132 results on '"Mark E. Lowe"'
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2. The Arg92Cys colipase polymorphism impairs function and secretion by increasing protein misfolding
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Xunjun Xiao, Michael R. Ferguson, Kelsey E. Magee, Pamela D. Hale, Yan Wang, and Mark E. Lowe
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enterostatin ,fat digestion ,lag time ,stability ,Biochemistry ,QD415-436 - Abstract
Colipase is essential for efficient fat digestion. An arginine-to-cysteine polymorphism at position 92 of colipase (Arg92Cys) associates with an increased risk for developing type-2 diabetes through an undefined mechanism. To test our hypothesis that the extra cysteine increases colipase misfolding, thereby altering its intracellular trafficking and function, we expressed Cys92 colipase in HEK293T cells. Less Cys92 colipase is secreted and more is retained intracellularly in an insoluble form compared with Arg92 colipase. Nonreducing gel electrophoresis suggests the folding of secreted Cys92 colipase differs from Arg92 colipase. Cys92 colipase misfolding does not trigger the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress. The ability of secreted Cys92 colipase to stimulate pancreatic triglyceride lipase (PTL) is reduced with all substrates tested, particularly long-chain triglycerides. The reaction of Cys92 colipase with triolein and Intralipid has a much longer lag time, reflecting decreased ability to anchor PTL on those substrates. Our data predicts that humans with the Arg92Cys substitution will secrete less functional colipase into the duodenum and have less efficient fat digestion. Whether inefficient fat digestion or another property of colipase contributes to the risk for developing diabetes remains to be clarified.
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- 2013
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3. Kinetic properties of mouse pancreatic lipase-related protein-2 suggest the mouse may not model human fat digestion
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Xunjun Xiao, Leah E. Ross, Rita A. Miller, and Mark E. Lowe
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triglyceride ,colipase ,interaction affinity ,binding ,PTL deficiency ,Biochemistry ,QD415-436 - Abstract
Genetically engineered mice have been employed to understand the role of lipases in dietary fat digestion with the expectation that the results can be extrapolated to humans. However, little is known about the properties of mouse pancreatic triglyceride lipase (mPTL) and pancreatic lipase-related protein-2 (mPLRP2). In this study, both lipases were expressed in Pichia Pastoris GS115, purified to near homogeneity, and their properties were characterized. Mouse PTL displayed the kinetics typical of PTL from other species. Like mPTL, mPLRP2 exhibited strong activity against various triglycerides. In contrast to mPTL, mPLRP2 was not inhibited by increasing bile salt concentration. Colipase stimulated mPLRP2 activity 2- to 4-fold. Additionally, mPTL absolutely required colipase for absorption to a lipid interface, whereas mPLRP2 absorbed fully without colipase. mPLRP2 had full activity in the presence of BSA, whereas BSA completely inhibited mPTL unless colipase was present. All of these properties of mPLRP2 differ from the properties of human PLRP2 (hPLRP2). Furthermore, mPLRP2 appears capable of compensating for mPTL deficiency. These findings suggest that the molecular mechanisms of dietary fat digestion may be different in humans and mice. Thus, extrapolation of dietary fat digestion in mice to humans should be done with care.
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- 2011
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4. A polymorphism in the gene encoding procolipase produces a colipase, Arg92Cys, with decreased function against long-chain triglycerides
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Sheryl D'Silva, Xunjun Xiao, and Mark E. Lowe
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lipase ,type 2 diabetes ,digestion ,recombinant protein ,mutagenesis ,Biochemistry ,QD415-436 - Abstract
Type 2 diabetes mellitus is a multifactorial and polygenic disorder with increasing prevalence. Recently, a polymorphism in the gene encoding procolipase, a cysteine for arginine substitution at position 92, was associated with type 2 diabetes in two human populations. Because procolipase plays a critical role in dietary fat metabolism, polymorphisms that affect the function of procolipase could influence the development of type 2 diabetes. We hypothesized that the Arg92Cys polymorphism has functional consequences. To test our hypothesis, we expressed recombinant cysteine 92 (Cys92) procolipase in a yeast expression system and compared the function and stability of purified Cys92 with that of the more common arginine 92 (Arg92) procolipase. Cys92 fully restored the activity of bile-salt inhibited lipase with short- and medium-chain triglycerides but only had 50% of Arg92 function with long-chain triglycerides. After storage at 4°C, Cys92 lost the ability to restore pancreatic triglyceride lipase activity with medium- and long-chain triglycerides. The loss of function correlated with the inability of Cys92 to anchor lipase on an emulsion surface and oxidation of the cysteine. No detectable degradation or intramolecular disulfide formation occurred in Cys92 after storage. Our findings demonstrate that the Arg92Cys polymorphism decreases the function of Cys92 colipase. This change may contribute to the development of type 2 diabetes.
