Association of hypoxia and mitochondrial damage associated molecular patterns in the pathogenesis of vein graft failure: a pilot study.

Coronary artery bypass grafting (CABG) is the standard treatment modality in revascularization of the myocardium. However, the graft failure remains the major complication following CABG procedure. Involvement of mitochondrial damage-associated molecular patterns (mt-DAMPs) in the pathogenesis of vein-graft failure is largely unknown. Here, we investigated the expression of major protein-mt-DAMPs, cytochrome-C (Cyt-C), heat shock protein-60 (Hsp-60), mitochondrial transcription factor A (mtTFA), in the occluded graft and associated tissues, including distal left anterior descending (LAD), LAD adjacent to anastomosis, and left internal mammary artery (LIMA) in the microswine CABG model. The protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was significantly decreased in the graft and LIMA, whereas the protein expression of hypoxia inducible factor-1 alpha (HIF-1α) and Cyt-C was decreased and that of mtTFA and Hsp60 was increased in all tissues compared to controls. There was no significant difference in the protein expression of citrate synthase, complex-1, and mitochondrial pyruvate dehydrogenase in the graft and associated tissues compared to control. Hypoxia in cultured smooth muscle cells (SMCs) significantly upregulated all mitochondrial biomarkers and mt-DAMPs compared to normoxia. The increased reactive oxygen species (ROS) content and compromised membrane integrity in the hypoxic SMCs correlated well with increased mt-DAMPs in the graft and associated tissues, suggesting a possible role of mt-DAMPs in the pathogenesis of graft failure. These findings suggest that the pathological signals elicited by mt-DAMPs could reveal targets for better therapeutic approaches and diagnostic strategies in the management of CABG graft failure.

Spray-Processed Composites with High Conductivity and Elasticity.

Highly conductive elastic composites were constructed using multistep solution-based fabrication methods that included the deposition of a nonwoven polymer fiber mat through solution blow spinning and nanoparticle nucleation. High nanoparticle loading was achieved by introducing silver nanoparticles into the fiber spinning solution. The presence of the silver nanoparticles facilitates improved uptake of silver nanoparticle precursor in subsequent processing steps. The precursor is used to generate a second nanoparticle population, leading to high loading and conductivity. Establishing high nanoparticle loading in a microfibrous block copolymer network generated deformable composites that can sustain electrical conductivities reaching 9000 S/cm under 100% tensile strain. These conductive elastic fabrics can retain at least 70% of their initial electrical conductivity after being stretched to 100% strain and released for 500 cycles. This composite material system has the potential to be implemented in wearable electronics and robotic systems.

Simple and inexpensive quantification of ammonia in whole blood.

Quantification of ammonia in whole blood has applications in the diagnosis and management of many hepatic diseases, including cirrhosis and rare urea cycle disorders, amounting to more than 5 million patients in the United States. Current techniques for ammonia measurement suffer from limited range, poor resolution, false positives or large, complex sensor set-ups. Here we demonstrate a technique utilizing inexpensive reagents and simple methods for quantifying ammonia in 100 µL of whole blood. The sensor comprises a modified form of the indophenol reaction, which resists sources of destructive interference in blood, in conjunction with a cation-exchange membrane. The presented sensing scheme is selective against other amine containing molecules such as amino acids and has a shelf life of at least 50 days. Additionally, the resulting system has high sensitivity and allows for the accurate reliable quantification of ammonia in whole human blood samples at a minimum range of 25 to 500 µM, which is clinically for rare hyperammonemic disorders and liver disease. Furthermore, concentrations of 50 and 100 µM ammonia could be reliably discerned with p = 0.0001.

Sprayable elastic conductors based on block copolymer silver nanoparticle composites.

Block copolymer silver nanoparticle composite elastic conductors were fabricated through solution blow spinning and subsequent nanoparticle nucleation. The reported technique allows for conformal deposition onto nonplanar substrates. We additionally demonstrated the ability to tune the strain dependence of the electrical properties by adjusting nanoparticle precursor concentration or localized nanoparticle nucleation. The stretchable fiber mats were able to display electrical conductivity values as high as 2000 ± 200 S/cm with only a 12% increase in resistance after 400 cycles of 150% strain. Stretchable elastic conductors with similar and higher bulk conductivity have not achieved comparable stability of electrical properties. These unique electromechanical characteristics are primarily the result of structural changes during mechanical deformation. The versatility of this approach was demonstrated by constructing a stretchable light emitting diode circuit and a strain sensor on planar and nonplanar substrates.

Granular fingering in fluid injection into dense granular media in a Hele-Shaw cell.

