In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.

BackgroundCruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease.Methodology/principal findingsWRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported.ConclusionsWe demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery.Chemistry and Chemical Biolog

Andersen And The Market For Lemons In Audit Reports

Previous accounting ethics research berates auditors for ethical lapses that contribute to the failure of Andersen (e.g., Duska, R.: 2005, Journal of Business Ethics 57, 17-29; Staubus, G.: 2005, Journal of Business Ethics 57, 5-15; however, some of the blame must also fall on regulatory and professional bodies that exist to mitigate auditors\u27 ethical lapses. In this paper, we consider the ethical and economic context that existed and facilitated Andersen\u27s failure. Our analysis is grounded in Akerlof\u27s (1970, Quarterly Journal of Economics August, 488-500) Theory of the Market for Lemons and we characterize the market for audit reports as a market for lemons. Consistent with Akerlof\u27s model, we consider the appropriateness of the countervailing mechanisms that existed at the time of Andersen\u27s demise that appeared to have effectively failed in counteracting Andersen\u27s ethical shortcomings. Finally, we assess the appropriateness of the remedies proposed by the Sarbanes-Oxley Act of 2002 (SOA) to ensure that similar ethical lapses will not occur in the future. Our analysis indicates that the SOA regulatory reforms should counteract some of the necessary conditions of the Lemons Model, and thereby mitigate the likelihood of audit failures. However, we contend that the effectiveness of the SOA critically depends upon the focus and attention of the Public Companies Accounting Oversight Board (PCAOB) towards assessing the ethical climates of public accounting firms. Assessments by the PCAOB of public accounting firm\u27s ethical climate are needed to sufficiently ensure that public accounting firms effectively promote and maintain audit quality in situations where unconscious bias or economic incentives may erode the public accounting firm\u27s independence. © Springer Science+Business Media B.V. 2007

The Effects Of Public Pressure On Csr Behavior In A Capital Market Experiencing Excessive Moral Debt

The events surrounding the passage of the Sarbanes-Oxley Act of 2002 (Sarbanes) offer an opportunity to reflect on the influences of public pressure and possible public policy shifts on CSR behavior in a capital market experiencing excessive moral debt. Using the passage of Sarbanes to symbolize a potential public policy shift driven by public pressure, we examine the influence of social legitimacy variables on corporate social responsibility (CSR) behavior before (1991-2001) and after (2002-2005) the passage of the Sarbanes-Oxley Act of 2002. We posit that changes in CSR strategies surrounding the passage of Sarbanes were used to maximize stakeholder interests by addressing social legitimacy involving corporate accountability issues. Our findings support that CSR behaviors were significantly influenced by the public pressure variables of Sarbanes and company size, but were not significantly influenced by our economic legitimacy control measures, with the exception of a positive significant interaction between Leverage and Sarbanes for CSR Strengths. It appears that post- Sarbanes CSR behaviors were used to address social legitimacy concerns. Further, as CSR Weaknesses ratings exceeded CSR Strengths ratings post-Sarbanes, it appears that transparency of actual CSR performance may have improved post-Sarbanes. © 2012 American Accounting Association. All rights reserved

The effects of public pressure on CSR behavior in a capital market experiencing excessive moral debt

The events surrounding the passage of the Sarbanes-Oxley Act of 2002 (Sarbanes) offer an opportunity to reflect on the influences of public pressure and possible public policy shifts on CSR behavior in a capital market experiencing excessive moral debt. Using the passage of Sarbanes to symbolize a potential public policy shift driven by public pressure, we examine the influence of social legitimacy variables on corporate social responsibility (CSR) behavior before (1991-2001) and after (2002-2005) the passage of the Sarbanes-Oxley Act of 2002. We posit that changes in CSR strategies surrounding the passage of Sarbanes were used to maximize stakeholder interests by addressing social legitimacy involving corporate accountability issues. Our findings support that CSR behaviors were significantly influenced by the public pressure variables of Sarbanes and company size, but were not significantly influenced by our economic legitimacy control measures, with the exception of a positive significant interaction between Leverage and Sarbanes for CSR Strengths. It appears that post- Sarbanes CSR behaviors were used to address social legitimacy concerns. Further, as CSR Weaknesses ratings exceeded CSR Strengths ratings post-Sarbanes, it appears that transparency of actual CSR performance may have improved post-Sarbanes. © 2012 American Accounting Association. All rights reserved

Histopathology of mice infected by T. cruzi.

<p>I/I: Inflammation and infiltration.</p><p>+10A: Numerous nests of <i>T. cruzi</i> amastigotes.</p><p>+A: 1-3 nests of <i>T. cruzi</i> amastigotes.</p><p>N: Negative.</p