43 research outputs found
Pharmacovigilance Evaluation of the Association Between DPP-4 Inhibitors and Heart Failure: Stimulated Reporting and Moderation by Drug Interactions
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The Efficacy and Mechanism of Action of HDAC Inhibitors in Triple Negative Breast Cancer
Get PDFHistone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents which consist of a hydrophobic capping group, linker region, and Zn 2+ chelating pharmacophore. Manipulation of these three regions, such as the incorporation of a pyridine capping group, and hydroxythiopyridone Zn 2+ binding group has yielded Jazz-90, and M1S and M2S, respectively. Alongside vorinostat, these HDACis were tested for their cytotoxicity and activity in triple negative MDA-MB-231 and MDA-MB-468 breast cancer cells. The novel compound Jazz-90 displayed the greatest cytotoxic potency in MDA-MB-231 cells (EC 50 1.14 μM) while M1S had an EC 50 of 1.66 μM in MDA-MB-468 cells. Time-course cytotoxicity studies showed the compounds to have a cytostatic effect at the EC 50 concentration (1X) and a cytotoxic effect at four-fold the EC 50 concentration (4X). Furthermore, the effect on protein expression was determined using Western blotting at 24 h post-treatment. Relative to their cytotoxicity, the EC 50 of vorinostat (2.10 μM) showed the greatest increase in acetylated histone-H3 protein expression followed by 1X Jazz-90, 1472% and 1041%, respectively, compared to control in MDA-MB-231 cells; a similar trend was seen in MDA- MB-468 cells. Compared to vehicle control, only 4X of M1S (6.66 μM) and M2S (17.17 μM) significantly increased acetylated histone-H3 expression in MDA-MB-468 cells, 11404% and 10795%, respectively. Cell cycle protein analysis revealed that compared to control 1X of vorinostat, M1S, and M2S significantly downregulated cyclin B1 expression in MDA-MB-231 cells by 56%, 65%, and 29%, respectively, suggesting the compounds to induce G 2 /M-phase arrest. Interestingly, 1X of M1S and M2S were found to significantly increase cyclin D1 expression in MDA-MB-231 cells by 122% and 97%, respectively, suggesting that the compounds promote progression through the G 1 -phase. No change in total cyclin E2, Hsp90, or NF-κB p65 protein expression was seen in either cell line, p53 in MDA-MB-231 cells, or nuclear Hsp90 and nuclear NF-κB p65 in MDA-MB-468 cells. Thus, our findings provide evidence of the cytotoxic potency of Jazz-90, M1S, and M2S, but limited HDAC inhibitory effects in TNBC cells in vitro, hence warranting further modulation of the capping and Zn 2+ binding moieties to enhance their HDAC inhibitory profile
Deterministic annealing algorithm: tutorial, application to pickup and delivery problem and computational aspects
Get PDFThe deterministic annealing (DA) method, used for the solution of several nonconvex problems, offers the ability to avoid shallow local minima of a given cost surface and the ability to minimize the cost function even when there are many local minima. The method is established in a probabilistic framework through basic information-theoretic techniques such as maximum entropy and random coding. It arises naturally in the context of statistical mechanics by the emulation of a physical process whereby a solid is slowly cooled and at zero temperature assumes its minimum energy configuration. We start with the introduction to DA method and then present a tutorial to describe the algorithm steps. Also, we discuss the connections of DA method with Statistical Mechanics and Rate-Distortion Theory. Next, we present the application of DA method to pickup and deliver scheduling problem with time windows. Finally, a computational complexity analysis for DA is presented for a given temperature schedule. The case study focuses on the geometric cooling law , where is the temperature at time .Submission published under a 24 month embargo labeled 'U of I only', the embargo will last until 2017-05-01The student, Pratik Mayur Parekh, accepted the attached license on 2015-04-29 at 11:47.The student, Pratik Mayur Parekh, submitted this Thesis for approval on 2015-04-29 at 11:54.This Thesis was approved for publication on 2015-04-30 at 15:06.DSpace SAF Submission Ingestion Package generated from Vireo submission #8183 on 2015-07-22 at 14:19:02Made available in DSpace on 2015-07-22T22:34:01Z (GMT). No. of bitstreams: 2
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Previous issue date: 2015-04-30Embargo set by: Seth Robbins for item 79929
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The Cytotoxicity and Action of Curcumin Derivatives against Fn14+ Triple Negative Breast Cancer through repression of NF-κB p65
No full textTriple negative breast cancer (TNBC) is an aggressive subtype of the disease which lacks options for targeted systemic therapies due to a lack of actionable clinical targets. Molecular analysis has revealed that Fn14, a cytokine receptor, is over-expressed in 75% of invasive breast cancers but not in normal mammary epithelia. Ectopic Fn14 overexpression has been shown to induce canonical NF-κB signalling, which in response enhances Fn14 expression configuring an auto-regulatory loop that drives breast cancer cell malignant behavior. We hypothesised that suppression of the Fn14/NF-κB positive feedback loop may reduce Fn14 expression and the associated pro-migratory and pro- invasive characteristics of TNBC.