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- 2007
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5. Inhibition of lipases by ∊-polylysine
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Takahiro Tsujita, Maho Sumiyoshi, Takeshi Takaku, William E. Momsen, Mark E. Lowe, and Howard L. Brockman
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basic peptide ,complex ,lipid emulsion ,lipid monolayer ,Biochemistry ,QD415-436 - Abstract
Oral administration of ∊-polylysine to rats reduced the peak plasma triacylglycerol concentration. In vitro, ∊-polylysine and polylysine strongly inhibited the hydrolysis, by either pancreatic lipase or carboxylester lipase, of trioleoylglycerol (TO) emulsified with phosphatidylcholine (PC) and taurocholate. The ∊-polylysine concentration required for complete inhibition of pancreatic lipase, 10 μg/ml, is 1,000 times lower than that of BSA required for the same effect. Inhibition requires the presence of bile salt and, unlike inhibition of lipase by other proteins, is not reversed by supramicellar concentrations of bile salt. Inhibition increases with the degree of polylysine polymerization, is independent of lipase concentration, is independent of pH between 5.0 and 9.5, and is accompanied by an inhibition of lipase binding to TO-PC emulsion particles. However, ∊-polylysine did not inhibit the hydrolysis by pancreatic lipase of TO emulsions prepared using anionic surfactants, TO hydrolysis catalyzed by lingual lipase, or the hydrolysis of a water-soluble substrate. In the presence of taurocholate, ∊-polylysine becomes surface active and adsorbs to TO-PC monomolecular films.These results are consistent with ∊-polylysine and taurocholate forming a surface-active complex that binds to emulsion particles, thereby retarding lipase adsorption and triacylglycerol hydrolysis both in vivo and in vitro.
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- 2003
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6. The triglyceride lipases of the pancreas
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Mark E. Lowe
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triglyceride ,X-ray crystal structure ,C2-domain ,colipase ,site directed mutagenesis ,Biochemistry ,QD415-436 - Abstract
Pancreatic triglyceride lipase (P33333344) and its protein cofactor, colipase, are required for efficient dietary triglyceride digestion. In addition to PTL, pancreatic acinar cells synthesize two pancreatic lipase related proteins (PLRP1 and PLRP2), which have a high degree of sequence and structural homology with PTL. PLRP1 has no known activity. PTL and PLRP2 differ in substrate specificity, behavior in bile salts and dependence on colipase. Each protein has a globular amino-terminal (N-terminal) domain, which contains the catalytic site for PTL and PLRP2, and a β-sandwich carboxyl-terminal (C-terminal) domain, which includes the predominant colipase-binding site for PTL. Inactive and active conformations of PTL have been described. They differ in the position of a surface loop, the lid domain, and of the β5-loop. In the inactive conformation, the lid covers the active site and, upon activation by bile salt micelles and colipase or by lipid-water interfaces, the lid moves dramatically to open and configure the active site. After the lid movement, PTL and colipase create a large hydrophobic plateau that can interact with the lipid-water interface.A hydrophobic surface loop in the C-terminal domain, the β5′ loop, may also contribute to the interfacial-binding domain of the PTL-colipase complex.
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- 2002
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7. The open lid mediates pancreatic lipase function
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Yanqing Yang and Mark E. Lowe
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pancreatic lipase-related protein ,colipase ,site-directed mutagenesis ,bile salts ,Biochemistry ,QD415-436 - Abstract
Pancreatic triglyceride lipase (PTL) and the homologous pancreatic lipase related protein 2 (PLRP2) provide a unique opportunity to understand the molecular mechanism of lipolysis. They differ in substrate specificity, sensitivity to bile salts, and colipase dependence despite their close amino acid and tertiary structure identity. One important structure, present in both lipases, is the lid which occupies different positions in the inactive and active forms of PTL. We investigated the role of the lid in lipase function by site-specific mutagenesis. By exchanging the lids between PTL and PLRP2, we created two chimeric lipases. Additionally, we made multiple substitution mutations in the PTL lid. PLRP2 with the PTL lid had kinetic properties similar to PLRP2. PTL with the PLRP2 lid was greatly impaired and had no activity at micellar bile salt concentrations even in the presence of colipase. Both chimeras showed interfacial activation suggesting that the closed lid position was maintained. A series of substitution mutations were made in positions Arg257 and Asp258. These mutations demonstrated the importance of these two residues to maintaining the normal activity, triglyceride acyl chain specificity, and colipase interaction of PTL. The preserved interfacial activation in the chimeras, the similar crystal structure of the two lids in the closed position, and the importance of Arg257 and Asp258 in mediating the open conformation of the lid argue that the position of the open lid influences the differences in activity against triglycerides, in sensitivity to bile salts, and in colipase dependence between PTL and PLRP2. —Yang, Y., and M. E. Lowe. The open lid mediates pancreatic lipase function.
