Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2

Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis

Galactose protects against cell damage in mouse models of acute pancreatitis

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP

Clinical Utility of Radiologic Disease Reassessment in the Management of Pediatric B-Cell Non-Hodgkin Lymphoma

Although outcomes for children with B-cell non-Hodgkin lymphoma are excellent, between 20% and 40% demonstrate residual radiologic abnormalities at disease assessment during consolidation therapy, the significance of which remains uncertain. The authors report the outcomes for all children treated for B-cell non-Hodgkin lymphoma at our center over an 11-year period. Twenty-four of 64 (38%) children had residual radiologic abnormalities at disease remission assessment. Seven (29%) underwent histologic biopsies that were normal. No children with residual radiologic abnormalities experienced disease relapse or death, suggesting that imaging at this time point creates clinical uncertainty without indicating residual disease or predicting relapse

The development and validation of a decision aid to enhance shared decision‐making for the management of actinic keratosis

Actinic keratoses (AKs) are common pre‐malignant lesions. There are numerous management options including active surveillance, multiple topical therapies, cryotherapy, curettage and cautery, and photodynamic therapy, each with their own risks, benefits and efficacy. Best practice currently involves shared decision‐making between patient and clinician, particularly in the setting of multiple management options. Patient decision aids have been shown to be beneficial in the shared decision‐making process. In view of this, we have developed and validated a decision aid for the management of AKs, in concordance with the International Patient Decision Aids Standards

Mainstreaming biodiversity for food and nutrition into policies and practice: methodologies and lessons learned from four countries

This paper outlines the methodology for mainstreaming biodiversity developed by the Biodiversity for Food and Nutrition Project (BFN), a multi-country initiative led by Brazil, Kenya, Sri Lanka and Turkey. BFN explored the nutritional properties of traditional and/or neglected native edible species, both wild and cultivated (including varieties and landraces), and used this knowledge to incorporate local agricultural biodiversity into national and global policy instruments that address food and nutrition security through the promotion of healthy, diversified and sustainable diets. Across the four countries, the project adopted a three-pillar approach for mainstreaming biodiversity for food and nutrition into policies and practices by: 1) Providing Evidence, 2) Influencing Policy, and 3) Raising Awareness. Case study examples from Brazil, Kenya, Turkey, and Sri Lanka demonstrate how the approach can be adapted to suit specific country contexts and how a multi-level, cross-sectoral partnership-based approach can create an enabling environment for mainstreaming biodiversity to improve nutrition