Previously synthesised curcumin derivatives RL66 and RL71 have been shown to inhibit Fn14 and NF-κB p65 expression in triple negative BT-549 and MDA-MB-231 cell lines, while RL121 and RL118 have been shown to inhibit NF-κB activity in in vitro models of prostate cancer. Thus, we postulated that RL121 and RL118 would modulate Fn14 expression in TNBC. Investigations were conducted using two highly invasive Fn14+ TNBC cell lines, MDA-MB-231 and BT-549. RL121 and RL118 had a similar potency to previous derivatives in MDA-MB-231, IC50 0.57 μM and 0.45 μM respectively, and BT-549 cells, 0.16 μM and 0.30 μM respectively. Following 24 hr treatment with RL121, there was a 65% decrease in Fn14 and a 57% decrease in NF-κB p65 in MDA-MB-231 cells. In parallel, RL121 reduced both the invasive and migration capacity in vitro by 50% and 56%, respectively. RL118 was not found to effectively reduce NF-κB p65 or Fn14 expression and associated invasion and migration in either cell line.
RL121-mediated reduction in Fn14 expression and associated reduction in migration and invasion is likely due to our observed suppression of NF-κB p65 expression, which consequently prevents expression of pro-migratory and pro-invasive genes including Fn14. RL121 and RL118 exhibited contrasting mechanisms of action, while both drugs were cytotoxic, only RL121 inhibited expression of NF-κB p65 and Fn14, and reduced in vitro invasion and migration. The cytotoxic pharmacodynamics of RL118 in TNBC requires further investigation.
Our findings provide evidence that RL121 has potent anti-invasive activity in Fn14+ TNBC cells. Further investigation regarding the temporal downregulation of Fn14 and NF-κB p65, and identification of which invasive genes are being modulated are required
The Cytotoxicity and Action of Curcumin Derivatives against Fn14+ Triple Negative Breast Cancer through repression of NF-κB p65
No full textTriple negative breast cancer (TNBC) is an aggressive subtype of the disease which lacks options for targeted systemic therapies due to a lack of actionable clinical targets. Molecular analysis has revealed that Fn14, a cytokine receptor, is over-expressed in 75% of invasive breast cancers but not in normal mammary epithelia. Ectopic Fn14 overexpression has been shown to induce canonical NF-κB signalling, which in response enhances Fn14 expression configuring an auto-regulatory loop that drives breast cancer cell malignant behavior. We hypothesised that suppression of the Fn14/NF-κB positive feedback loop may reduce Fn14 expression and the associated pro-migratory and pro- invasive characteristics of TNBC.
Previously synthesised curcumin derivatives RL66 and RL71 have been shown to inhibit Fn14 and NF-κB p65 expression in triple negative BT-549 and MDA-MB-231 cell lines, while RL121 and RL118 have been shown to inhibit NF-κB activity in in vitro models of prostate cancer. Thus, we postulated that RL121 and RL118 would modulate Fn14 expression in TNBC. Investigations were conducted using two highly invasive Fn14+ TNBC cell lines, MDA-MB-231 and BT-549. RL121 and RL118 had a similar potency to previous derivatives in MDA-MB-231, IC50 0.57 μM and 0.45 μM respectively, and BT-549 cells, 0.16 μM and 0.30 μM respectively. Following 24 hr treatment with RL121, there was a 65% decrease in Fn14 and a 57% decrease in NF-κB p65 in MDA-MB-231 cells. In parallel, RL121 reduced both the invasive and migration capacity in vitro by 50% and 56%, respectively. RL118 was not found to effectively reduce NF-κB p65 or Fn14 expression and associated invasion and migration in either cell line.
RL121-mediated reduction in Fn14 expression and associated reduction in migration and invasion is likely due to our observed suppression of NF-κB p65 expression, which consequently prevents expression of pro-migratory and pro-invasive genes including Fn14. RL121 and RL118 exhibited contrasting mechanisms of action, while both drugs were cytotoxic, only RL121 inhibited expression of NF-κB p65 and Fn14, and reduced in vitro invasion and migration. The cytotoxic pharmacodynamics of RL118 in TNBC requires further investigation.