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- 2000
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8. The hydrophobic surface of colipase influences lipase activity at an oil–water interface
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Richard A. Cordle and Mark E. Lowe
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enzyme ,lipids ,membranes ,protein expression ,protein purification ,site-directed mutagenesis ,Biochemistry ,QD415-436 - Abstract
The interaction of pancreatic triglyceride lipase and colipase at an oil–water interface is required for efficient digestion of dietary fats and provides a model system for the interaction of proteins at biological membranes. Colipase has two important surfaces, a hydrophilic surface that interacts with lipase and a hydrophobic surface that presumably interacts with substrate. To begin our investigations into the role of the hydrophobic surface in the function of colipase, we replaced three neighboring tyrosine residues at positions 55, 58, and 59 in the hydrophobic surface with aspartic acid. Two of the three residues, Tyr55 and Tyr59, influenced the activity of colipase. Introducing aspartic acid at either position decreased the activity with long-chain triglycerides, but not with a short-chain triglyceride. Decreased ability of the mutants to anchor lipase to long-chain triglycerides did not explain the altered activity of the mutants. A mutant containing aspartic acid at positions 55 and 59 had no activity with any substrate and did not anchor lipase to either short- or long-chain triglycerides. These results identify the two tyrosine residues that interact with substrate and suggest that the hydrophobicity of the surface containing these tyrosines influences colipase function and the substrate selectivity of pancreatic triglyceride lipase.—Cordle, R. A., and M. E. Lowe. The hydrophobic surface of colipase influences lipase activity at an oil–water interface.
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- 1998
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9. Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors
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See Wan Tham, Fuchenchu Wang, Cheryl E. Gariepy, Gretchen A. Cress, Maisam A. Abu-El-Haija, Melena D. Bellin, Kate M. Ellery, Douglas S. Fishman, Tanja Gonska, Melvin B. Heyman, Tom K. Lin, Asim Maqbool, Brian A. McFerron, Veronique D. Morinville, Jaimie D. Nathan, Chee Y. Ooi, Emily R. Perito, Sarah Jane Schwarzenberg, Zachary M. Sellers, Uzma Shah, David M. Troendle, Michael Wilschanski, Yuhua Zheng, Ying Yuan, Mark E. Lowe, Aliye Uc, and Tonya M. Palermo
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Male ,Recurrence ,Risk Factors ,Pancreatitis, Chronic ,Pediatrics, Perinatology and Child Health ,Gastroenterology ,Quality of Life ,Humans ,Female ,Child ,Article ,Abdominal Pain - Abstract
OBJECTIVES: Abdominal pain, emergency department visits and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). However, data on health-related quality of life (HRQOL) in this population remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% females, mean age = 12.7 years, SD = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B =−10.28, p < .001), episodic and constant abdominal pain (B =−4.66, p =.03; B =−13.25, p
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- 2023
10. A Pre-clinical Mouse Model of a Misfolded PNLIP Variant Develops Chronic Pancreatitis
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Guoying Zhu, Steven J Wilhelm, Leah G George, Brett M Cassidy, Sammy Zino, Cliff J Luke, Mina Hanna, Stephen Stone, Nhung Phan, Neel Matiwala, Samuel J Ballentine, Mark E Lowe, and Xunjun Xiao
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Gastroenterology ,Article - Abstract
ObjectiveIncreasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism.DesignWe created a mouse model ofPnlipp.T221M and characterised the structural and biochemical changes in the pancreas aged 1–12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR.ResultsWe demonstrated the hallmarks of human CP inPnlipp.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. ThePnlipp.T221M pancreas had increased ER stress evidenced by dilated ER, increasedHspa5(BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation ofDdit3(CHOP), nuclear factor-κB and cell death.ConclusionExpression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP.
