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.

Wheat Mds-1 encodes a heat-shock protein and governs susceptibility towards the Hessian fly gall midge

Citation: Liu, X., . . . & Chen, M. (2013). Wheat Mds-1 encodes a heat-shock protein and governs susceptibility towards the Hessian fly gall midge. Nature Communication, 4(1), 2070. https://doi.org/10.1038/ncomms3070Gall midges induce formation of host nutritive cells and alter plant metabolism to utilize host resources. Here we show that the gene Mayetiola destructor susceptibility-1 (Mds-1) on wheat chromosome 3AS encodes a small heat-shock protein and is a major susceptibility gene for infestation of wheat by the gall midge M. destructor, commonly known as the Hessian fly. Transcription of Mds-1 and its homoeologs increases upon insect infestation. Ectopic expression of Mds-1 or induction by heat shock suppresses resistance of wheat mediated by the resistance gene H13 to Hessian fly. Silencing of Mds-1 by RNA interference confers immunity to all Hessian fly biotypes on normally susceptible wheat genotypes. Mds-1-silenced plants also show reduced lesion formation due to infection by the powdery mildew fungus Blumeria graminis f. sp. tritici. Modification of susceptibility genes may provide broad and durable sources of resistance to Hessian fly, B. graminis f. sp. tritici, and other pests