Background: During pancreatitis, autophagy is activated, but lysosomal degradation of dysfunctional organelles including mitochondria is impaired, resulting in acinar cell death. Retrospective cohort analyses demonstrated an association between simvastatin use and decreased acute pancreatitis incidence. Methods: We examined whether simvastatin can protect cell death induced by cerulein and the mechanisms involved during acute pancreatitis. Mice were pretreated with DMSO or simvastatin (20 mg/kg) for 24 h followed by 7 hourly cerulein injections and sacrificed 1 h after last injection to harvest blood and tissue for analysis. Results: Pancreatic histopathology revealed that simvastatin reduced necrotic cell death, inflammatory cell infiltration and edema. We found that cerulein triggered mitophagy with autophagosome formation in acinar cells. However, autophagosome-lysosome fusion was impaired due to altered levels of LAMP-1, AMPK and ULK-1, resulting in autophagosome accumulation (incomplete autophagy). Simvastatin abrogated these effects by upregulating LAMP-1 and activating AMPK which phosphorylated ULK-1, resulting in increased formation of functional autolysosomes. In contrast, autophagosomes accumulated in control group during pancreatitis. The effects of simvastatin to promote autophagic flux were inhibited by chloroquine. Mitochondria from simvastatin-treated mice were resistant to calcium overload compared to control, suggesting that simvastatin induced mitochondrial quality control to eliminate susceptible mitochondria. Clinical specimens showed a significant increase in cell-free mtDNA in plasma during pancreatitis compared to normal controls. Furthermore, genetic deletion of parkin abrogated the benefits of simvastatin. Conclusion: Our findings reveal the novel role of simvastatin in enhancing autophagic flux to prevent pancreatic cell injury and pancreatitis.

The heart failure (HF) patients with severe left ventricular (LV) systolic dysfunction still have unfavorable prognosis. We aimed to investigate if better global longitudinal strain (GLS) predicts improved clinical outcomes in these patients.

Madam — Substantial improvement in survival from cancer highlighted both physical and psychosocial issues of survivorship [ [1] Jena R. Coles C.E. Survivorship issues in radiation oncology. Clin Oncol. 2015; 27: 619-620 Abstract Full Text Full Text PDF Scopus (2) Google Scholar ]. Nasopharyngeal cancer (NPC) is a highly curable cancer by radiotherapy but treatment toxicities are common and quality of life (QoL) of survivors is impaired [ [2] Lee A.W.M. Sze W.M. Au J.S.K. et al. Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. Int J Radiat Oncol Biol Phys. 2005; 61: 1107-1116 Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar ]. Although treatment regret has been studied in highly curable diseases like breast cancer and prostate cancer, data in NPC are lacking [ 3 Fernandes-Taylor S. Bloom J.R. Post-treatment regret among young breast cancer survivors. Psychooncology. 2011; 20: 506-516 Crossref PubMed Scopus (46) Google Scholar , 4 Mahal B.A. Chen M.H. Bennett C.L. et al. The association between race and treatment regret among men with recurrent prostate cancer. Prostate Cancer Prostatic Dis. 2015; 18: 38-42 Crossref PubMed Scopus (16) Google Scholar ].

Harmful algal blooms (HAB), commonly referred to as 'red tides', involving the dinoflagellate Karenia brevis produce a series of neurotoxins known as brevetoxins (PbTx). Brevetoxins have long been associated with extensive fish kills, adverse human health effects such as neurotoxic shellfish poisoning, and have been associated with mortality events in aquatic mammals such as bottlenose dolphins (Tursiops truncatus). The immunotoxicological effects of these brevetoxins have been studied in manatees, humans, and cell lines, however, the effects in bottlenose dolphins remain unclear. There are increasing concerns that dolphins may be exposed to repeated/chronic, sub-lethal concentrations, which may impact their overall health. The objectives of this study were to measure the changes in innate (phagocytosis, respiratory burst, NK cell activity) and adaptive (mitogen-induced B and T lymphocyte proliferation) immune functions upon in vitro exposure to increasing concentrations of brevetoxin (PbTx-3) (0, 0.01, 0.1, 1, 10, 100, 500, and 1000 nM) using bottlenose dolphin peripheral blood immune cells. Brevetoxin significantly increased spontaneous lymphocyte proliferation at 0.1–1000 nM compared to the unexposed control. Brevetoxin significantly increased T lymphocyte proliferation upon suboptimal (0.1 μg/ml) and optimal (1.0 μg/ml) Con-A stimulation at 0.01–100 nM and 0.1 nM of PbTx-3 respectively, as well as suboptimal (0.05 μg/ml) and optimal (5.0 μg/ml) LPS-induced B lymphocyte proliferation at 0.01–100 nM and 0.01–500 nM of PbTx-3, respectively. Both neutrophil and monocyte respiratory burst were significantly increased at 500 and 1000 nM. There were no significant effects on neutrophil or monocyte phagocytosis or NK cell activity. Importantly, concentrations that modulated immune functions in vitro were within the range measured in the blood of dolphins during two unusual mortality events, suggesting that naturally exposed dolphins may be at risk for immunomodulation. Brevetoxin-induced immunomodulation may increase an animal's susceptibility to bacterial, viral, or fungal infections. Understanding the risk for immunomodulation upon HAB toxin exposure can contribute in the health assessment and management of marine mammals, as well as guide veterinarians and wildlife rehabilitators in caring for and treating afflicted animals.