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- 2023
11. The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis.
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Balázs Csaba Németh, Zsófia Gabriella Pesei, Eszter Hegyi, Ákos Szücs, Andrea Szentesi, Péter Hegyi, Mark E Lowe, and Miklós Sahin-Tóth
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Medicine ,Science - Abstract
A nonsense variant (p.W358X) of human pancreatic lipase related protein 2 (PNLIPRP2) is present in different ethnic populations with a high allele frequency. In cell culture experiments, the truncated protein mainly accumulates inside the cells and causes endoplasmic reticulum stress. Here, we tested the hypothesis that variant p.W358X might increase risk for chronic pancreatitis through acinar cell stress. We sequenced exon 11 of PNLIPRP2 in a cohort of 256 subjects with chronic pancreatitis (152 alcoholic and 104 non-alcoholic) and 200 controls of Hungarian origin. We observed no significant difference in the distribution of the truncation variant between patients and controls. We analyzed mRNA expression in human pancreatic cDNA samples and found the variant allele markedly reduced. We conclude that the p.W358X truncation variant of PNLIPRP2 is expressed poorly and has no significant effect on the risk of chronic pancreatitis.
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- 2018
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12. Vascular Complications in Pediatric Pancreatitis: A Case Series
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Mark E. Lowe, Cynthia M. Tsai, Aliye Uc, Gretchen A. Cress, David M. Troendle, Emily R. Perito, Chee Y. Ooi, Tanja Gonska, Douglas S. Fishman, and Chinenye R. Dike
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medicine.medical_specialty ,Left gastric artery ,medicine.drug_class ,Article ,Pseudoaneurysm ,Pancreatitis, Chronic ,medicine.artery ,Humans ,Medicine ,Child ,Adverse effect ,Venous Thrombosis ,business.industry ,Anticoagulant ,Gastroenterology ,medicine.disease ,Surgery ,Venous thrombosis ,Splenic Vein ,Splenic vein ,Acute Disease ,Pediatrics, Perinatology and Child Health ,cardiovascular system ,Pancreatitis ,Acute pancreatitis ,business - Abstract
We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated.
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- 2021
13. The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice
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Karianne Fjeld, Anny Gravdal, Ranveig S. Brekke, Jahedul Alam, Steven J. Wilhelm, Khadija El Jellas, Helene N. Pettersen, Jianguo Lin, Marie H. Solheim, Solrun J. Steine, Bente B. Johansson, Pål R. Njølstad, Caroline S. Verbeke, Xunjun Xiao, Mark E. Lowe, and Anders Molven
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Mice ,Hepatology ,Risk Factors ,Endocrinology, Diabetes and Metabolism ,Pancreatitis, Chronic ,Gastroenterology ,Humans ,Animals ,Infant ,Lipase ,Minisatellite Repeats ,Alleles ,Aged - Abstract
Background & aims: The CEL gene encodes the digestive enzyme carboxyl ester lipase. CEL-HYB1, a hybrid allele of CEL and its adjacent pseudogene CELP, is a genetic variant suggested to increase the risk of chronic pancreatitis (CP). Our aim was to develop a mouse model for CEL-HYB1 that enables studies of pancreatic disease mechanisms. Methods: We established a knock-in mouse strain where the variable number of tandem repeat (VNTR) region of the endogenous mouse Cel gene was substituted with the mutated VNTR of the human CEL-HYB1 allele. Heterozygous and homozygous Cel-HYB1 mice and littermate wildtype controls were characterized with respect to pancreatic pathology and function. Results: We successfully constructed a mouse model with pancreatic expression of a humanized CEL-HYB1 protein. The Cel-HYB1 mice spontaneously developed features of CP including inflammation, acinar atrophy and fatty replacement, and the phenotype became more pronounced as the animals aged. Moreover, Cel-HYB1 mice were normoglycemic at age 6 months, whereas at 12 months they exhibited impaired glucose tolerance. Immunostaining of pancreatic tissue indicated the formation of CEL protein aggregates, and electron microscopy showed dilated endoplasmic reticulum. Upregulation of the stress marker BiP/GRP78 was seen in pancreatic parenchyma obtained both from Cel-HYB1 animals and from a human CEL-HYB1 carrier. Conclusions: We have developed a new mouse model for CP that confirms the pathogenicity of the human CEL-HYB1 variant. Our findings place CEL-HYB1 in the group of genes that increase CP risk through protein misfolding-dependent pathways. publishedVersion
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- 2022
