Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

Time course-dependent changes in the transcriptome of human skeletal muscle during recovery from endurance exercise: From inflammation to adaptive remodeling

Re-programming of gene expression is fundamental for skeletal muscle adaptations in response to endurance exercise. This study investigated the time-course dependent changes in the muscular transcriptome following an endurance exercise trial consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Skeletal muscle samples were taken at baseline, 3 h, 48 h, and 96 h post-exercise from eight healthy, endurance-trained, male individuals. RNA was extracted from muscle. Differential gene expression was evaluated using Illumina microarrays and validated with qPCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Three h post-exercise, 102 gene sets were up-regulated [family wise error rate (FWER), P < 0.05]; including groups of genes related with leukocyte migration, immune and chaperone activation, and cyclic AMP responsive element binding protein (CREB) 1-signaling. Forty-eight h post-exercise, among 19 enriched gene sets (FWER, P < 0.05), two gene sets related to actin cytoskeleton remodeling were up-regulated. Ninety-six h post-exercise, 83 gene sets were enriched (FWER, P < 0.05), 80 of which were up-regulated; including gene groups related to chemokine signaling, cell stress management, and extracellular matrix remodeling. These data provide comprehensive insights into the molecular pathways involved in acute stress, recovery, and adaptive muscular responses to endurance exercise. The novel 96 h post-exercise transcriptome indicates substantial transcriptional activity, potentially associated with the prolonged presence of leukocytes in the muscles. This suggests that muscular recovery, from a transcriptional perspective, is incomplete 96 h after endurance exercise involving muscle damage.

Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2 : prognostic factors and treatment selection based on two large randomized clinical trials

Purpose: Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2. Patients and Methods: Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy. Results: Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival imes were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0-2 risk factors had similar outcomes independent of treatment, whereas patients with 3-4 factors had a nonsignificant improvement in median survival with combination chemotherapy. Conclusion: Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy. © 2009 by the International Association for the Study of Lung Cancer.

Pulse-coupled neural network performance for real-time identification of vegetation during forced landing

Safety concerns in the operation of autonomous aerial systems require safe-landing protocols be followed during situations where the a mission should be aborted due to mechanical or other failure. On-board cameras provide information that can be used in the determination of potential landing sites, which are continually updated and ranked to prevent injury and minimize damage. Pulse Coupled Neural Networks have been used for the detection of features in images that assist in the classification of vegetation and can be used to minimize damage to the aerial vehicle. However, a significant drawback in the use of PCNNs is that they are computationally expensive and have been more suited to off-line applications on conventional computing architectures. As heterogeneous computing architectures are becoming more common, an OpenCL implementation of a PCNN feature generator is presented and its performance is compared across OpenCL kernels designed for CPU, GPU and FPGA platforms. This comparison examines the compute times required for network convergence under a variety of images obtained during unmanned aerial vehicle trials to determine the plausibility for real-time feature detection.

Posttraumatic growth in family members living with a relative diagnosed with schizophrenia

Family members living with a relative diagnosed with schizophrenia have reported challenges and traumatic stressors, as well as perceived benefits and personal growth. This study explored factors associated with posttraumatic growth (PTG) within such families. Personality, stress, coping, social support and PTG were assessed in 110 family members. Results revealed that a multiplicative mediational path model with social support and emotional or instrumental coping strategies as multi-mediators had a significant indirect effect on the relationship between extraversion and PTG. Clinically relevant concepts that map onto the multi-mediator model are discussed, translating these findings into clinical practice to facilitate naturally occurring PTG processes.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

Pro-osteogenic topographical cues promote early activation of osteoprogenitor differentiation via enhanced TGFβ, Wnt, and Notch signaling

Objectives Titanium implant surfaces with modified topographies have improved osteogenic properties in vivo. However, the molecular mechanisms remain obscure. This study explored the signaling pathways responsible for the pro-osteogenic properties of micro-roughened (SLA) and chemically/nanostructurally (modSLA) modified titanium surfaces on human alveolar bone-derived osteoprogenitor cells (BCs) in vitro. Materials and methods The activation of stem cell signaling pathways (TGFβ/BMP, Wnt, FGF, Hedgehog, Notch) was investigated following early exposure (24 and 72 h) of BCs to SLA and modSLA surfaces in the absence of osteogenic cell culture supplements. Results Key regulatory genes from the TGFβ/BMP (TGFBR2, BMPR2, BMPR1B, ACVR1B, SMAD1, SMAD5), Wnt (Wnt/β-catenin and Wnt/Ca2+) (FZD1, FZD3, FZD5, LRP5, NFATC1, NFATC2, NFATC4, PYGO2, LEF1) and Notch (NOTCH1, NOTCH2, NOTCH4, PSEN1, PSEN2, PSENEN) pathways were upregulated on the modified surfaces. These findings correlated with a higher expression of osteogenic markers bone sialoprotein (IBSP) and osteocalcin (BGLAP), and bone differentiation factors BMP2, BMP6, and GDF15, as observed on the modified surfaces. Conclusions These findings demonstrate that the activation of the pro-osteogenic cell signaling pathways by modSLA and SLA surfaces leads to enhanced osteogenic differentiation as evidenced after 7 and 14 days culture in osteogenic media and provides a mechanistic insight into the superior osseointegration on the modified surfaces observed in vivo.

