CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor ...(EGFR).
Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m2) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.
From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001 as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877).
CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.
NCT00891579.
MicroRNAs (miRNAs) are a family of small non-coding RNA molecules of about 20-23 nucleotides in length, which negatively regulate protein-coding genes at post-transcriptional level. Using a stem-loop ...real-time-PCR method, we quantified the expression levels of 270 human miRNAs in 13 nasopharyngeal carcinoma (NPC) samples and 9 adjacent normal tissues, and identified 35 miRNAs whose expression levels were significantly altered in NPC samples. Several known oncogenic miRNAs, including miR-17-92 cluster and miR-155, are among the miRNAs upregulated in NPC. Tumour suppressive miRNAs, including miR-34 family, miR-143, and miR-145, are significantly downregulated in NPC. To explore the roles of these dysregulated miRNAs in the pathogenesis of NPC, a computational analysis was performed to predict the pathways collectively targeted by the 22 significantly downregulated miRNAs. Several biological pathways that are well characterised in cancer are significantly targeted by the downregulated miRNAs. These pathways include TGF-Wnt pathways, G1-S cell cycle progression, VEGF signalling pathway, apoptosis and survival pathways, and IP3 signalling pathways. Expression levels of several predicted target genes in G1-S progression and VEGF signalling pathways were elevated in NPC tissues and showed inverse correlation with the down-modulated miRNAs. These results indicate that these downregulated miRNAs coordinately regulate several oncogenic pathways in NPC.
Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms ...involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic ...circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner.
Background and purpose
Physical activity is associated with a reduced incidence of first‐time stroke. However, few studies have examined the effect of pre‐stroke physical activity on post‐stroke ...complications and clinical outcomes.
Methods
A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre‐stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure‐time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups.
Results
The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post‐stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post‐stroke.
Conclusion
Dedicated leisure‐time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post‐stroke complications, lower mortality and better outcomes.
Background
Whether there is a difference in survival after neoadjuvant chemoradiotherapy plus surgery (CRT‐S) compared with definitive chemoradiotherapy (dCRT) in patients with locally advanced ...oesophageal squamous cell carcinoma (SCC) remains controversial.
Methods
Patients with SCC who underwent curative treatment from 2008 to 2014 were identified from the Taiwan Cancer Registry. Propensity score matching was undertaken to balance pretreatment clinical variables. Overall survival was compared between patients undergoing CRT‐S or dCRT. Univariable and multivariable analyses were performed to identify prognostic factors for overall survival.
Results
A total of 5832 patients with clinical stage II and III oesophageal SCC receiving CRT‐S (1754) or dCRT (4078) were included. After propensity score matching, each group included 1661 patients. The 3‐year overall survival rate for patients treated with CRT‐S was 41·1 per cent compared with 17·9 per cent for those who had dCRT (P < 0·001). In multivariable analysis, treatment modality was an independent prognostic factor in the overall cohort before propensity score matching: hazard ratio 0·45 (95 per cent c.i. 0·40 to 0·51) for CRT‐S versus dCRT (P < 0·001). In separate analyses of patients with clinical stage II and those with stage III disease, CRT‐S was associated with significantly better overall survival than dCRT.
Conclusion
Neoadjuvant chemoradiotherapy and oesophagectomy is associated with better overall survival than dCRT in patients with stage II and III oesophageal SCC.
Surgery indicated after chemoradiation
The recent focus on topological insulators is due to the scientific interest in the new state of quantum matter as well as the technology potential for a new generation of THz optoelectronics, ...spintronics and quantum computations. It is important to elucidate the dynamics of the Dirac fermions in the topologically protected surface state. Hence we utilized a novel ultrafast optical pump mid-infrared probe to explore the dynamics of Dirac fermions near the Dirac point. The femtosecond snapshots of the relaxation process were revealed by the ultrafast optics. Specifically, the Dirac fermion-phonon coupling strength in the Dirac cone was found to increase from 0.08 to 0.19 while Dirac fermions were away from the Dirac point into higher energy states. Further, the energy-resolved transient reflectivity spectra disclosed the energy loss rate of Dirac fermions at room temperature was about 1 meV/ps. These results are crucial to the design of Dirac fermion devices.
Soil microorganisms are key to biological diversity and many ecosystem processes in terrestrial ecosystems. Despite the current alarming loss of plant diversity, it is unclear how plant species ...diversity affects soil microorganisms. By conducting a global meta-analysis with paired observations of plant mixtures and monocultures from 106 studies, we show that microbial biomass, bacterial biomass, fungal biomass, fungi:bacteria ratio, and microbial respiration increase, while Gram-positive to Gram-negative bacteria ratio decrease in response to plant mixtures. The increases in microbial biomass and respiration are more pronounced in older and more diverse mixtures. The effects of plant mixtures on all microbial attributes are consistent across ecosystem types including natural forests, planted forests, planted grasslands, croplands, and planted containers. Our study underlines strong relationships between plant diversity and soil microorganisms across global terrestrial ecosystems and suggests the importance of plant diversity in maintaining belowground ecosystem functioning.
Various compatible solutes enable plants to tolerate abiotic stress, and glycinebetaine (GB) is one of the most-studied among such solutes. Early research on GB focused on the maintenance of cellular ...osmotic potential in plant cells. Subsequent genetically engineered synthesis of GB-biosynthetic enzymes and studies of transgenic plants demonstrated that accumulation of GB increases tolerance of plants to various abiotic stresses at all stages of their life cycle. Such GB-accumulating plants exhibit various advantageous traits, such as enlarged fruits and flowers and/or increased seed number under non-stress conditions. However, levels of GB in transgenic GB-accumulating plants are relatively low being, generally, in the millimolar range. Nonetheless, these low levels of GB confer considerable tolerance to various stresses, without necessarily contributing significantly to cellular osmotic potential. Moreover, low levels of GB, applied exogenously or generated by transgenes for GB biosynthesis, can induce the expression of certain stress-responsive genes, including those for enzymes that scavenge reactive oxygen species. Thus, transgenic approaches that increase tolerance to abiotic stress have enhanced our understanding of mechanisms that protect plants against such stress.
Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of ...an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged ≥ 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow-up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality.
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