Mid-term evaluation of CATIE's program on ecologically-based participatory implementation of IPM and agroforestry in Nicaragua and Central America (CATI-MIP/AF) Phase III

CATIE-MIP/AF is a well-conceived and well-managed program that has capitalized on lessons learned in previous phases and from other programs. It developed in response to the weakening of the extension function within national agricultural systems in Central America and has contributed to the reorientation of the linear transfer-of-technology model prevailing in Nicaragua and other Central American Countries into a participatory extension approach that links farm families, extensionists, researchers and trainers, and decision-makers. The participatory methodologies developed by the program are a major strength in addressing challenges posed by modern-day complexity, uncertainty and dynamism in agriculture and natural resource management by farmers. The Program has catalyzed the establishment of a field-based multi-level, multi-institutional platform for participatory development and extension of technology for three important Central American farming systems, coffee, vegetables and basic grains (maize and beans), combining these with a broad array of ecological practices based on principles of agroforestry, integrated pest management, and natural resource conservation. The participatory capacity-building supported by the program develops powers of ecological reasoning, and incorporates a gender and family focus. The program has supported participatory training of 19,964 farmers, 861extensionists, 133 trainers (specialists) and has involved 380 decision-makers in joint planning and public monitoring of the process. Benefits to participating farmers of at least US$3.7 million have accrued during the first three years of the program. High priorities during the remaining two years of the program include Sustained effort in: systematization of program experience, promotion of institutional learning in CATIE about the MIP/AF experience; capacity-building to develop ecological reasoning; development of the regionalization process for scaling-out the work of the program to pilot areas in other Central Amercian countries capacity-building work on basic grains, The mission also recommends formulation of a plan to ensure devolution of the field based, multi-level, multi-institutional process in Nicaragua and elswhere when appropriate. This could occur by establishment of a process for promoting proposal development by counterparts, and by the program, that will ensure the future integrity of the multinstitutional platform and of the integrated MIP/AF focus. The review mission recommends further sustained funding counterpart organisations and to the program. The mission sees a need for developing empresarial reasoning as a complement to the current focus on ecological reasoning. Combining the two within a new cycle of funding involving both counterpart organisations and CATIE will increase the sustainability of achievements and the chances of significant impact on poverty alleviation in the future

Low incidence of inflammatory bowel disease adverse events in adalimumab clinical trials across nine different diseases

OBJECTIVE: Adalimumab is approved for treatment of Crohn's disease and ulcerative colitis. Thus, we postulated that exacerbation or new-onset of inflammatory bowel disease (IBD) would be rare events in patients treated with adalimumab for non-IBD indications. This analysis evaluated the incidence of IBD adverse events (AEs) across adalimumab trials. METHODS: IBD AE rates in 75 adalimumab clinical trials in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, pediatric enthesitis-related arthritis, uveitis, hidradenitis suppurativa, adult and pediatric psoriasis, psoriatic arthritis, non-psoriatic arthritis peripheral spondyloarthritis (pSpA), axial spondyloarthritis (axSpA), including non-radiographic axSpA and ankylosing spondylitis, were analyzed. Search terms for IBD AEs (new onset or worsening/flare) included IBD, ulcerative colitis, Crohn's disease, and ulcerative proctitis. RESULTS: This analysis included 24,114 patients, representing 36,508 patient-years (PY) of adalimumab exposure. The overall rate (95% CI) of IBD AEs in adalimumab-treated patients was 0.1 (0.1-0.2)/100 PY (41 events), ranging from no events (psoriatic arthritis, uveitis, and pediatric trials) to 0.8 (0.2-2.2)/100 PY in pSpA; the rate of IBD in axSpA was 0.6 (0.4-1.0)/100 PY. During placebo-controlled trials, the overall IBD rate was 0.1 (0.0-0.3)/100 PY for adalimumab (3 events in 6781 patients; 2752 PY of exposure) and 0.1 (0.0-0.4)/100 PY for placebo (1 event in 3493 patients; 1246 PY of exposure) groups; IBD rates in axSpA were 0.5 (0.1-1.4)/100 PY and 0.6 (0.0-3.1)/100 PY, respectively. CONCLUSION: The rates of IBD AEs in adalimumab clinical trials were generally low across the evaluated diseases, including axSpA; all events occurred in adult patients

