Arctic hydroclimate variability during the last 2000 years: current understanding and research challenges

Reanalysis data show an increasing trend in Arctic precipitation over the 20th century, but changes are not homogenous across seasons or space. The observed hydroclimate changes are expected to continue and possibly accelerate in the coming century, not only affecting pan-Arctic natural ecosystems and human activities, but also lower latitudes through the atmospheric and ocean circulations. However, a lack of spatiotemporal observational data makes reliable quantification of Arctic hydroclimate change difficult, especially in a long-term context. To understand Arctic hydroclimate and its variability prior to the instrumental record, climate proxy records are needed. The purpose of this review is to summarise the current understanding of Arctic hydroclimate during the past 2000 years. First, the paper reviews the main natural archives and proxies used to infer past hydroclimate variations in this remote region and outlines the difficulty of disentangling the moisture from the temperature signal in these records. Second, a comparison of two sets of hydroclimate records covering the Common Era from two data-rich regions, North America and Fennoscandia, reveals inter- and intra-regional differences. Third, building on earlier work, this paper shows the potential for providing a high-resolution hydroclimate reconstruction for the Arctic and a comparison with last-millennium simulations from fully coupled climate models. In general, hydroclimate proxies and simulations indicate that the Medieval Climate Anomaly tends to have been wetter than the Little Ice Age (LIA), but there are large regional differences. However, the regional coverage of the proxy data is inadequate, with distinct data gaps in most of Eurasia and parts of North America, making robust assessments for the whole Arctic impossible at present. To fully assess pan-Arctic hydroclimate variability for the last 2 millennia, additional proxy records are required.</p

Classification of current anticancer immunotherapies

© 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.info:eu-repo/semantics/publishedVersio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Asymmetric Transfer Hydrogenation of Ketones with Modified Grubbs Metathesis Catalysts: On the Way to a Tandem Process

Herein, we report the successful transformation of a 1st generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation (ATH) catalyst. Upon addition of a chiral amine ligand, an alcohol and a base, the 1st generation Hoveyda-Grubbs catalyst (HG-I) was found to promote the enantioselective reduction of acetophenone to 1-phenylethanol. After optimizing the order of addition and the reaction conditions, the substrate scope was assessed leading to enantiomeric excesses up to 97% ee. NMR experiments were run in order to get information about the in situ-generated ATH catalyst. Furthermore, the possibility to perform olefin metathesis and ketone transfer hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis-ketone asymmetric transfer hydrogenation was carried out

A Mixed Ligand Approach for the Asymmetric Hydrogenation of 2-Substituted Pyridinium Salts

Herein we describe a new methodology for the asymmetric hydrogenation (AH) of 2-substituted pyridinium salts. An iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine was shown to hydrogenate N-benzyl-2-arylpyiridinium bromides to the corresponding N-benzyl-2-arylpiperidines with full conversion and good enantioselectivity. The mechanism of the reaction under optimized conditions was investigated via kinetic measurements and isotopic labeling experiments. Our study suggests that the hydrogenation starts with a 1,4-hydride addition and that the enantiodiscriminating step involves the reduction of an iminium intermediate. (Figure presented.)

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

PurposeThe combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma.MethodsPatients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis.ResultsOverall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm.ConclusionT-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone