Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asparaginase (ASNase) causes pancreatitis in approximately 10% of leukemia patients, and the mechanisms underlying this painful complication are not known. ASNase primarily depletes circulating asparagine, and the endogenously expressed enzyme, asparagine synthetase (ASNS), replenishes asparagine. ASNS was suggested previously to be highly expressed in the pancreas. In this study, we determined the expression pattern of ASNS in the pancreas and the mechanism for increased pancreatic ASNS abundance. Compared with other organs, ASNS was highly expressed in both the human and mouse pancreas, and, within the pancreas, ASNS was present primarily in the acinar cells. The high baseline pancreatic ASNS was associated with higher baseline activation of protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in the pancreas, and inhibition of PERK in acinar cells lessened ASNS expression. ASNase exposure, but not the common pancreatitis triggers, uniquely up-regulated ASNS expression, indicating that the increase is mediated by nutrient stress. The up-regulation of acinar ASNS with ASNase exposure was owing to increased transcriptional rather than delayed degradation. Knockdown of ASNS in the 266-6 acinar cells provoked acinar cell injury and worsened ASNase-induced injury, whereas ASNS overexpression protected against ASNase-induced injury. In summary, ASNS is highly expressed in the pancreatic acinar cells through heightened basal activation of PERK, and ASNS appears to be crucial to maintaining acinar cell integrity. The implications are that ASNS is especially hardwired in the pancreas to protect against both baseline perturbations and nutrient deprivation stressors, such as during ASNase exposure.
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PMID:Asparagine Synthetase Is Highly Expressed at Baseline in the Pancreas Through Heightened PERK Signaling. 3142 Dec 61

The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy.
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PMID:Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia. 3153 35

Recent studies have shown that BRAF inhibitors, such as vemurafenib, are effective in inducing long periods of remission in relapsed hairy cell leukaemia. Acute pancreatitis is one of the rare complications that is reported with vemurafenib use. As severe pancreatitis can be life threatening, physicians should be vigilant of this side effect and promptly treat patients that develop clinical signs and symptoms while receiving vemurafenib. We present an interesting case of vemurafenib-induced pancreatitis that not only resolved but also did not recur after reintroduction of the drug at a reduced dose.
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PMID:Vemurafenib-induced pancreatitis in a patient with recurrent hairy cell leukaemia. 3292 33

Insufficient exposure to asparaginase therapy is a barrier to optimal treatment and survival in childhood acute lymphoblastic leukaemia (ALL). Three important reasons for inactivity or discontinuation of asparaginase therapy are infusion related reactions (IRRs), pancreatitis and life-threatening central nervous system (CNS). For IRRs, real-time therapeutic drug monitoring (TDM) and premedication are important aspects to be considered. For pancreatitis and CNS thrombosis one key question is if patients should be re-exposed to asparaginase after their occurrence.An expert panel met during the Congress of the International Society for Paediatric Oncology in Lyon in October 2019 to discuss strategies for diminishing the impact of these three toxicities. The panel agreed that TDM is particularly useful for optimising asparaginase treatment and that when a tight pharmacological monitoring programme is established premedication could be implemented more broadly to minimise the risk of IRR. Re-exposure to asparaginase needs to be balanced against the anticipated risk of leukemic relapse. However, more prospective data are needed to give clear recommendations if to re-expose patients to asparaginase after the occurrence of severe pancreatitis and CNS thrombosis.
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PMID:Increasing completion of asparaginase treatment in childhood acute lymphoblastic leukaemia (ALL): summary of an expert panel discussion. 3296 20

With recent prospective clinical trials that used paediatric regimens with multiple doses of pegylated form of asparaginase (PEG asparaginase) in adults reporting significantly improved survival compared with historical data with regimens that used less asparaginase, PEG asparaginase is increasingly being used in the treatment of adult acute lymphoblastic leukaemia (ALL). However, administering asparaginase still comes with its challenges, especially in adult patients. Therefore, it is important to understand how to manage its toxicities properly. An expert group met in November 2019 in London to discuss recent data of paediatric as well as adult studies using paediatric regimens with regard to the best management of several key toxicities that can occur in adults treated with asparaginase including hepatotoxicity, pancreatitis, hypertriglyceridaemia, thrombosis and hypersensitivity. Several recommendations were made for each one of these toxicities, with the goal of safe administration of the drug and to educate clinicians when the drug can be continued despite side effects.
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PMID:Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open-Cancer Horizons roundtable discussion. 3303 33


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