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1.  A Small Molecule Inhibitor of ETV1, YK-4-279, Prevents Prostate Cancer Growth and Metastasis in a Mouse Xenograft Model 
PLoS ONE  2014;9(12):e114260.
Background
The erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.
Methods and Findings
We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S)-YK-4-279 is the active enantiomer in prostate cancer cells.
Conclusion
Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential therapeutic tool for treatment of human prostate cancer at different stages.
doi:10.1371/journal.pone.0114260
PMCID: PMC4257561  PMID: 25479232
2.  Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects 
Aims
Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc.
Methods
Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction.
Results
Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.
Conclusions
These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.
doi:10.1111/j.1365-2125.2012.04416.x
PMCID: PMC3612716  PMID: 22882281
cardiac repolarization; exenatide; thorough QT/QTc study
3.  A novel mRNA binding protein complex promotes localized plasminogen activator inhibitor-1 accumulation at the myoendothelial junction 
Objective
Plasminogen activator inhibitor-1 (PAI-1) has previously been shown to be key to the formation of myoendothelial junctions (MEJs) in normal and pathological states (e.g., obesity). We there for sought to identify the mechanism whereby PAI-1 could be selectively accumulated at the MEJ.
Methods and Results
We identified PAI-1 protein enrichment at the MEJ in obese mice and in response to TNF-α with a vascular cell co-culture. However, PAI-1 mRNA was also found at the MEJ and transfection with a PAI-1-GFP with TNF-α did not demonstrate trafficking of the protein to the MEJ. We there for hypothesized the PAI-1 mRNA was being locally translated and identified serpine binding protein-1, which stabilizes PAI-1 mRNA, as being enriched in obese mice and after treatment with TNF-α, while staufen, which degrades PAI-1 mRNA, was absent in obese mice and after TNF- α application. We identified nicotinamide phosphoribosyl transferase as a serpine binding protein-1 binding partner with a functional tau-like microtubule binding domain. Application of peptides against the microtubule binding domain significantly decreased the number of MEJs and the amount of PAI-1 at the MEJ.
Conclusions
We conclude that PAI-1 can be locally translated at the MEJ due to a unique mRNA binding protein complex.
doi:10.1161/ATVBAHA.112.246371
PMCID: PMC3331922  PMID: 22383705
plasminogen activator inhibitor-1; myoendothelial junction; serpine binding protein-1 (SERBP1); Staufen; mRNA binding protein; nicotinamide phosphoribosyl transferase (NAMPT)
4.  Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals 
Background
Diabetes is associated with a higher risk for adverse cardiovascular outcomes. To improve the health outcomes of patients with type 2 diabetes (T2DM), the American Diabetes Association (ADA) recommended target goals for the improvement of glycemic control and the reduction of cardiovascular risk factors associated with the disease. This retrospective analysis calculated the absolute benefit increase (ABI) of using exenatide once weekly (QW), a glucagon-like peptide-1 (GLP-1) receptor agonist, vs an oral glucose-lowering medication or insulin glargine to achieve ADA-recommended goals. The number needed to treat (NNT) to achieve these goals was also calculated and provides a useful clinical metric for comparing potential therapies from different drug classes.
Methods
Patient data from three double-blind or open label, 26-week, randomized, controlled trials were retrospectively analyzed separately. ABI and NNT were calculated by comparing the percentage of patients treated with exenatide QW (N = 641) vs metformin (N = 246), sitagliptin (N = 329), pioglitazone (N = 328), or insulin glargine (N = 223), who achieved a single glycemic, weight, blood pressure, or lipid goal or a composite of these recommended goals, during the DURATION-2, -3, and -4 clinical trials.
Results
Significant ABIs favoring exenatide QW over all four glucose-lowering medications were observed for at least one HbA1c glycemic goal. NNTs of 4 and 5 were calculated when exenatide QW was compared to sitagliptin for attaining HbA1c goals of <7.0% and ≤6.5%, respectively. Additionally, significantly more patients using exenatide QW compared to sitagliptin, pioglitazone, or insulin glargine attained the composite goal of HbA1c <7% or ≤6.5%, without weight gain or hypoglycemia. Exenatide QW was also favored over sitagliptin and insulin glargine for the achievement of the composite goals of HbA1c <7% (or ≤6.5%), systolic blood pressure <130 mm Hg, and low-density lipoprotein <2.59 mmol/L. For most goals, exenatide QW and metformin had similar effects in treatment naïve patients.
Conclusions
This analysis assessed the between-therapy differences in achieving therapeutic goals with therapies commonly used for glycemic control in patients with T2DM. In clinical trials, exenatide QW assisted more patients in reaching the majority of ADA-recommended therapeutic goals than treatment with sitagliptin, pioglitazone, or insulin glargine.
Trial registration
NCT00637273, NCT00641056, NCT00676338
doi:10.1186/1475-2840-12-48
PMCID: PMC3622579  PMID: 23522121
Number needed to treat; Absolute benefit; Exenatide; Type 2 diabetes; Diabetes mellitus; ADA treatment guidelines; GLP-1
5.  Health and economic outcomes for exenatide once weekly, insulin, and pioglitazone therapies in the treatment of type 2 diabetes: a simulation analysis 
Background
Patients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies.
Patients and methods
The Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999–2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m2, weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ≥ 8% (treat to target A1C < 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs.
Results
By year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively.
Conclusions
This long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected.
doi:10.2147/VHRM.S28744
PMCID: PMC3346268  PMID: 22566747
diabetes; modeling; exenatide; pioglitazone; insulin; cardiovascular risk
6.  A new method for in vivo visualization of vessel remodeling using a near-infrared dye 
Intro
Vascular obstructive events can be partially compensated for by remodeling processes that increase vessel diameter and collateral tortuosity. However, methods for visualizing remodeling events in vivo and with temporal comparisons from the same animal remain elusive.
