The novel coronavirus disease

Patient-related factors are as important as procedure-related factors in determining high-risk predictors for post-ERCP overall complications and pancreatitis. However, the risk factors for asymptomatic hyperamylasemia may be mostly procedure related.

Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCIDrab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone mineral density (BMD) of the implanted myelomatous bone in control mice was reduced during the experimental period, the BMD in mice treated with anti-DKK1 increased from pretreatment levels (P < .001). Histologic examination revealed that myelomatous bones of anti-DKK1-treated mice had increased numbers of osteocalcin-expressing osteoblasts and reduced number of multinucleated TRAP-expressing osteoclasts. The bone anabolic effect of anti-DKK1 was associated with reduced MM burden (P < .04). Anti-DKK1 also significantly increased BMD of the implanted bone and murine femur in nonmyelomatous SCIDrab mice, suggesting that DKK1 is physiologically an important regulator of bone remodeling in adults. We conclude that DKK1 is a key player in MM bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation, and helps control MM growth. IntroductionMultiple myeloma (MM), a tumor of terminally differentiated plasma cells that home to and expand in the bone marrow (BM), is associated with osteolytic bone disease. This debilitating condition is caused by an uncoupling of bone remodeling as a result of increased activity of osteoclasts and decreased activity of osteoblasts. 1,2 Much of the research on the mechanisms of osteolysis in MM has focused on the role of osteoclasts in shifting the uncoupling process. 2,3 Although bone resorption can be blocked by bisphosphonates, which inhibit osteoclastogenesis, 4,5 the inability of these compounds to induce bone formation and repair lytic lesions indicates that a functional defect of osteoblasts is also involved. Indeed, alterations in the number and function of osteoblasts is a primary event in MM. 6,7 Recent studies have revealed that Wnt signaling is involved in both normal skeletogenesis 8,9 and cancer-related bone disease. 10,11 The first link between Wnt signaling and human bone disease came from the observations that inactivating mutations in the Wnt coreceptor, LRP5, causes the osteoporosis-pseudoglioma (OPPG) syndrome. 12 Subsequently it was shown that in the syndrome of hereditary high bone density 13 mutations in LRP5, distinct from those seen in OPPG, prevent binding of Dickkopf-1 (DKK1), a soluble inhibitor of Wnt and high-affinity ligand for LRP5. 14 The importance of DKK1 in normal skeletal development has also been demonstrated by the extra digits in DKK1 null mice and loss of bony structures in chicken and mice exposed to elevated levels of DKK1. 15.16 To determine the role of DKK1 in vivo and overcome the embryonic le...

In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.

Background & AimsSustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release–activated calcium modulator ORAI1 is the most abundant Ca2+ entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice.MethodsMouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects.ResultsGSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis.ConclusionsCytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis.