Citations

The signaling molecule adenosine has been implicated in attenuating acute lung injury (ALI). Adenosine signaling is terminated by its uptake through equilibrative nucleoside transporters (ENTs). We hypothesized that ENT‐dependent adenosine uptake could be targeted to enhance adenosine‐mediated lung protection. To address this hypothesis, we exposed mice to high‐pressure mechanical ventilation to induce ALI. Initial studies demonstrated time‐dependent repression of ENT1 and ENT2 transcript and protein levels during ALI. To examine the contention that ENT repression represents an endogenous adaptive response, we performed functional studies with the ENT inhibitor dipyridamole. Dipyridamole treatment (1 mg/kg; EC 50 =10 μM) was associated with significant increases in ALI survival time (277 vs. 395 min; P <0.05). Subsequent studies in gene‐targeted mice for Ent1 or Ent2 revealed a selective phenotype in Ent2 ‐/‐ mice, including attenuated pulmonary edema and improved gas exchange during ALI in conjunction with elevated adenosine levels in the bronchoalveolar fluid. Furthermore, studies in genetic models for adenosine receptors implicated the A 2B adenosine receptor (Adora2b) in mediating ENT‐dependent lung protection. Notably, dipyridamole‐dependent attenuation of lung inflammation was abolished in mice with alveolar epithelial Adora2b gene deletion. Our newly identified crosstalk pathway between ENT2 and alveolar epithelial Adora2b in lung protection during ALI opens possibilities for combined therapies targeted to this protein set.—Eckle, T., Hughes, K., Ehrentraut, H., Brodsky, K. S., Rosenberger, P., Choi, D.‐S., Ravid, K., Weng, T., Xia, Y., Blackburn, M. R.Eltzschig, H. K., Crosstalk between the equilibrative nucleoside transporter ENT2 and alveolar Adora2b adenosine receptors dampens acute lung injury. FASEB J. 27, 3078–3089 (2013). www.fasebj.org

Background and Study Aims. Endoscopic placement of self-expanding metal stents (SEMSs) is indicated for palliation of inoperable malignant biliary obstruction. A fully covered biliary SEMS (WallFlex Biliary RX Boston Scientific, Natick, USA) was assessed for palliation of extrahepatic malignant biliary obstruction.Patients and Methods. 58 patients were included in this prospective, multicenter series conducted under an FDA-approved IDE. Main outcome measurements included (1) absence of stent occlusion within six months or until death, whichever occurred first and (2) technical success, need for reintervention, bilirubin levels, stent patency, time to stent occlusion, and adverse events.Results. Technical success was achieved in 98% (57/58), with demonstrated acute removability in two patients. Adequate clinical palliation until completion of followup was achievedin 98% (54/55) ofevaluablepatients, with 1 reintervention due to stent obstruction after 142 days. Mean total bilirubin decreased from 8.9 mg/dL to 1.2 mg/dL at 1 month. Device-related adverse events were limited and included 2 cases of cholecystitis. One stent migrated following radiation therapy.Conclusions. The WallFlex Biliary fully covered stent yielded technically successful placement with uncomplicated acute removal where required, appropriate reduction in bilirubin levels, and low rates of stent migration and occlusion. This SEMS allows successful palliation of malignant extrahepatic biliary obstruction.

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Abstract The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632–42. ©2013 AACR.

Objective— Endothelial outgrowth cells (EOC) decrease inflammation and improve endothelial repair. Inflammation aggravates kidney injury in renal artery stenosis (RAS), and may account for its persistence upon revascularization. We hypothesized that EOC would decrease inflammatory (M1) macrophages and improve renal recovery in RAS. Approach and Results— Pigs with 10 weeks of RAS were studied 4 weeks after percutaneous transluminal renal angioplasty (PTRA+stenting) or sham, with or without adjunct intrarenal delivery of autologous EOC (10×10 6 ), and compared with similarly treated normal controls (n=7 each). Single-kidney function, microvascular and tissue remodeling, inflammation, oxidative stress, and fibrosis were evaluated. Four weeks after PTRA, EOC were engrafted in injected RAS-kidneys. Stenotic-kidney glomerular filtration rate was restored in RAS+EOC, RAS+PTRA, and RAS+PTRA+EOC pigs, whereas stenotic-kidney blood flow and angiogenesis were improved and fibrosis attenuated only in EOC-treated pigs. Furthermore, EOC increased cell proliferation and decreased the ratio of M1 (inflammatory)/M2 (reparative) macrophages, as well as circulating levels and stenotic-kidney release of inflammatory cytokines. Cultured-EOC released microvesicles in vitro and induced phenotypic switch (M1-to-M2) in cultured monocytes, which was inhibited by vascular endothelial growth factor blockade. Finally, a single intrarenal injection of rh-vascular endothelial growth factor (0.05 μg/kg) in 7 additional RAS pigs also restored M1/M2 ratio 4 weeks later. Conclusions— Intrarenal infusion of EOC after PTRA induced a vascular endothelial growth factor–mediated attenuation in macrophages inflammatory phenotype, preserved microvascular architecture and function, and decreased inflammation and fibrosis in the stenotic kidney, suggesting a novel mechanism and therapeutic potential for adjunctive EOC delivery in experimental RAS to improve PTRA outcomes.