Understanding the fabric of social interactions for ridesharing through mining social networking sites

The design of applications for dynamic ridesharing or carpooling is often formulated as a matching problem of connecting people with an aligned set of transport needs within a reasonable interval of time and space. This problem formulation relegates social connections to being secondary factors. Technology assisted ridesharing applications that put the matching problem first have revealed that they suffer from being unable to address the factor of social comfort, even after adding friend features or piggybacking on social networking sites. This research aims to understand the fabric of social interactions through which ridesharing happens. We take an online observation approach in order to understand the fabric of social interactions for ridesharing that is happening in highly subscribed online groups of local residents. This understanding will help researchers to identify design challenges and opportunities to support ridesharing in local communities. This paper contributes a fundamental understanding of how social interactions and social comfort precede rideshare requests in local communities.

A novel energy efficient controllable stiffness joint

Achieving energy efficient legged locomotion is an important goal for the future of robot mobility. This paper presents a novel joint for legged locomotion that is energy efficient for two reasons. The first reason is the configuration of the elastic elements and actuator which we show analytically has lower energy losses than the typical arrangement. The second is that the joint stiffness, and hence stance duration, is controllable without requiring any energy from the actuator. Further, the joint stiffness can be changed significantly during the flight phase, from zero to highly rigid. Results obtained from a prototype hopper, demonstrate that the joint allows continuous and peak hopping via torque control. The results also demonstrate that the hopping frequency can be varied between 2.2Hz and 4.6Hz with associated stance duration of between 0.35 and 0.15 seconds.

A novel method for analysing lighting variance

Robust descriptor matching across varying lighting conditions is important for vision-based robotics. We present a novel strategy for quantifying the lighting variance of descriptors. The strategy works by utilising recovered low dimensional mappings from Isomap and our measure of the lighting variance of each of these mappings. The resultant metric allows different descriptors to be compared given a dataset and a set of keypoints. We demonstrate that the SIFT descriptor typically has lower lighting variance than other descriptors, although the result depends on semantic class and lighting conditions.

Low cost localisation for agricultural robotics

This paper presents a pose estimation approach that is resilient to typical sensor failure and suitable for low cost agricultural robots. Guiding large agricultural machinery with highly accurate GPS/INS systems has become standard practice, however these systems are inappropriate for smaller, lower-cost robots. Our positioning system estimates pose by fusing data from a low-cost global positioning sensor, low-cost inertial sensors and a new technique for vision-based row tracking. The results first demonstrate that our positioning system will accurately guide a robot to perform a coverage task across a 6 hectare field. The results then demonstrate that our vision-based row tracking algorithm improves the performance of the positioning system despite long periods of precision correction signal dropout and intermittent dropouts of the entire GPS sensor.

(Im)moral bodies : intersex and auto/biographical documentary

In this paper I question the representation of and ethical responsibilities to young people with intersex (hermaphroditic) conditions in documentary film, and explore the creative practice challenges working with bodies with intersex, embedded in the production of a feature auto/biographical documentary entitled Orchids. Bodies with intersex conditions are often presented as abject, in need of ‘fixing’ during infancy and early childhood, undesirable, and incapable of desire. Seen through the lens of experience and memory, Orchids takes a personal coming-of-age narrative and reconfigures understandings of the (im)moral body in the light of its transformative potential. Just as practice research challenges the dominant hegemony of quantitative and qualitative research, my creative work positions itself as a nuanced performative piece, and through its distinctive distillation and celebration of a new form of discursive rupturing discovers the intersex voice.

Effectiveness of pilot car operations in reducing speeds in a long-term rural highway work zone

Pilot cars are used in one-lane two-way work zones to guide traffic and keep their speeds within posted limits. While many studies have examined the effectiveness of measures to reduce vehicle speeds in work zones, little is known about the reductions achievable through the use of pilot cars. This paper examines the effectiveness of a pilot car in reducing travel speeds in a rural highway work zone in Queensland, Australia. Analysis of speed data covering a period of five days showed that a pilot car reduced average speeds at the treatment location, but not downstream. The proportion of vehicles speeding through the activity area was also reduced, particularly those traveling at 10 km/h or more above the posted limit. Motorists were more likely to speed during the day, under a 40 kh/h limit, when traffic volumes were higher and when there were fewer vehicles in the traffic stream. Medium vehicles were less likely to speed in the presence of a pilot car than light vehicles. To maximize these benefits, it is necessary to ensure that the pilot car itself is not speeding.

Dispelling ageing myths in technology design

We present a review of literature from the fields of gerontology, gerontechnology, HCI and government policy that deals with social and technical solutions for the ageing population. We highlight common assumptions about ageing people, which we argue are still embedded in much of the research related to the domain of ageing. This paper challenges six common assumptions across four broad themes that we identified in the literature. It aims to provide a reminder and resource for designers to eschew assumptions during designing technology for 'older' users.

An investigation of schizotypy in injecting amphetamine users

A fully dimensional view of psychiatric disorder conceptualises schizotypy as both a continuous personality trait and an underlying vulnerability to the development of psychotic illness. Such a model would predict that the structure of schizotypal traits would closely parallel the structure of schizophrenia or psychosis. This was investigated in injecting amphetamine users (N = 322), a clinical population who have high rates of acute psychotic episodes and subclinical schizotypal experiences. Schizotypy was assessed using the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE), and psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Using confirmatory factor analysis, O-LIFE subscale scores were mapped onto latent variables with their more clinical counterparts from the BPRS. A four-factor model comprising positive schizotypy, disorganisation, negative schizotypy, and disinhibition provided the best model fit, consistent with prior research into the structure of schizotypy. The model provided a good fit to the data, lending support to the theory that schizotypy and psychotic symptoms map onto common underlying dimensions.