The spatiotemporal variations of surface air pollutants (O3, NO2, SO2, CO, and PM10) with four land-use types, residence (R), commerce (C), industry (I) and greenbelt (G), have been investigated at ...283 stations in South Korea during 2002-2013, using routinely observed data. The volatile organic compound (VOC) data at nine photochemical pollutant monitoring stations available since 2007 were utilized in order to examine their effect on the ozone chemistry. The land-use types, set by the Korean government, were generally consistent with the satellite-derived land covers and with the previous result showing anti-correlation between O3 and NO2 in diverse urban areas. The relationship between the two pollutants in the Seoul Metropolitan Area (SMA) residence land-use areas was substantially different from that outside of the SMA, probably due to the local differences in vehicle emissions. The highest concentrations of air pollutants in the diurnal, weekly, and annual cycles were found in industry for SO2 and PMPM10, in commerce for NO2 and CO, and in greenbelt for O3. The concentrations of air pollutants, except for O3, were generally higher in big cities during weekdays, while O3 showed its peak in suburban areas or small cities during weekends. The weekly cycle and trends of O3 were significantly out of phase with those of NO2, particularly in the residential and commercial areas, suggesting that vehicle emission was a major source in those areas. The ratios of VOCs to NO2 for each of the land-use types were in the order of I (10.2) > C (8.7) > G (3.9) > R (3.6), suggesting that most areas in South Korea were likely to be VOC-limited for ozone chemistry. The pollutants (NO2, SO2, CO, and PMPM10 except for O3 have decreased, most likely due to the effective government control. The total oxidant values (OX = O3 + NO2) with the land-use types were analyzed for the local and regional (or background) contributions of O3, respectively, and the order of OX (ppb) was C (57.4) > R (53.6) > I (50.7) > G (45.4), indicating the greenbelt observation was close to the background.
A long-standing paradigm in astrophysics is that collisions- or mergers-of two neutron stars form highly relativistic and collimated outflows (jets) that power Y-ray bursts of short (less than two ...seconds) duration. The observational support for this model, however, is only indirect. A hitherto outstanding prediction is that gravitational-wave events from such mergers should be associated with Y-ray bursts, and that a majority of these bursts should be seen off-axis, that is, they should point away from Earth. Here we report the discovery observations of the X-ray counterpart associated with the gravitational-wave event GW170817. Although the electromagnetic counterpart at optical and infrared frequencies is dominated by the radioactive glow (known as a 'kilonova') from freshly synthesized rapid neutron capture (r-process) material in the merger ejecta, observations at X-ray and, later, radio frequencies are consistent with a short Y-ray burst viewed off-axis. Our detection of X-ray emission at a location coincident with the kilonova transient provides the missing observational link between short Y-ray bursts and gravitational waves from neutron-star mergers, and gives independent confirmation of the collimated nature of the Y-ray-burst emission.
The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of ...epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease ...progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear.
This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort.
The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months 95% confidence interval (CI) 5.0–16.6; the median OS was 16.9 months 95% CI 7.9–not reached (NR). In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1–NR); the median PFS was 8.0 months (95% CI 7.2–NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1–2.
Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.
•Osimertinib 160 mg exhibited promising ORR and survival benefit in EGFR T790M-positive NSCLC patients with CNS metastasis.•As it caused only grade 1–2 adverse events, osimertinib 160 mg also showed a tolerable safety profile.•It is suitable for BM or LM patients after EGFR TKI treatment and those treated with EGFR T790M-targeting agents or radiotherapy.
We compared late thoracic radiotherapy (TRT) with early TRT in the treatment of limited-disease small-cell lung cancer (LD-SCLC).
Patients with LD-SCLC received four cycles of etoposide plus ...cisplatin every 21 days. Patients were randomly assigned to receive either TRT administered concurrently with the first cycle (early TRT) or the third cycle (late TRT) of chemotherapy. The primary end point was complete response rate.