We study experimentally spontaneous pattern formation in a dry dense granular medium invaded by an aqueous glycerin solution in a radial Hele-Shaw cell. By varying the invading fluid viscosity via the weight concentration of glycerin, and by adjusting the normalized injection velocity via the injection rate and the gap size of the cell, we observe four distinct fluid-grain displacement regimes: (i) a simple radial flow regime, (ii) an infiltration-dominated regime, (iii) a grain displacement-dominated regime, and (iv) a viscous fingering-dominated regime. We argue that these displacement regimes emerge as a result of competition among the various energy dissipation mechanisms and can be classified based on the characteristic times involved in the injection process.

Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.

PURPOSE: This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain. RESULTS: Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01). CONCLUSION: Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.

Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer.

PURPOSE: Efaproxiral (RSR13) reduces hemoglobin oxygen-binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10. RESULTS: Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%). CONCLUSION: Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.

Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer.

BACKGROUND: We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non-small-cell lung cancer. METHODS: We randomly assigned patients with completely resected stage IB or stage II non-small-cell lung cancer to vinorelbine plus cisplatin or to observation. The primary end point was overall survival; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen. RESULTS: A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (<10 percent). Overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (94 vs. 73 months; hazard ratio for death, 0.69; P=0.04), as was relapse-free survival (not reached vs. 46.7 months; hazard ratio for recurrence, 0.60; P<0.001). Five-year survival rates were 69 percent and 54 percent, respectively (P=0.03). CONCLUSIONS: Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected early-stage non-small-cell lung cancer.

Weekly paclitaxel and gemcitabine chemotherapy for metastatic non-small cell lung carcinoma (NSCLC): a dose-optimizing phase II trial.

BACKGROUND: The current dose-optimizing Phase II study evaluated the effect of weekly paclitaxel and gemcitabine on the response rate and survival of patients with non-small cell lung carcinoma (NSCLC) using dose modifications that permitted optimal treatment intensity. METHODS: Forty-five patients (40 with TNM Stage IV and 5 with TNM Stage IIIB NSCLC) were treated with gemcitabine at 1000 mg/m(2) via a 30-minute intravenous (i.v.) infusion and with paclitaxel at 100 mg/m(2) via a 60-minute i.v. infusion. The first 3 patients received chemotherapy on Days 1, 8, and 15 every 4 weeks; the next 42 patients, participating in the Phase II trial, received chemotherapy on Days 1 and 8 every 3 weeks. RESULTS: The 3 patients who received paclitaxel and gemcitabine on Days 1, 8, and 15 every 4 weeks tolerated the treatment poorly. One patient died suddenly after Day 15 treatment during the first cycle, and the other 2 patients discontinued the treatment because of unacceptable toxicity before the third cycle of chemotherapy. The next 42 patients, 40 of whom were evaluable, entered this trial between May 2000 and April 2001. They received paclitaxel at 100 mg/m(2) i.v. followed by gemcitabine at 1000 mg/m(2) i.v. on Days 1 and 8 every 3 weeks. Two patients (5%) achieved complete response, 20 (50%) achieved partial response, and 8 (20%) had stable disease. Median survival (MS) was 9.8 months; and 1-year survival was 35%. The 32 patients with performance status (PS) 0 or 1 had an MS of 11 months; the 8 patients with PS 2 had an MS of 3 months. Toxicity (especially hematologic toxicity, neuropathy, and alopecia) was minimal. CONCLUSION: A weekly paclitaxel and gemcitabine regimen that incorporated the authors' dose modifications resulted in good efficacy with minimal toxicity.

A Quebec survey of issues in cancer pain management.

We report the results of a cancer pain survey mailed to Quebec hematologist-oncologists and palliative care physicians in 1999. The survey was designed to sample views on the current status of pain management and on obstacles to the provision of adequate pain relief for patients. The survey, formulated by an ethics network centered at the Clinical Research Institute of Montreal, was distributed to all members of the Association of Hematologist-Oncologists of Quebec and to all physician members of the Quebec Palliative Care Association. Responses were obtained from 138 Palliative Care Association members (response rate 61%) and 76 hematologist-oncologists (response rate 45%). Major obstacles reported included inadequate assessment of both contributory psychosocial issues and severity of pain, patient reluctance to take opioids, and inadequate access to non-drug techniques for pain relief. Access to opioids was not regarded as a problem. Both groups felt generally competent in their ability to manage various aspects of cancer pain therapy. They gave little credit to their formal medical school or residency training. Fifty-six percent of the palliative care group and 57% of the hemato-oncologists rated their medical school experience as only "poor" or "fair" on a 4-point scale. Residency ratings were modestly better. We conclude that medical faculties should assign a high priority to teaching health professionals patient assessment techniques. Simple symptom assessment scales should be routinely used in oncology/palliative care practice. Medical school training in pain management is not highly regarded and should be enhanced. We also note that, based on response to the scenario of a patient presenting with severe pain, many physicians, while feeling competent in the use of opioids, may be overly conservative in their initial use.