14. Diabetes Mellitus in Children with Acute Recurrent and Chronic Pancreatitis: Data From the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort
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M. Bridget Zimmerman, Veronique D. Morinville, Douglas S. Fishman, Uzma Shah, Tanja Gonska, Cheryl E. Gariepy, Bradley A. Barth, Chee Y. Ooi, Melena D. Bellin, Matthew J. Giefer, Mark E. Lowe, Maisam Abu-El-Haija, Brian A. McFerron, Ryan Himes, Quin Liu, Michael Wilschanski, Tom K. Lin, Sarah Jane Schwarzenberg, Jaimie D. Nathan, Steven D. Freedman, David M. Troendle, John F. Pohl, Steven L. Werlin, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Asim Maqbool, Emily R. Perito, and Maria R. Mascarenhas
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First episode ,Hereditary pancreatitis ,medicine.medical_specialty ,business.industry ,Hypertriglyceridemia ,Gastroenterology ,Odds ratio ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Cohort ,medicine ,Acute pancreatitis ,Pancreatitis ,030211 gastroenterology & hepatology ,business - Abstract
Objectives Adults with chronic pancreatitis (CP) have a high risk for developing pancreatogenic diabetes mellitus (DM), but little is known regarding potential risk factors for DM in children with acute recurrent pancreatitis (ARP) or CP. We compared demographic and clinical features of children with ARP or CP, with and without DM, in the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE) registry. Methods We reviewed the INSPPIRE database for the presence or absence of physician-diagnosed DM in 397 children, excluding those with total pancreatectomy with islet autotransplantation, enrolled from August 2012 to August 2017. Patient demographics, BMI percentile, age at disease onset, disease risk factors, disease burden, and treatments were compared between children with DM (n = 24) and without DM (n = 373). Results Twenty-four children (6% of the cohort) had a diagnosis of DM. Five of 13 tested were positive for beta cell autoantibodies. The DM group was 4.2 years [95% confidence interval (CI) 3-5.4] older at first episode of acute pancreatitis, and tended to more often have hypertriglyceridemia [odds ratio (OR) 5.21 (1.33-17.05)], coexisting autoimmune disease [OR 3.94 (0.88-13.65)] or pancreatic atrophy [OR 3.64 (1.13, 11.59)]. Conclusion Pancreatic atrophy may be more common among children with DM, suggesting more advanced exocrine disease. However, data in this exploratory cohort also suggest increased autoimmunity and hypertriglyceridemia in children with DM, suggesting that risk factors for type 1 and type 2 DM, respectively may play a role in mediating DM development in children with pancreatitis.
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- 2019
15. Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis
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András Szabó, Prachand Issarapu, Emmanuelle Masson, Peter Bugert, Denise Lasher, Sumit Paliwal, Claudia Ruffert, Shin Hamada, K. Radha Mani, Helmut Laumen, Jian-Min Chen, Atsushi Masamune, David A. Groneberg, Katharina Seltsam, Kiyoshi Kume, Xunjun Xiao, Maren Ewers, Eriko Nakano, M. Michael Barmada, Tooru Shimosegawa, Jonas Rosendahl, Giriraj R. Chandak, Thomas Müller, Mark E. Lowe, Miklós Sahin-Tóth, Heiko Witt, Seema Bhaskar, David C. Whitcomb, and Claude Férec
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.medical_treatment ,DNA Mutational Analysis ,medicine.disease_cause ,Article ,Pathogenesis ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Pancreatitis, Chronic ,Internal medicine ,medicine ,Humans ,Pancreatic lipase ,Genetic Predisposition to Disease ,Child ,Gene ,Early onset ,Mutation ,Protease ,Virulence ,Hepatology ,biology ,business.industry ,Infant, Newborn ,Gastroenterology ,Infant ,DNA ,Lipase ,medicine.disease ,Trypsin ,Endocrinology ,Child, Preschool ,030220 oncology & carcinogenesis ,biology.protein ,Pancreatitis ,Female ,030211 gastroenterology & hepatology ,business ,Biomarkers ,Follow-Up Studies ,Peptide Hydrolases ,medicine.drug - Abstract
OBJECTIVES. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. METHODS. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. RESULTS. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P
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- 2019
16. Updates in Pediatric Pancreatology: Proceedings of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Frontiers in Pediatric Pancreatology Symposium
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Vikesh K. Singh, Mark E. Lowe, Veronique D. Morinville, Maisam Abu-El-Haija, Timothy B. Gardner, Jaimie D. Nathan, John F. Eisses, Tonya M. Palermo, Aliye Uc, Amit S. Grover, Quin Y. Liu, Andrew T. Trout, Sohail Z. Husain, and Alvin J. Freeman
