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.

Operons

Operons (clusters of co-regulated genes with related functions) are common features of bacterial genomes. More recently, functional gene clustering has been reported in eukaryotes, from yeasts to filamentous fungi, plants, and animals. Gene clusters can consist of paralogous genes that have most likely arisen by gene duplication. However, there are now many examples of eukaryotic gene clusters that contain functionally related but non-homologous genes and that represent functional gene organizations with operon-like features (physical clustering and co-regulation). These include gene clusters for use of different carbon and nitrogen sources in yeasts, for production of antibiotics, toxins, and virulence determinants in filamentous fungi, for production of defense compounds in plants, and for innate and adaptive immunity in animals (the major histocompatibility locus). The aim of this article is to review features of functional gene clusters in prokaryotes and eukaryotes and the significance of clustering for effective function

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Apical control of conidiation in Aspergillus nidulans

21 p.-2 fig.The infection cycle of filamentous fungi consists of two main stages: invasion (growth) and dispersion (development). After the deposition of a spore on a host, germination, polar extension and branching of vegetative cells called hyphae allow a fast and efficient invasion. Under suboptimal conditions, genetic reprogramming of hyphae results in the generation of asexual spores, allowing dissemination to new hosts and the beginning of a new infection cycle. In the model filamentous fungus Aspergillus nidulans, asexual development or conidiation is induced by the upstream developmental activation (UDA) pathway. UDA proteins transduce signals from the tip, the polarity site of hyphae, to nuclei, where developmental programs are transcriptionally activated. The present review summarizes the current knowledge on this tip-to-nucleus communication mechanism, emphasizing its dependence on hyphal polarity. Future approaches to the topic will also be suggested, as stimulating elements contributing to the understanding of how apical signals are coupled with the transcriptional control of development and pathogenesis in filamentous fungi.Work at the UPV/EHU was funded by the UPV/EHU (Grant EHUA15/08) and the Basque Government (Grant IT599-13). Work at CIB-CSIC was funded by MINECO (BFU2012-33142).Peer reviewe

Oxygen and an Extracellular Phase Transition Independently Control Central Regulatory Genes and Conidiogenesis in Aspergillus fumigatus

Conidiogenesis is the primary process for asexual reproduction in filamentous fungi. As the conidia resulting from the conidiogenesis process are primarily disseminated via air currents and/or water, an outstanding question has been how fungi recognize aerial environments suitable for conidial development. In this study, we documented the somewhat complex development of the conidia-bearing structures, termed conidiophores, from several Aspergillus species in a subsurface (gel-phase) layer of solid media. A subset of the isolates studied was able to develop conidiophores in a gel-phase environment, but exposure to the aeriform environment was required for the terminal developmental transition from phialide cells to conidia. The remaining Aspergilli could not initiate the conidiogenesis process until they were exposed to the aeriform environment. Our observations of conidiophore development in high or low oxygen conditions in both aeriform and gel-phase environments revealed that oxygen and the aeriform state are positive environmental factors for inducing conidiogenesis in most of the aspergilli tested in this study. Transcriptional analysis using A. fumigatus strain AF293 confined to either the aeriform or gel-phase environments revealed that expression of a key regulatory gene for conidiophore development (AfubrlA) is facilitated by oxygen while expression of another regulatory gene controlling conidia formation from phialides (AfuabaA) was repressed regardless of oxygen levels in the gel-embedded environment. Furthermore, by comparing the developmental behavior of conidiation-defective mutants lacking genes controlling various regulatory checkpoints throughout the conidiogenesis pathway, we propose that this aerial response by the fungus requires both oxygen and the phase transition (solid to aeriform), with these environmental signals integrating into the upstream regulatory pathway and central regulatory pathway of conidiogenesis, respectively. Our findings provide not only novel insight into how fungi respond to an aerial environment to trigger development for airborne conidia production but also the relationship between environmental factors and conidiogenesis regulation in aspergilli