Our findings provide evidence that RL121 has potent anti-invasive activity in Fn14+ TNBC cells. Further investigation regarding the temporal downregulation of Fn14 and NF-κB p65, and identification of which invasive genes are being modulated are required
Telomerase-associated apoptotic events by mushroom Ganoderma lucidum on premalignant human urothelial cells
No full textAuthor name used in this publication: Mayur Danny I. Gohel2007-2008 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishedGreen (AAM
Synergistic cytotoxic effects of ganoderma lucidum and bacillus calmette guérin on premalignant urothelial HUC-PC cells and its regulation on proinflammatory cytokine secretion
No full textAuthor name used in this publication: John Wai-man YuenAuthor name used in this publication: Mayur-Danny I. Gohel2012-2013 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishedC
Numerical analysis of unsteady compressible flow in the hose of Bubble Curtain Technology
No full textThe offshore wind industry is rapidly advancing, expected to play a crucial role in renewable energy production, with a growing emphasis on addressing associated environmental concerns, particularly the impact of underwater noise generated during the installation of wind turbines. In response, bubble curtain technology (BCT) has emerged as a potential solution. While the BCT operational concept has been demonstrated in practice, a detailed investigation related to fluid dynamics, geometric characteristics, and operational parameters has yet to be conducted. It's important to note that this need for investigation is specifically applicable to large BCT systems. This research aims to enhance the understanding of unsteady compressible flow inside BCT hoses and examine the impact of operational parameters on the pneumatic aspects of the bubble curtain system along the hose length.This thesis systematically defined its fundamental objectives, beginning with the development of a 1D unsteady model for compressible flow in pipeline systems. This model, which served as the basis for subsequent studies, was verified against the existing literature, revealing a 2-4% difference in flow rates and pressure responses. Subsequently, the scope was broadened to include nozzle configurations, which were gradually included in the pipeline model. The model evolved through configurations with one, three, and five nozzles, where larger diameters increased dampening on transient pressure fluctuations. As the research progressed, the final model, incorporating five nozzles, was used as the basis for the scaled Bubble Curtain Technology (BCT) model.A sensitivity analysis for this study was carried out utilizing parameters from existing research. The sensitivity study specifically emphasized the influence of geometric (hose and nozzle diameters, hose length, nozzle spacing) and operational factors (discharge coefficient, water depth, air flow rate) on the flow dynamic of Bubble Curtain Technology (BCT). The main findings from this research included reducing backflow with smaller diameters and lowering reverse flow with greater discharge coefficients and airflow rates. Changing the hose length and nozzle spacing proved effective for adjusting the required flow rates. The investigation also found that nozzle diameter and discharge coefficient had a considerable impact on nozzle flow rates, with a 2-3% increase over reference values at the maximum value range. Other geometric and operational parameters in the tested ranges had a relatively lower influence on the nozzle flow rates or generated pressure variations.The scaled BCT unsteady compressible flow dynamics model presented in this thesis is still in its early stages of development, but it can serve as a basis for the development of full-scale pneumatic models that can enhance BCT and lessen the environmental impact of offshore wind farm operations.Offshore and Dredging Engineerin
Subjective Versus Objective: An Exploratory Analysis of Latino Primary Care Patients With Self-Perceived Depression Who Do Not Fulfill Primary Care Evaluation of Mental Disorders Patient Health Questionnaire Criteria for Depression
No full textObjective: Identification and treatment of depression may be difficult for primary care providers when there is a mismatch between the patient’s subjective experiences of illness and objective criteria. Cultural differences in presentation of symptoms among Latino immigrants may hinder access to care for treatment of depression. This article seeks to describe the self-perceptions and symptoms of Latino primary care patients who identify themselves as depressed but do not meet screening criteria for depression.
Method: A convenience sample of Latino immigrants (N = 177) in Corona, Queens, New York, was obtained from a primary care practice from August 2008 to December 2008. The sample was divided into 3 groups according to whether participants met Patient Health Questionnaire diagnostic criteria for depression and whether or not participants had a self-perceived mental health problem and self-identified their problem as “depression” from a checklist of cultural idioms of distress. Psychosocial, demographic, and treatment variables were compared between the 3 groups.
Results: Participants’ descriptions of symptoms had a predominantly somatic component. The most common complaints were ánimo bajo (low energy) and decaimiento (weakness). Participants with “subjective” depression had mean scores of somatic symptoms and depression severity that were significantly lower than the participants with “objective” depression and significantly higher than the group with no depression (P < .0001).
Conclusions: Latino immigrants who perceive that they need help with depression, but do not meet screening criteria for depression, still have significant distress and impairment. To avoid having these patients “fall through the cracks,” it is important to take into account culturally accepted expressions of distress and the meaning of illness for the individual.Peer reviewe