Methods
Using a novel infrared conjugated polyethylene glycol dye, we investigated the possibility of intravital vascular imaging of the mouse ear before and after ligation of the primary feeder artery. For comparison, we used two different mouse models known to have impaired vascular remodeling post ligation (i.e. aged and PAI-1−/− mice). The results obtained with the infrared dye were confirmed using immunofluorescence labeling of the ear microvasculature with confocal microscopy.
Results
After ligation, increases in vessel diameter (between 10% and 60%) and tortuosity (approximately 15%) were observed in C57Bl/6 mice using both the infrared dye and the immunofluorescence technique. However, aged C57Bl/6 and PAI-1−/− mice did not show vascular remodeling following ligation.
Conclusion
Vascular remodeling can be visualized and accurately quantified using a new infrared dye in vivo. This analysis technique could be generally employed for quantitative investigations of changes in vascular remodeling.
doi:10.1111/j.1549-8719.2011.00085.x
PMCID: PMC3081403  PMID: 21418375
vascular remodeling; in vivo imaging; plasminogen activator inhibitor-1; aging
7.  Vitamin D and sepsis 
Dermato-endocrinology  2012;4(2):101-108.
Vitamin D insufficiency and sepsis are both highly prevalent worldwide problems and this article reviews the emerging science that is defining the intersections of these conditions. The importance of vitamin D’s role in skeletal health has long been understood but recent evidence is beginning to highlight its role in the functioning of other physiologic systems of the body. Basic science data reveal its integral role in local immune responses to pathogens and the systemic inflammatory pathways of sepsis. Furthermore, clinical scientists have found associations with respiratory infections, critical illness and sepsis but the causal relationship and its clinical impact have yet to be clearly defined. The article ends with speculations on the connections between racial disparities and seasonal differences in sepsis and vitamin D insufficiency.
doi:10.4161/derm.19859
PMCID: PMC3427188  PMID: 22928065
vitamin D; sepsis; severe sepsis; critical care medicine; nutrition; infection
8.  Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials 
Background
Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes.
Methods
Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12–52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated.
Results
Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166–171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%).
Conclusion
Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.
doi:10.2147/DMSO.S28387
PMCID: PMC3287409  PMID: 22375098
exenatide; safety; adverse events; risk difference
9.  Rational or rationalized choices in fluid resuscitation? 
Critical Care  2010;14(6):1006.
The war between colloids and crystalloids wages on. In a large multinational survey of fluid prescribing practices in critically ill patients, we have a new and intriguing snapshot of global fluid resuscitation practices. Colloids are more often used for impaired perfusion or low cardiac output, and the choice of colloid or crystalloid varies enormously between countries. Why are some ICUs prescribing colloids more often than crystalloids when there is little convincing evidence that colloids are superior for fluid resuscitation? Are colloids advantageous in certain diseases, or in specific regional patient populations that have not yet been elucidated? Perhaps we should look inwards: the answer may not be more randomized clinical trials, but better adherence to current guidelines and treatment recommendations.
doi:10.1186/cc9305
PMCID: PMC3220017  PMID: 21092151
10.  Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2 
Circulation research  2010;107(6):737-746.
Rationale
Macrophages change their phenotype and biological functions depending on the microenvironment. In atherosclerosis, oxidative tissue damage accompanies chronic inflammation, however, macrophage phenotypic changes in response to oxidatively modified molecules are not known.
Objective
To examine macrophage phenotypic changes in response to oxidized phospholipids that are present in atherosclerotic lesions.
Methods and Results
We show that oxidized phospholipid-treated macrophages develop into a novel phenotype (Mox), strikingly different from the conventional M1 and M2 macrophage phenotypes. Compared to M1 and M2, Mox show a different gene expression pattern, as well as decreased phagocytotic and chemotactic capacity. Treatment with oxidized phospholipids induces both M1 and M2 macrophages to switch to the Mox phenotype. Whole genome expression array analysis and subsequent gene ontology clustering revealed that the Mox phenotype was characterized by abundant over-representation of Nrf2-mediated expression of redox-regulatory genes. In macrophages isolated from Nrf2−/− mice, oxidized phospholipid-induced gene expression and regulation of redox status were compromised. Moreover, we found that Mox macrophages comprise 30% of all macrophages cells in advanced atherosclerotic lesions of LDL receptor knockout mice.
Conclusions
Together, we identify Nrf2 as a key regulator in the formation of a novel macrophage phenotype (Mox) that develops in response to oxidative tissue damage. The unique biological properties of Mox suggest this phenotype may play an important role in atherosclerotic lesion development as well as in other settings of chronic inflammation.
doi:10.1161/CIRCRESAHA.109.215715
PMCID: PMC2941538  PMID: 20651288
Macrophages; Oxidized Phospholipids; Atherosclerosis; Nrf2
11.  Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years 
Background
The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes.
Methods
A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years.
Results
In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed.
Conclusions
Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW.
Trial Registration
ClinicalTrials.gov NCT00308139
doi:10.1186/1472-6823-11-9
PMCID: PMC3112417  PMID: 21529363
12.  Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes 
It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies.
Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety
doi:10.1186/1475-2840-10-22
PMCID: PMC3070629  PMID: 21410975
GLP-1 receptor agonist; diabetes; cardiovascular safety
13.  Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects 
Aims
Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc.
Methods
Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction.
Results
Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.
Conclusions
These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.
doi:10.1111/j.1365-2125.2012.04416.x
PMCID: PMC3612716  PMID: 22882281
cardiac repolarization; exenatide; thorough QT/QTc study

Results 1-13 (13)