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medicine.medical_specialty ,Surgical approach ,Extramural ,business.industry ,Gastroenterology ,MEDLINE ,Hepatology ,medicine.disease ,Natural history ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Family medicine ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Pancreatitis ,030211 gastroenterology & hepatology ,Interdisciplinary communication ,business ,Pediatric gastroenterology - Abstract
The Pancreas Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition aims to promote awareness of pediatric pancreatic diseases, support clinical and basic science research in the field, educate pediatric gastroenterologists, and advocate on behalf of pediatric patients with pancreatic disorders. At the 2017 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the Pancreas Committee held a full day symposium on pediatric pancreatic diseases, entitled, "Frontiers in Pediatric Pancreatology." The symposium served as a timely and novel academic meeting that brought together individuals with a vested interest in the care of children with pancreatic disorders. The objective of this day-long course was to update practicing gastroenterologists on the latest advances in research, management algorithms, endoscopic therapies, radiographic resources, surgical approaches, and novel drug therapies targeted to pediatric pancreatitis. Presentations were divided into 4 modules: diagnosis, risk factors, and natural history of pancreatitis; pancreatic imaging and exocrine function; management of pancreatitis; and new frontiers in pediatric pancreatitis research. The course fostered a unique ecosystem for interdisciplinary collaboration, in addition to promoting discussion and stimulating new research hypotheses regarding pediatric pancreatic disorders. Oral presentations by experts in various fields of pancreatology led to thought-provoking discussion; in addition, a meet-the-professor luncheon stimulated critical evaluation of current research in pediatric pancreatic diseases, highlighting knowledge gaps and future research endeavors. The current report summarizes the major learning points from this novel symposium focusing on the growing demographic of pediatric pancreatic diseases.
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- 2019
17. Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis
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Mark E. Lowe, Marc T. Goodman, Gregory A. Coté, Marshall J. Glesby, Mark Haupt, Nicholas J. Schork, Vikesh K. Singh, Dana K. Andersen, Stephen J. Pandol, Aliye Uc, and David C. Whitcomb
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Biomedical Research ,Endocrinology, Diabetes and Metabolism ,Clinical Sciences ,pancreatitis ,Article ,Oral and gastrointestinal ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Endocrinology ,Drug Development ,Recurrence ,Clinical Research ,Internal Medicine ,Humans ,Chronic ,Cancer ,Clinical Trials as Topic ,Gastroenterology & Hepatology ,Hepatology ,drug trials ,Diabetes ,United States ,Good Health and Well Being ,Pharmaceutical Preparations ,National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) ,patient-reported outcomes ,030220 oncology & carcinogenesis ,Acute Disease ,030211 gastroenterology & hepatology ,Digestive Diseases - Abstract
Recurrent acute pancreatitis (RAP) is a complex clinical syndrome with significant morbidity, unpredictable outcomes, and limited treatment options. The National Institute of Diabetes and Digestive and Kidney Disease sponsored a workshop on July 25, 2018, in Pittsburgh, Pennsylvania, to address research gaps impeding development of effective therapies for pancreatitis. The RAP working group identified challenges to clinical progress using existing definitions, risk assessment, diagnostic and severity criteria, disease trajectories, outcomes, and research methods. Recurrent acute pancreatitis includes all the risk of acute pancreatitis and often progresses to chronic pancreatitis with variable complications of chronic pain, exocrine insufficiency, diabetes, and pancreatic cancer. However, the great variability among individuals with RAP requires better precision in defining the risks, individual episodes, as well as their frequency, pathogenic pathways, and specific outcome measures for each of the systems affected by pancreatic inflammation. Because of disease complexity, few patients are similar enough for traditional studies and methods to conduct clinical trials with small sample sizes are required. The need for genetic testing, biomarker development, and better imaging methods was highlighted. Adaptive and N-of-one study designs, better endpoints, and outcome measures including patient-reported outcomes should considered early in developing future therapeutic trial design and include all stakeholders.