Omega-3 fatty acids found in fish oil have been suggested to protect against cardiovascular disease, yet underlying mechanisms remain unclear. Despite the well-documented link between mental stress and cardiovascular risk, no study has examined neural cardiovascular reactivity to mental stress after fish oil supplementation. We hypothesized that fish oil would blunt the blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA) responsiveness to mental stress and/or augment limb vasodilation associated with mental stress. Blood pressure, HR, MSNA, forearm vascular conductance (FVC), and calf vascular conductance (CVC) responses were recorded during a 5-min mental stress protocol in 67 nonhypertensive subjects before and after 8 wk of fish oil ( n = 34) or placebo supplementation ( n = 33). Fish oil blunted HR reactivity to mental stress (group × condition × time interactions, P = 0.012) but did not alter blood pressure reactivity to mental stress (interactions, P > 0.05). Fish oil blunted total MSNA reactivity to mental stress (interaction, P = 0.039) but did not alter MSNA burst frequency and burst incidence reactivity (interactions, P > 0.05). Finally, fish oil significantly blunted CVC reactivity to mental stress (interaction, P = 0.013) but did not alter FVC reactivity (interaction, P > 0.05). In conclusion, 8 wk of fish oil supplementation significantly attenuated both HR and total MSNA reactivity to mental stress and elicited a paradoxical blunting of calf vascular conductance. These findings support and extend the growing evidence that fish oil may have positive health benefits regarding neural cardiovascular control in humans.

Lung cancer is the leading cause of cancer-related death in the United States. Here, we evaluated the potential clinical utility of soluble human epidermal growth factor receptor 2 (sHER2) for the risk assessment, screening, and diagnosis of non-small cell lung cancer (NSCLC) using an unmatched case-control study design. Serum sHER2 concentrations were measured by immunoassay in 244 primary NSCLC cases and 218 healthy controls. Wilcoxon rank-sum tests, logistic regression models, and receiver operating characteristic plots were used to assess whether sHER2 is associated with lung cancer. Median serum sHER2 concentrations are higher in patients with adenocarcinoma than squamous cell carcinoma regardless of gender, and sHER2 is a weak, independent biomarker of adenocarcinoma, but not of squamous cell carcinoma, adjusted for age and gender. The age-adjusted relative risk (odds) of adenocarcinoma is 3.95 (95% CI: 1.22, 12.81) and 7.93 (95% CI: 2.26, 27.82) greater for women and men with high sHER2 concentrations (≥6.60 ng/mL) vs. low sHER2 concentrations (≤1.85 ng/mL), respectively. When adjusted for each other, sHER2, age, and gender discern healthy controls from patients with primary adenocarcinomas of the lung with 85.9% accuracy. We conclude that even though serum sHER2 is not a strong, stand-alone discriminatory biomarker of adenocarcinoma, sHER2 may be a useful, independent covariate in multivariate risk assessment, screening, and diagnostic models of lung cancer.

Background: The optimal choice for intervention for recalcitrant lateral elbow tendinopathy remains unclear as various treatment modalities have documented comparable results in the literature. Purpose: To explore the safety, tolerability, and early efficacy of a new minimally invasive mode of treatment that delivers focused, calibrated ultrasonic energy, effectively microresecting the pathological tendon and removing only pathological tissue. Study Design: Case series; Level of evidence, 4. Methods: Seven male and 13 female patients aged 33 to 65 years averaging 12.5 months (range, 4-48) of failed nonoperative therapy underwent the ultrasonic microresection procedure in an outpatient clinic setting. The procedure involved a sterile, ultrasound-guided percutaneous microresection with a proprietary device (TX1) performed through a stab incision under local anesthesia. The duration of the procedure and complications of the device or procedure were assessed. Outcome parameters included patient satisfaction; visual analog scale (VAS) pain scores; Disabilities of the Arm, Shoulder and Hand (DASH) scores at 1, 3, 6, and 12 months; and ultrasound assessment at 3 and 6 months. Results: The median duration for the sterile confirmatory ultrasound examination (phase 1) was 88.5 seconds (range, 39-211; SD, ±47.6), the median duration of the procedure proper (phase 2) was 10.1 minutes (range, 4.1-19.4; SD, ±3.7), and the median energy time (duration the TX1 device was activated) was 32.5 seconds (range, 18-58; SD, ±11.0). No complications were encountered. A significant improvement in VAS score (from 5.5 to 3.3; P < .001) occurred by 1 week, and significant improvements in both DASH-Compulsory (from 21.7 to 11.3; P = .001) and DASH-Work (from 25.0 to 6.3; P = .012) scores occurred by 1 month. The VAS scores further improved at 3, 6, and 12 months (from 2.0 to 1.0 to 0.50; P = .003 and .023). The DASH-Compulsory score improved significantly from 3 to 6 months (from 8.6 to 4.6; P = .003), and both the DASH-Compulsory and DASH-Work scores were sustained by 12 months. Sonographically reduced tendon thickness (19 patients), resolved or reduced hypervascularity (17 patients), and reduced hypoechoic area (18 patients) occurred by 6 months. Nineteen of the 20 patients (95%) expressed satisfaction with the procedure, with 9 patients being very satisfied with their overall experience at 6 months after the procedure, 10 patients somewhat satisfied, and 1 patient neutral. Conclusion: Ultrasonic microresection of diseased tissue with the TX1 device provides a focally directed, safe, specific, minimally invasive, and well-tolerated treatment for recalcitrant lateral elbow tendinopathy in an office-based or ambulatory surgical setting with good evidence of some level of efficacy in 19 of 20 patients (95%) that is sustained for at least 1 year.