Arctic feedbacks accelerate climate change through carbon releases from thawing permafrost and higher solar absorption from reductions in the surface albedo, following loss of sea ice and land snow. ...Here, we include dynamic emulators of complex physical models in the integrated assessment model PAGE-ICE to explore nonlinear transitions in the Arctic feedbacks and their subsequent impacts on the global climate and economy under the Paris Agreement scenarios. The permafrost feedback is increasingly positive in warmer climates, while the albedo feedback weakens as the ice and snow melt. Combined, these two factors lead to significant increases in the mean discounted economic effect of climate change: +4.0% ($24.8 trillion) under the 1.5 °C scenario, +5.5% ($33.8 trillion) under the 2 °C scenario, and +4.8% ($66.9 trillion) under mitigation levels consistent with the current national pledges. Considering the nonlinear Arctic feedbacks makes the 1.5 °C target marginally more economically attractive than the 2 °C target, although both are statistically equivalent.
The anti-B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma.
In this first-in-human study, up to 10 cycles of AMG 420 were given ...(4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/10
bone marrow cells by flow cytometry.
Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year.
In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.
Convective Available Potential Energy (CAPE) and Convective Inhibition (CIN) play a dominant role in convective precipitation, its genesis and intensity. A global climatology of CAPE and CIN is ...presented in terms of seasonal means, variances, and trends based on 44 years (1958–2001) of six-hourly ERA-40 reanalysis (European Centre for Medium-Range Weather Forecast ECMWF, T106 resolution). CAPE shows large values and high variability in the tropics with maxima over the continents; the seasonal changes are dominated by specific humidity. CIN shows large means and variability in the subtropics. Significant trends in CAPE and CIN give the following results: (i) In general, a CAPE increase is noted during all seasons while, in particular, in autumn CIN shows a decrease over continents. (ii) Splitting of the time series reveals a sign change in trend commencing at the end of the 70s; this is observed in parts of the tropical continents and North America. CAPE and CIN show trends of opposite sign with CAPE increasing in the first half and a decrease during the second half (and vice versa for CIN).
The ability to forecast sea ice (both extent and thickness) and weather conditions are the major factors when it comes to safe marine transportation in the Arctic Ocean. This paper presents findings ...focusing on sea ice and weather prediction in the Arctic Ocean for navigation purposes, in particular along the Northeast Passage. Based on comparison with the observed sea ice concentrations for validation, the best performing Earth system models from the Intergovernmental Panel on Climate Change (IPCC) program (CMIP5—Coupled Model Intercomparison Project phase 5) were selected to provide ranges of potential future sea ice conditions. Our results showed that, despite a general tendency toward less sea ice cover in summer, internal variability will still be large and shipping along the Northeast Passage might still be hampered by sea ice blocking narrow passages. This will make sea ice forecasts on shorter time and space scales and Arctic weather prediction even more important.
The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish ...whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol.
We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381.
5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events.
Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD.
Boehringer Ingelheim and Pfizer.
AIM： To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer. METHODS： Genomic DNA was extracted from paraffinembedded tissues of 122 patients with ...primary gastric carcinoma and from the blood of 820 healthy white individuals. Allelic discrimination was performed by quantitative real-time polymerase chain reaction. Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan-Meier approach and with multivariate analysis by multiple stepwise regression. RESULTS： Thirty-nine （32%） patients displayed a CC genotype, 57 （46.7%） a CT genotype and 26 （21.3%） a TT genotype. The frequency of the C allele （fC） in the patient group was 0.55, which was not significantly different from that of healthy blood donors. The distribution was compatible with the Hardy-Weinberg equilibrium. Analysis of clinicopathological parameters did not show any significant correlation of the T393C genotype with gender （P = 0.50）, differentiation （P = 0.29）, pT-category （P = 0.19）, pN-category （P = 0.30）, pM-category （P = 0.25）, R-category （P = 0.95）, the classifications according to WHO （P = 0.34）, Lauren （P = 0.16）, Goseki （P = 1.00） and Ming （P =0.74）. Dichotomization between C＋ （CC＋CT） and C-genotypes （FI）, however, revealed significantly more advanced tumor stages （P = 0.023） and lower survival rates （P = 0.043） for C allele carriers. CONCLUSION： The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers.
Background: Polymorphisms in genes encoding subunits of heterotrimeric G proteins have been repeatedly associated with the
course of cancer. As previously shown, intron 1 of GNB4 harbours distinct ...haplotype blocks and block 1 is associated with
survival and disease progression in urothelial bladder cancer. This study investigated whether haplotype block 2 is associated
with survival in colorectal cancer patients. Patients and Methods: The haplotype tagging polymorphism of GNB4 haplotype block
2 was genotyped in 136 colorectal cancer patients and associated with demographic and clinical data and survival. Results:
Haplotype block 2 is associated with survival in colorectal cancer patients. Patients with advanced tumour stages carrying
the 2*1 haplotype revealed decreased survival (HR 2.04, 95% CI 0.91-3.69). In multivariate analysis, the diplotypes were independent
prognostic factors. Conclusion: Intron-1 haplotypes of GNB4 might be predictive markers for survival of patients with advanced
colorectal cancer, thus influencing the clinical management of these patients.
Background: The human X-ray repair cross-complementing group 1 (XRCC1) enzyme plays an important role in response to DNA damage.
Two common polymorphisms in XRCC1, Arg194Trp and Arg399Gln, have been ...repeatedly associated with risk for and outcome of numerous
types of cancer treated with radio- and chemotherapy. Recently, a Japanese study suggested these polymorphisms both as risk
factors and outcome predictors in renal cell carcinoma (RCC). Patients and Methods: In the present study, 142 Caucasian patients
suffering from RCC were genotyped and analyzed for tumor-related and overall survival and time to metastasis and progression.
Results: Analyses revealed absence of the pre-described risk haplotype (194Trp/399Gln) as well as a lack of a statistically
significant difference between the different endpoints and genotypes and diplotypes, respectively. Conclusion: We conclude
that in Caucasian patients, XRCC1 polymorphisms do not influence the outcome of RCC.
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