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- 2018
18. INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study
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Kate Ellery, Sarah Jane Schwarzenberg, Douglas S. Fishman, Ying Yuan, David M. Troendle, Matthew J. Giefer, Bradley A. Barth, Quin Y. Liu, Jose Serrano, Melena D. Bellin, John F. Pohl, Asim Maqbool, Emily R. Perito, Mark E. Lowe, Brian A. McFerron, Maria R. Mascarenhas, Sohail Z. Husain, Ryan Himes, Maisam Abu-El-Haija, Steven L. Werlin, Aliye Uc, Melvin B. Heyman, Veronique D. Morinville, Jaimie D. Nathan, Cheryl E. Gariepy, Tom K. Lin, Uzma Shah, Sue Rhee, Michael Wilschanski, Chee Y. Ooi, Tanja Gonska, Yuhua Zheng, and Zachary M. Sellers
- Subjects
Research design ,medicine.medical_specialty ,Biomedical Research ,Endocrinology, Diabetes and Metabolism ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Quality of life ,Pancreatitis, Chronic ,Surveys and Questionnaires ,030225 pediatrics ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Child ,Depression (differential diagnoses) ,Hepatology ,business.industry ,International Agencies ,medicine.disease ,Pancreatic Neoplasms ,Observational Studies as Topic ,Pancreatitis ,Research Design ,Social history (medicine) ,Child, Preschool ,Acute Disease ,Cohort ,030211 gastroenterology & hepatology ,business ,Psychosocial ,Cohort study - Abstract
We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.
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- 2018
19. Adipose saturation reduces lipotoxic systemic inflammation and explains the obesity paradox
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Bara El-Kurdi, Pawan Noel, Andre Guerra, Douglas O. Faigel, Sergiy Kostenko, Mark E. Lowe, Krutika Patel, Vijay P. Singh, Michael D. Crowell, Christopher Rood, Biswajit Khatua, and Jordan R. Yaron
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medicine.medical_specialty ,Immunology ,Adipose tissue ,Context (language use) ,macromolecular substances ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Animals ,Medicine ,Lipolysis ,Obesity ,Triglycerides ,Research Articles ,Inflammation ,Triglyceride lipase ,Multidisciplinary ,Triglyceride ,business.industry ,Unsaturated fat ,SciAdv r-articles ,Endocrinology ,Adipose Tissue ,Pancreatitis ,chemistry ,Lipotoxicity ,030220 oncology & carcinogenesis ,Acute Disease ,030211 gastroenterology & hepatology ,business ,Obesity paradox ,Research Article - Abstract
Saturated fat breaks down less during sudden illnesses, resulting in lower monomer concentrations, and reducing disease severity., Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context of dietary patterns of the countries from which the studies originated. Increased severity was noted in leaner populations with a higher proportion of unsaturated fat intake. In mice, greater hydrolysis of unsaturated visceral triglyceride caused worse organ failure during pancreatitis, even when the mice were leaner than those having saturated triglyceride. Saturation interfered with triglyceride’s interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox.
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- 2021
20. The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines pathogenicity
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Xunjun Xiao, Bente B. Johansson, Miriam Cnop, Anders Molven, Mark E. Lowe, Karianne Fjeld, K. El Jellas, Anny Gravdal, and Pål R. Njølstad
- Subjects
Exon ,Variable number tandem repeat ,Proteotoxicity ,Tandem repeat ,Endoplasmic reticulum ,Unfolded protein response ,Secretion ,Biology ,Molecular biology ,Gene - Abstract
Variable number of tandem repeat (VNTR) sequences present in the genome can have functional consequences that contribute to human disease. This is the case for theCELgene, which encodes the digestive enzyme carboxyl ester lipase.CELhas a VNTR located in exon 11, and rare single-base deletions (DELs) within this region cause MODY8, an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Here, we have studied how the position of single-base deletions within theCELVNTR affects the protein’s pathogenic properties. We investigated four naturally occurringCELvariants with single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, DEL13), of which only DEL1 and DEL4 have been observed in MODY8 patients. When expressed in a cellular model system, only DEL1 and DEL4 exhibited significantly reduced secretion and increased intracellular aggregation compared to normal CEL. We found that all DEL variants had slightly decreased enzymatic activity and that their level of O-glycosylation was affected. Moreover, only DEL1 and DEL4 significantly increased endoplasmic reticulum (ER) stress. In conclusion,CELsingle-base deletion variants have the highest pathogenic potential when the mutational event has taken place in the proximal VNTR part, resulting in the longest aberrant protein tails. Thus, DEL1 and DEL4 are pathogenicCELvariants, whereas we consider DEL13 as benign and DEL9 as likely benign. These findings have implications for our understanding of howCELmutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to ER stress and activation of the unfolded protein response.