The life of plant mitochondrial complex I

The mitochondrial NADH dehydrogenase complex (complex I) of the respiratory chain has several remarkable features in plants: (i) particularly many of its subunits are encoded by the mitochondrial genome, (ii) its mitochondrial transcripts undergo extensive maturation processes (e.g. RNA editing, trans-splicing), (iii) its assembly follows unique routes, (iv) it includes an additional functional domain which contains carbonic anhydrases and (v) it is, indirectly, involved in photosynthesis. Comprising about 50 distinct protein subunits, complex I of plants is very large. However, an even larger number of proteins are required to synthesize these subunits and assemble the enzyme complex. This review aims to follow the complete "life cycle" of plant complex I from various molecular perspectives. We provide arguments that complex I represents an ideal model system for studying the interplay of respiration and photosynthesis, the cooperation of mitochondria and the nucleus during organelle biogenesis and the evolution of the mitochondrial oxidative phosphorylation system. © 2014 Elsevier B.V

The Arabidopsis class II sirtuin is a lysine deacetylase and interacts with mitochondrial energy metabolism

The posttranslational regulation of proteins by lysine (Lys) acetylation has recently emerged to occur not only on histones, but also on organellar proteins in plants and animals. In particular, the catalytic activities of metabolic enzymes have been shown to be regulated by Lys acetylation. The Arabidopsis (Arabidopsis thaliana) genome encodes two predicted sirtuin-type Lys deacetylases, of which only Silent Information Regulator2 homolog (SRT2) contains a predicted presequence for mitochondrial targeting. Here, we have investigated the function of SRT2 in Arabidopsis. We demonstrate that SRT2 functions as a Lys deacetylase in vitro and in vivo. We show that SRT2 resides predominantly at the inner mitochondrial membrane and interacts with a small number of protein complexes mainly involved in energy metabolism and metabolite transport. Several of these protein complexes, such as the ATP synthase and the ATP/ADP carriers, show an increase in Lys acetylation in srt2 loss-of-function mutants. The srt2 plants display no growth phenotype but rather a metabolic phenotype with altered levels in sugars, amino acids, and ADP contents. Furthermore, coupling of respiration to ATP synthesis is decreased in these lines, while the ADP uptake into mitochondria is significantly increased. Our results indicate that SRT2 is important in fine-tuning mitochondrial energy metabolism

Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.]

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Low Energy Electron Irradiation Is a Potent Alternative to Gamma Irradiation for the Inactivation of (CAR-)NK-92 Cells in ATMP Manufacturing

Background: With increasing clinical use of NK-92 cells and their CAR-modified derivatives in cancer immunotherapy, there is a growing demand for efficient production processes of these “off-the-shelf” therapeutics. In order to ensure safety and prevent the occurrence of secondary tumors, (CAR-)NK-92 cell proliferation has to be inactivated before transfusion. This is commonly achieved by gamma irradiation. Recently, we showed proof of concept that low energy electron irradiation (LEEI) is a new method for NK-92 inactivation. LEEI has several advantages over gamma irradiation, including a faster reaction time, a more reproducible dose rate and much less requirements on radiation shielding. Here, LEEI was further evaluated as a promising alternative to gamma irradiation yielding cells with highly maintained cytotoxic effector function. Methods: Effectiveness and efficiency of LEEI and gamma irradiation were analyzed using NK-92 and CD123-directed CAR-NK-92 cells. LEE-irradiated cells were extensively characterized and compared to gamma-irradiated cells via flow cytometry, cytotoxicity assays, and comet assays, amongst others. Results: Our results show that both irradiation methods caused a progressive decrease in cell viability and are, therefore, suitable for inhibition of cell proliferation. Notably, the NKmediated specific lysis of tumor cells was maintained at stable levels for three days postirradiation, with a trend towards higher activities after LEEI treatment as compared to gamma irradiation. Both gamma irradiation as well as LEEI led to substantial DNA damage and an accumulation of irradiated cells in the G2/M cell cycle phases. In addition, transcriptomic analysis of irradiated cells revealed approximately 12-fold more differentially expressed genes two hours after gamma irradiation, compared to LEEI. Analysis of surface molecules revealed an irradiation-induced decrease in surface expression of CD56, but no changes in the levels of the activating receptors NKp46, NKG2D, or NKp30. Conclusions: The presented data show that LEEI inactivates (CAR-)NK-92 cells as efficiently as gamma irradiation, but with less impact on the overall gene expression. Due to logistic advantages, LEEI might provide a superior alternative for the manufacture of (CAR-)NK-92 cells for clinical application