Background: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). Materials and methods: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. Results: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: −0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed

Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis–Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.

Purpose: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination.Experimental Design: Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C max for each drug alone compared with its C max during combination therapy.Results: The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C max for any of the drugs alone compared with the C max during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib.Conclusions: Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.

We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. Here, we used chemical genomic and proteomic profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, activates two pathways, one eliciting cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation and driving the transcriptional downregulation of the androgen receptor, and a second pathway that activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response (UPR). SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy.

Background: Understanding the differences in how patient complexity varies across surgical specialties can inform policy decisions about appropriate resource allocation and reimbursement. This study evaluated variation in patient complexity across surgical specialties and the correlation between complexity and work relative value units. Study design: The 2017 American College of Surgeons National Surgical Quality Improvement Program was queried for cases involving otolaryngology and general, neurologic, vascular, cardiac, thoracic, urologic, orthopedic, and plastic surgery. A total of 10 domains of patient complexity were measured: American Society of Anesthesiologists class 4, number of major comorbidities, emergency operation, major complications, concurrent procedures, additional procedures, length of stay, non-home discharge, readmission, and mortality. Specialties were ranked by their complexity domains and the domains summed to create an overall complexity score. Patient complexity then was evaluated for correlation with work relative value units. Results: Overall, 936,496 cases were identified. Cardiac surgery had the greatest total complexity score and was most complex across 4 domains: American Society of Anesthesiologists class 4 (78.5%), 30-day mortality (3.4%), major complications (56.9%), and mean length of stay (9.8 days). Vascular surgery had the second greatest complexity score and ranked the greatest on the domains of major comorbidities (2.7 comorbidities) and 30-day readmissions (10.1%). The work relative value units did not correlate with overall complexity score (Spearman's r ¼ 0.07; P < .01). Although vascular surgery had the second most complex patients, it ranked fifth greatest in median work relative value units. Similarly, general surgery was the fifth most complex but had the second-least median work relative value units. Conclusion: Substantial differences exist between patient complexity across specialties, which do not correlate with work relative value units. Physician effort is determined largely by patient complexity, which is not captured appropriately by the current work relative value units.