and estimating model parameters in a Bayesian framework, we find the average effect of democracy on early-life mortality to be close to zero, but with considerable variation at the country-level. Democratization was followed by fewer child deaths in 21 countries, an increase in deaths in eight, and no measurable changes in the remaining 32 cases. Transitions were usually beneficial in Europe, neutral or beneficial in Africa and Asia, and neutral or harmful in Latin America. The distribution of country-level effects is not consistent with common arguments about the conditional effects of democratic transitions. Our results open a new line of research into the sources of theses heterogeneous effects.

Recent research has shown that social integration, involving community integration and social support, can be protective resources for the health of homeless individuals. However, it is not clear how social integration affects health in the transition from homelessness into housing, and subsequent housing retention. This paper examines, through mixed quantitative and qualitative methods, how social integration changes over time, and how these changes relate to housing stability, substance use and mental health outcomes among a sample of homeless individuals experiencing mental illness participating in the At Home/Chez Soi Housing First randomized controlled trial in Canada.

Longitudinal quantitative data (baseline, 6, 12, 24 month) and qualitative data ( 18 month) from the five trial sites (Moncton, Montreal, Toronto, Winnipeg and Vancouver) were examined using mixed models, mediation analyses, and thematic analysis.

Social integration (i.e., social network size, social interest, psychological integration) increased over time among study participants, with social network size increasing significantly more among Housing First participants than Treatment as Usual participants.