Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile ca...Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells. Ca<sup>2+</sup> overload is a key early event and is crucial in the pathogenesis of many diseases. In pancreatic acinar cells, pathological Ca<sup>2+</sup> signaling (stimulated by bile, alcohol metabolites and other causes) is a key contributor to the initiation of cell injury due to prolonged and global Ca<sup>2+</sup> elevation that results in trypsin activation, vacuolization and necrosis, all of which are crucial in the development of pancreatitis. Increased release of Ca<sup>2+</sup> from stores in the intracellular endoplasmic reticulum and/or increased Ca<sup>2+</sup> entry through the plasma membrane are causes of such cell damage. Failed mitochondrial adenosine triphosphate (ATP) production reduces re-uptake and extrusion of Ca<sup>2+</sup> by the sarco/endoplasmic reticulum Ca<sup>2+</sup>-activated ATPase and plasma membrane Ca<sup>2+</sup>-ATPase pumps, which contribute to Ca<sup>2+</sup> overload. Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca<sup>2+</sup> signals in pancreatitis. The lack of available specific treatments is therefore an objective of ongoing research. Research is currently underway to establish the mechanisms and interactions of Ca<sup>2+</sup> signals in the pathogenesis of pancreatitis.展开更多
Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation...Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.展开更多
Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and ...Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin(IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly antiinflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the antiautophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.展开更多
Acute pancreatitis is a severe inflammatory disorder with limited treatment options.Improved understanding of disease mechanisms has led to new and potential therapies.Here we summarize what we view as some of the mos...Acute pancreatitis is a severe inflammatory disorder with limited treatment options.Improved understanding of disease mechanisms has led to new and potential therapies.Here we summarize what we view as some of the most promising new therapies for treating acute pancreatitis,emphasizing the rationale of specific treatments based on disease mechanisms.Targeted pharmacologic interventions are highlighted.We explore potential treatment benefits and risks concerning reducing acute injury,minimizing complications,and improving long-term outcomes.Mechanisms associated with acute pancreatitis initiation,perpetuation,and reconstitution are highlighted,along with potential therapeutic targets and how these relate to new treatments.展开更多
基金Supported by grants from the National Natural Science Foundation of China No.30171167,No.30901945the Specialized Research Fund for the Doctoral Program of Higher Education No.20130201130009
文摘Pancreatitis is an increasingly common and sometimes severe disease that lacks a specific therapy. The pathogenesis of pancreatitis is still not well understood. Calcium (Ca<sup>2+</sup>) is a versatile carrier of signals regulating many aspects of cellular activity and plays a central role in controlling digestive enzyme secretion in pancreatic acinar cells. Ca<sup>2+</sup> overload is a key early event and is crucial in the pathogenesis of many diseases. In pancreatic acinar cells, pathological Ca<sup>2+</sup> signaling (stimulated by bile, alcohol metabolites and other causes) is a key contributor to the initiation of cell injury due to prolonged and global Ca<sup>2+</sup> elevation that results in trypsin activation, vacuolization and necrosis, all of which are crucial in the development of pancreatitis. Increased release of Ca<sup>2+</sup> from stores in the intracellular endoplasmic reticulum and/or increased Ca<sup>2+</sup> entry through the plasma membrane are causes of such cell damage. Failed mitochondrial adenosine triphosphate (ATP) production reduces re-uptake and extrusion of Ca<sup>2+</sup> by the sarco/endoplasmic reticulum Ca<sup>2+</sup>-activated ATPase and plasma membrane Ca<sup>2+</sup>-ATPase pumps, which contribute to Ca<sup>2+</sup> overload. Current findings have provided further insight into the roles and mechanisms of abnormal pancreatic acinar Ca<sup>2+</sup> signals in pancreatitis. The lack of available specific treatments is therefore an objective of ongoing research. Research is currently underway to establish the mechanisms and interactions of Ca<sup>2+</sup> signals in the pathogenesis of pancreatitis.
文摘Pancreatic carcinomas with acinar differentiation are rare,accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma(PACC),pancreatoblastoma,and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry. Surgical resection of PACC is the preferred treatment for localized and resectable tumors. The efficacy of adjuvant treatment is unclear. Metastatic PACCs are generally not curable and treated with systemic chemotherapy. They are moderately responsive to chemotherapy with different regimens showing various degrees of response in case reports/series. Most of these regimens were developed to treat patients with pancreatic ductal adenocarcinomas or colorectal adenocarcinomas. Review of PACC's molecular profiling showed a number of gene alterations such as: SMAD4,BRAF,BRCA2,TP53,RB1,MEN1,JAK-1,BRCA-1,BRCA-2,and DNA mismatch repair abnormalities. PACCs had multiple somatic mutations with some targetable with available drugs. Therefore,molecular profiling of PACC should be an option for patients with refractory PACC.
文摘Acute pancreatitis(AP) is a disorder characterized by parenchymal injury of the pancreas controlled by immune cell-mediated inflammation. AP remains a significant challenge in the clinic due to a lack of specific and effective treatment. Knowledge of the complex mechanisms that regulate the inflammatory response in AP is needed for the development of new approaches to treatment, since immune cell-derived inflammatory cytokines have been recognized to play critical roles in the pathogenesis of the disease. Recent studies have shown that interleukin(IL)-22, a cytokine secreted by leukocytes, when applied in the severe animal models of AP, protects against the inflammation-mediated acinar injury. In contrast, in a mild AP model, endogenous IL-22 has been found to be a predominantly antiinflammatory mediator that inhibits inflammatory cell infiltration via the induction of Reg3 proteins in acinar cells, but does not protect against acinar injury in the early stage of AP. However, constitutively over-expressed IL-22 can prevent the initial acinar injury caused by excessive autophagy through the induction of the antiautophagic proteins Bcl-2 and Bcl-XL. Thus IL-22 plays different roles in AP depending on the severity of the AP model. This review focuses on these recently reported findings for the purpose of better understanding IL-22's regulatory roles in AP which could help to develop a novel therapeutic strategy.
基金supported by a Veterans Administration Senior Clinical Scientist Merit Award(BX003250)a Department of Defense Investigator Initiated Award(PR220457)the Henry and Joan Binder Endowment
文摘Acute pancreatitis is a severe inflammatory disorder with limited treatment options.Improved understanding of disease mechanisms has led to new and potential therapies.Here we summarize what we view as some of the most promising new therapies for treating acute pancreatitis,emphasizing the rationale of specific treatments based on disease mechanisms.Targeted pharmacologic interventions are highlighted.We explore potential treatment benefits and risks concerning reducing acute injury,minimizing complications,and improving long-term outcomes.Mechanisms associated with acute pancreatitis initiation,perpetuation,and reconstitution are highlighted,along with potential therapeutic targets and how these relate to new treatments.
