Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species

Background Genome mining tools have enabled us to predict biosynthetic gene clusters that might encode compounds with valuable functions for industrial and medical applications. With the continuously increasing number of genomes sequenced, we are confronted with an overwhelming number of predicted clusters. In order to guide the effective prioritization of biosynthetic gene clusters towards finding the most promising compounds, knowledge about diversity, phylogenetic relationships and distribution patterns of biosynthetic gene clusters is necessary. Results Here, we provide a comprehensive analysis of the model actinobacterial genus Amycolatopsis and its potential for the production of secondary metabolites. A phylogenetic characterization, together with a pan-genome analysis showed that within this highly diverse genus, four major lineages could be distinguished which differed in their potential to produce secondary metabolites. Furthermore, we were able to distinguish gene cluster families whose distribution correlated with phylogeny, indicating that vertical gene transfer plays a major role in the evolution of secondary metabolite gene clusters. Still, the vast majority of the diverse biosynthetic gene clusters were derived from clusters unique to the genus, and also unique in comparison to a database of known compounds. Our study on the locations of biosynthetic gene clusters in the genomes of Amycolatopsis’ strains showed that clusters acquired by horizontal gene transfer tend to be incorporated into non-conserved regions of the genome thereby allowing us to distinguish core and hypervariable regions in Amycolatopsis genomes. Conclusions Using a comparative genomics approach, it was possible to determine the potential of the genus Amycolatopsis to produce a huge diversity of secondary metabolites. Furthermore, the analysis demonstrates that horizontal and vertical gene transfer play an important role in the acquisition and maintenance of valuable secondary metabolites. Our results cast light on the interconnections between secondary metabolite gene clusters and provide a way to prioritize biosynthetic pathways in the search and discovery of novel compounds

TET2 chemically modifies tRNAs and regulates tRNA fragment levels

The ten-eleven translocation 2 (TET2) protein, which oxidizes 5-methylcytosine in DNA, can also bind RNA; however, the targets and function of TET2-RNA interactions in vivo are not fully understood. Using stringent affinity tags introduced at the Tet2 locus, we purified and sequenced TET2-crosslinked RNAs from mouse embryonic stem cells (mESCs) and found a high enrichment for tRNAs. RNA immunoprecipitation with an antibody against 5-hydroxymethylcytosine (hm5C) recovered tRNAs that overlapped with those bound to TET2 in cells. Mass spectrometry (MS) analyses revealed that TET2 is necessary and sufficient for the deposition of the hm5C modification on tRNA. Tet2 knockout in mESCs affected the levels of several small noncoding RNAs originating from TET2-bound tRNAs that were enriched by hm5C immunoprecipitation. Thus, our results suggest a new function of TET2 in promoting the conversion of 5-methylcytosine to hm5C on tRNA and regulating the processing or stability of different classes of tRNA fragments

Scoring of tumour response after neoadjuvant therapy in resected pancreatic cancer: systematic review

BACKGROUND: Preoperative chemo(radio)therapy is used increasingly in pancreatic cancer. Histological evaluation of the tumour response provides information on the efficacy of preoperative treatment and is used to determine prognosis and guide decisions on adjuvant treatment. This systematic review aimed to provide an overview of the current evidence on tumour response scoring systems in pancreatic cancer.METHODS: Studies reporting on the assessment of resected pancreatic ductal adenocarcinoma following neoadjuvant chemo(radio)therapy were searched using PubMed and EMBASE. All original studies reporting on histological tumour response in relation to clinical outcome (survival, recurrence-free survival) or interobserver agreement were eligible for inclusion. This systematic review followed the PRISMA guidelines.RESULTS: The literature search yielded 1453 studies of which 25 met the eligibility criteria, revealing 13 unique scoring systems. The most frequently investigated tumour response scoring systems were the College of American Pathologists system, Evans scoring system, and MD Anderson Cancer Center system, investigated 11, 9 and 5 times respectively. Although six studies reported a survival difference between the different grades of these three systems, the reported outcomes were often inconsistent. In addition, 12 of the 25 studies did not report on crucial aspects of pathological examination, such as the method of dissection, sampling approach, and amount of sampling.CONCLUSION: Numerous scoring systems for the evaluation of tumour response after preoperative chemo(radio)therapy in pancreatic cancer exist, but comparative studies are lacking. More comparative data are needed on the interobserver variability and prognostic significance of the various scoring systems before best practice can be established

Fire-adapted traits of Pinus arose in the fiery Cretaceous

9 páginas, 3 figuras.The mapping of functional traits onto chronograms is an emerging approach for the identification of how agents of natural selection have shaped the evolution of organisms. Recent research has reported fire-dependent traits appearing among flowering plants from 60 million yr ago (Ma). Although there are many records of fossil charcoal in the Cretaceous (65-145Ma), evidence of fire-dependent traits evolving in that period is lacking. We link the evolutionary trajectories for five fire-adapted traits in Pinaceae with paleoatmospheric conditions over the last 250million yr to determine the time at which fire originated as a selective force in trait evolution among seed plants. Fire-protective thick bark originated in Pinus c. 126Ma in association with low-intensity surface fires. More intense crown fires emerged c. 89Ma coincident with thicker bark and branch shedding, or serotiny with branch retention as an alternative strategy. These innovations appeared at the same time as the Earth's paleoatmosphere experienced elevated oxygen levels that led to high burn probabilities during the mid-Cretaceous. The fiery environments of the Cretaceous strongly influenced trait evolution in Pinus. Our evidence for a strong correlation between the evolution of fire-response strategies and changes in fire regime 90-125Ma greatly backdates the key role that fire has played in the evolution of seed plants.T.H. acknowledges support from the Australian Research Council (LP100100620 and DP120103389), J.G.P. from the VIRRA project (CGL2009-12048 ⁄ BOS, Spanish Government) and C.M.B. from a European Union Marie Curie Intra-European Fellowship (FILE-PIEF-GA-2009-253780). We thank M. Bonilla, T. Nangchuk, M. Panayotov, D.A. Rodríguez-Trejo, W. Zheng, S. Li and Z. Zhang for providing trait data, and three referees for their helpful comments.Peer reviewe