Two hundred twenty-two patients were randomly assigned. Late TRT was not inferior to early TRT in terms of the complete response rate (early versus late; 36.0% versus 38.0%). Other efficacy measures including overall survival median, 24.1 versus 26.8 months; hazard ratio (HR) 0.90; 95% CI 0.18–1.62 and progression-free survival (median, 12.4 versus 11.2 months; HR 1.10; 95% CI 0.37–1.84) were not different between two arms. No statistical difference was noted in the pattern of treatment failures. However, neutropenic fever occurred more commonly in the early TRT arm than the late TRT arm (21.6% versus 10.2%; P = 0.02).
In LD-SCLC treatment, TRT starting in the third cycle of chemotherapy seemed to be noninferior to early TRT, and had a more favorable profile with regard to neutropenic fever.
Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been ...the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs.
In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000mg/m2 on days 1 and 8, and oxaliplatin 100mg/m2 on day 1) or XELOX (capecitabine 1000mg/m2, twice daily, on days 1–14 and oxaliplatin 130mg/m2 on day 1) as first-line treatment, given every 3weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate.
In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3months for the GEMOX group and 5.8months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was −12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001).
XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs.
This study was registered in ClinicalTrials.gov (number NCT01470443).
Summary
Background
Whether 10‐day or 14‐day sequential therapy is superior to 14‐day triple therapy in the first‐line treatment of Helicobacter pylori remains controversial.
Aim
To compare the ...efficacy of 10‐day or 14‐day sequential therapy vs. 14‐day triple therapy.
Methods
Randomised controlled trials (RCTs) comparing 10‐day or 14‐day sequential therapy and 14‐day triple therapy as first‐line treatment in adults were searched from the PubMed and Cochrane databases from 2000 to October 2015. s from international annual conferences were also searched. The primary and secondary outcomes were the eradication rate according to the intention‐to‐treat analysis and adverse effects, respectively.
Results
Of the 109 articles identified, 13 RCTs including 2749 patients in the sequential therapy group and 2424 patients in the 14‐day triple therapy group were eligible. Overall, sequential therapy for 10 or 14 days was not significantly superior to 14‐day triple therapy Risk ratio (RR) 1.04, 95% confidence interval (CI) 0.99–1.08, P = 0.145. However, there was significant heterogeneity (I2 = 57.6%, P = 0.005). In the subgroup analysis of four trials, we found that 14‐day sequential therapy was significantly more effective than 14‐day triple therapy (RR: 1.09, 95% CI: 1.04–1.16, P = 0.002), and there was no significant heterogeneity (I2 = 0%, P = 0.624) in this comparison. Sequential therapy given for 10 days was not superior to 14‐day triple therapy (RR: 1.03, 95% CI: 0.98–1.09, P = 0.207). There was no significant difference in the risk of adverse effects.
Conclusion
Sequential therapy given for 14 days, but not 10 days, was more effective than 14‐day triple therapy as first‐line treatment.
Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and ...differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.
Aims/hypothesis Insulin resistance (IR) is associated with obesity, but can also develop in individuals with normal body weight. We employed comprehensive profiling methods to identify metabolic ...events associated with IR, while controlling for obesity. Methods We selected 263 non-obese (BMI approximately 24 kg/m²) Asian-Indian and Chinese men from a large cross-sectional study carried out in Singapore. Individuals taking medication for diabetes or hyperlipidaemia were excluded. Participants were separated into lower and upper tertiles of IR based on HOMA indices of ≤1.06 or ≥1.93, respectively. MS-based metabolic profiling of acylcarnitines, amino acids and organic acids was combined with hormonal and cytokine profiling in all participants. Results After controlling for BMI, commonly accepted risk factors for IR, including circulating fatty acids and inflammatory cytokines, did not discriminate the upper and lower quartiles of insulin sensitivity in either Asian-Indian or Chinese men. Instead, IR was correlated with increased levels of alanine, proline, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine and ornithine, and a cluster of branched-chain and related amino acids identified by principal components analysis. These changes were not due to increased protein intake by individuals in the upper quartile of IR. Increased abdominal adiposity and leptin, and decreased adiponectin and IGF-binding protein 1 were also correlated with IR. Conclusions/interpretation These findings demonstrate that perturbations in amino acid homeostasis, but not inflammatory markers or NEFAs, are associated with IR in individuals of relatively low body mass.
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