James E. Ferguson

Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease

Background—This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients. Methods and Results—Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P =0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P =0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P <0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban. Conclusions—Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Mechanisms of Endothelial Differentiation in Embryonic Vasculogenesis

The formation of new blood vessels in the adult organism not only contributes to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. In this review, we describe the current understanding of where endothelial differentiation from pluripotent progenitor cells occurs during development, how this process is controlled at the molecular level, and what model systems can be used to investigate the earliest steps of blood vessel formation.

ASB4 Is a Hydroxylation Substrate of FIH and Promotes Vascular Differentiation via an Oxygen-Dependent Mechanism

ABSTRACT The molecular mechanisms of endothelial differentiation into a functional vascular network are incompletely understood. To identify novel factors in endothelial development, we used a microarray screen with differentiating embryonic stem (ES) cells that identified the gene for ankyrin repeat and SOCS box protein 4 (ASB4) as the most highly differentially expressed gene in the vascular lineage during early differentiation. Like other SOCS box-containing proteins, ASB4 is the substrate recognition molecule of an elongin B/elongin C/cullin/Roc ubiquitin ligase complex that mediates the ubiquitination and degradation of substrate protein(s). High levels of ASB4 expression in the embryonic vasculature coincide with drastic increases in oxygen tension as placental blood flow is initiated. However, as vessels mature and oxygen levels stabilize, ASB4 expression is quickly downregulated, suggesting that ASB4 may function to modulate an endothelium-specific response to increasing oxygen tension. Consistent with the hypothesis that ASB4 function is regulated by oxygen concentration, ASB4 interacts with the factor inhibiting HIF1α (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mechanism. Additionally, overexpression of ASB4 in ES cells promotes differentiation into the vascular lineage in an oxygen-dependent manner. We postulate that hydroxylation of ASB4 in normoxia promotes binding to and degradation of substrate protein(s) to modulate vascular differentiation.

Break the Cycle: The Role of Cell-Cycle Modulation in the Prevention of Vasculoproliferative Diseases

Atherosclerosis is a major health problem in the western world, and the effectiveness of interventional therapeutic modalities for symptomatic atherosclerotic lesions is limited by vessel restenosis. Proliferation and migration of smooth muscle cells (SMCs) play a central role in post-interventional restenosis. Accordingly, many therapeutic approaches attempt to inhibit SMC proliferation. As the cell cycle is a final common pathway in SMC proliferation, proteins of the cell cycle have emerged as logical targets for the treatment and prevention of restenotic lesions. In this review we discuss current approaches that target the cell cycle in smooth muscle cells, and also describe recent and ongoing clinical trials that involve cell-cycle manipulation in the treatment of vasculoproliferative diseases.

Cost Analysis of Robot-Assisted Laparoscopic Versus Hand-Assisted Laparoscopic Partial Nephrectomy

PURPOSE To perform a cost comparison of three approaches to partial nephrectomy (PN): Open (OPN), hand-assisted laparoscopic (HALPN), and robot-assisted (RAPN). PATIENTS AND METHODS We retrospectively evaluated cost and clinical data from patients undergoing OPN, HALPN, and RAPN from 2007 to 2010 (n=89). Baseline demographic data, patient comorbidities, R.E.N.A.L. nephrometry score, and perioperative outcomes were assessed. Costs and subcosts from the operating room (OR) and hospital were evaluated using nonparametric statistical analyses. RESULTS Patient demographics and tumor characteristics were similar between HALPN and RAPN, while OPN patients had more comorbidities and more difficult-to-resect tumors. Thus, HALPN and RAPN were directly compared, while OPNs were excluded from the analysis. No difference was found in overall costs between HALPN and RAPN (

The ubiquitin ligase ASB4 promotes trophoblast differentiation through the degradation of ID2.

13,560 vs

Phosphodiesterase type 5 inhibitors as a treatment for erectile dysfunction: Current information and new horizons

13,439, P=0.29). OR costs were higher for RAPN (

Epidemiology of Prostate and Testicular Cancer.

7276 vs

MP98-07 LIMD2 EXPRESSION IS UPREGULATED IN BLADDER CANCER LYMPH NODE METASTASES, CORRELATES WITH THE AGGRESSIVE BASAL MOLECULAR PHENOTYPE, AND IS IMPLICATED IN BLADDER CANCER METASTASIS.

5708, P=0.0001) because of the higher robotic capital and reusable equipment costs that outweighed higher disposable costs in the HALPN group. OR time-related costs were similar between groups. RAPN patients had a shorter length of stay (LOS), which decreased postoperative hospital costs (

PD36-11 COMPARISON OF TOTAL 90 DAY COSTS FOR OPEN VERSUS ROBOTIC CYSTECTOMY

4371 vs