In silico discovery of novel Retinoic Acid Receptor agonist structures

BACKGROUND: Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. RESULTS: We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro. CONCLUSIONS: Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy

Adenosine pharmacologic stress myocardial perfusion tomographic imaging in patients with significant aortic stenosis Diagnostic efficacy and comparison of clinical, hemodynamic and electrocardiographic variables with 100 age-matched control subjects

AbstractObjectives. This study assessed the safety and diagnostic accuracy of adenosine stress myocardial perfusion scintigraphy for the detection of coronary artery disease using single-photon emission computed tomography (SPECT) in patients with significant aortic stenosis.Background. Exercise cardiac stress testing in patients with significant aortic stenosis is generally avoided because of concerns for safety. In addition, those studies that have analyzed the utility of exercise testing both with and without myocardial thallium-201 scintigraphy for the diagnosis of coronary artery disease have yielded low specificity. Currently, no safe and accurate means exists to noninvasively assess the presence, extent and severity of coronary artery disease in patients with significant aortic stenosis.Methods. The study included 35 patients with moderate to severe aortic stenosis (mean [±SD] aortic valve area 0.84 ± 0.16 cm2, range 0.5 to 1.2; mean maximal instantaneous aortic valve gradient 44.4 ± 15.9 mm Hg, range 20 to 84). All patients underwent a 6-min adenosine infusion (140 μg/kg body weight per min) protocol and either separate acquisition rest thallium-201/stress technetium-99m sestamibi or stress and 4-h redistribution thallium-201 SPECT. Visual 20-segment SPECT analysis used a standard five-point scoring system from 0 (normal tracer uptake) to 4 (absent uptake). The SPECT results were considered abnormal if more than two segments had a stress score ≥2. Hemodynamic, electrocardiographic and clinical responses were compared with those in a reference group of 100 consecutive age-matched patients undergoing adenosine SPECT who did not have aortic stenosis.Results. Hemodynamic responses during adenosine stress testing between the study and control patients demonstrated no significant difference in the net change in systolic blood pressure (18% of baseline vs. 14%, patients with aortic stenosis vs. control subjects), heart rate (21% vs. 19%), rate-pressure product (0% vs. 2%) or incidence of chest pain (23% vs. 35%) or transient second- (9% vs. 9%) or third-degree atrioventricular block (3% vs. 1%). In the 20 patients who had coronary angiography, sensitivity for detection of coronary artery disease was 92% (12 of 13) and specificity was 71% (5 of 7).Conclusions. In this preliminary study, adenosine was found to be well tolerated and diagnostically accurate in patients with moderate to severe aortic stenosis

967-21 Long Term Results of Balloon Expandable Slotted-Tube Nitinol Stents in Canine Coronary Arteries

This study evaluated delivery performance, quantitative angiographic parameters, intravascular ultrasound appearance. long term patency and vascular histology of radio-opaque, slotted-tube nickel titanium (nitinoll stents permanently implanted in canine coronary arteries. Dogs were treated with aspirin for 1 month. Follow-up angiography and histology were performed at 0.5, 1, 3, and 6 months (number of vessels = 2, 4, 6, and 26, respectively).ResultsThirty-eight of 39 (97%) stents were successfully implanted in the mid LAD and LCX of 20 dogs. One stent, which was undersized, was successfully removed by thermal recovery. Tandem stents were placed in 2 dogs without difficulty. Intravascular ultrasound of 6 stents showed symmetrical expansion with good wall contact. Acute angiographic parameters:nominal stent size (mm)ANOVA p3.03.54.0number42212–inflation pressure (atm)5.5±056.1±1.45.9±1.60.47minimal diameter (mm)2.93±0.073.24±0.143.48±0.160.0003balloon to artery ratio1.23±0.031.25±0.101.25±0.080.65stent to artery ratio1.09±0.031.14±0.091.13±0.070.30percent recoil11.0±1.88.4±1.89.9±1.80.05At follow-up, all vessels and 9 of 9 stented sidebranches were patent. The mean percent stenosis at 3 to 6 months was –1.6±5.2 and the late loss was 0.2±0.3 mm. All struts were covered with neointima at 2 weeks. At 6 months the maximal neointimal thickness was 260±50 μm and was located adjacent to the struts. No thrombi and only occasional areas of granulation tissue with rare inflammatory cells were seen.ConclusionsA slotted tube nitinol stent has delivery performance characteristics and recoil similar to stainless steel slotted-tube stents. Nitinol stents endothelialize rapidly and intimal proliferation is insufficient to create a stenosis in this animal model. These data suggest that a slotted-tube, balloon expandable nitinol stent is sufficiently reliable and biocompatible to warrant clinical trials

Safety of Coronary Reactivity Testing in Women With No Obstructive Coronary Artery Disease Results From the NHLBI-Sponsored WISE (Women's Ischemia Syndrome Evaluation) Study

ObjectivesThis study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD).BackgroundMicrovascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown.MethodsThe authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded.ResultsCRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%).ConclusionsIn women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00832702

The Development of Accounting in the Franc Zone Countries in Africa

This paper develops a taxonomy of the different accounting systems that have evolved in Africa from the colonial era, through the early years of independence, to modern times. A preliminary test of the classification scheme for the current era of International Financial Reporting Standards (IFRS) was carried out using data from a PricewaterhouseCoopers (2011) survey. The results confirm Nobes’ (2008) hypotheses on patterns of national reaction to IFRS. The results also show that a distinctive approach to financial accounting, which is alien to Anglo-American practitioners, and modelled on long-established French traditions, is still entrenched in Africa’s franc zone countries in the 21st century despite sustained pressure from the World Bank and the International Monetary Fund for large entities to adopt IFRS. These findings provide some evidence against Alexander and Archer’s (2000) claim that the contemporary notion of “Anglo-Saxon accounting” is a myth

A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types

Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours

Does the implementation of a Quality Improvement Care Bundle reduce the incidence of acute kidney injury in patients undergoing emergency laparotomy?

Previous work has demonstrated a survival improvement following the introduction of an enhanced recovery protocol in patients undergoing emergency laparotomy (the emergency laparotomy pathway quality improvement care (ELPQuiC) bundle). Implementation of this bundle increased the use of intra-operative goal directed fluid therapy and ICU admission, both evidence-based strategies recommended to improve kidney outcomes. The aim of this study was to determine if the observed mortality benefit could be explained by a difference in the incidence of AKI pre- and post-implementation of the protocol.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Identification of the Cis-Acting Elements and Trans-Acting Factors That Mediate Cell-Specific and Thyroid Hormone Stimulation of Growth Hormone Gene Expression

This chapter reviews the physical and biological properties of thyroid hormone receptors and the relationship of the receptor to the avian erythroblastosis virus (AEV) v-erbA gene. The properties of thyroid hormone nuclear receptors derived from studies using GHi and GC cells are described in the chapter. The thyroid hormone receptor is related to the avian erythroblastosis virus v-erbA gene. The AEV—a defective leukemia retrovirus—induces sarcomas and erythroblastosis in vivo and induces the transformation of fibroblasts and erythroblasts to neoplastic phenotypes in vitro. The chapter also reviews the studies in which the rat growth hormone gene was used as a model to identify cis-acting DNA sequences and transacting regulatory proteins that are essential for cell-specific expression and transcriptional stimulation of the gene by the thyroid hormone. The thyroid hormone regulates the growth hormone gene expression at the transcriptional level. A detailed functional and protein-DNA footprint analysis of the elements that are involved in mediating thyroid hormone and cell-specific basal expression of the gene is also presented in the chapter.Peer reviewe