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- 2020
21. Clinical and Practice Variations in Pediatric Acute Recurrent or Chronic Pancreatitis: Report From the INSPPIRE Study
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Brian A. McFerron, Steven L. Werlin, Maria R. Mascarenhas, Matthew J. Giefer, Asim Maqbool, Uzma Shah, Sarah Jane Schwarzenberg, A. Uc, David M. Troendle, Quin Liu, Michael Wilschanski, Tanja Gonska, Jaimie D. Nathan, Chee Y. Ooi, Sohail Z. Husain, Emily R. Perito, Mark E. Lowe, Yuhua Zheng, John F. Pohl, Douglas S. Fishman, Chinenye R. Dike, Cheryl E. Gariepy, Melena D. Bellin, Maisam Abu-El-Haija, Melvin B. Heyman, Bridget Zimmerman, Veronique D. Morinville, Bradley A. Barth, and Tom K. Lin
- Subjects
medicine.medical_specialty ,Referral ,medicine.medical_treatment ,acute recurrent pancreatitis ,Medical and Health Sciences ,Oral and gastrointestinal ,chronic pancreatitis ,03 medical and health sciences ,0302 clinical medicine ,Endoscopic Retrograde ,Recurrence ,Clinical Research ,030225 pediatrics ,Internal medicine ,Pancreatitis, Chronic ,pediatric pancreatitis ,Medicine ,Humans ,pancreas ,Chronic ,Child ,Disease burden ,Cholangiopancreatography, Endoscopic Retrograde ,Pediatric ,Endoscopic retrograde cholangiopancreatography ,medicine.diagnostic_test ,Gastroenterology & Hepatology ,business.industry ,Gastroenterology ,Gallstones ,medicine.disease ,Autotransplantation ,Cholangiopancreatography ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,Cohort ,Acute Disease ,Acute pancreatitis ,Biomedical Imaging ,030211 gastroenterology & hepatology ,business ,Digestive Diseases ,pancreatic disease - Abstract
ObjectiveThe aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites.Study designData were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test.ResultsOut of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P
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- 2020
22. Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding
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Mark E. Lowe, Karianne Fjeld, Sammy Zino, Brett M. Cassidy, Xunjun Xiao, and Anders Molven
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Protein Folding ,Mutation, Missense ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Article ,law.invention ,03 medical and health sciences ,law ,Pancreatitis, Chronic ,Genetics ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Lipase ,Allele ,Genetics (clinical) ,Alleles ,030304 developmental biology ,0303 health sciences ,biology ,Endoplasmic reticulum ,030305 genetics & heredity ,Haplotype ,Molecular biology ,HEK293 Cells ,Proteotoxicity ,Gain of Function Mutation ,biology.protein ,Recombinant DNA ,Pseudogenes - Abstract
Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p ≤ .001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation.
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- 2020
23. Pediatric chronic pancreatitis without prior acute or acute recurrent pancreatitis: A report from the INSPPIRE consortium
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Brian A. McFerron, Ryan Himes, Tanja Gonska, Bridget Zimmerman, Maria R. Mascarenhas, Cheryl E. Gariepy, Melena D. Bellin, Asim Maqbool, Jaimie D. Nathan, Tom K. Lin, Quin Liu, Maisam Abu-El-Haija, John F. Pohl, Douglas S. Fishman, Emily R. Perito, Steven L. Werlin, Mark E. Lowe, Matthew J. Giefer, Sohail Z. Husain, David M. Troendle, Uzma Shah, Veronique D. Morinville, Chee Y. Ooi, Bradley A. Barth, Michael Wilschanski, Steve Freedman, Melvin B. Heyman, Aliye Uc, and Sarah Jane Schwarzenberg
- Subjects
Male ,medicine.medical_specialty ,Hepatology ,Adolescent ,business.industry ,Endocrinology, Diabetes and Metabolism ,Gastroenterology ,MEDLINE ,Infant ,medicine.disease ,Article ,Pancreatitis ,Risk Factors ,Internal medicine ,Child, Preschool ,Pancreatitis, Chronic ,Acute recurrent pancreatitis ,Acute Disease ,medicine ,Humans ,Female ,business ,Child - Published
- 2020
24. IP3 receptor type 2 deficiency is associated with a secretory defect in the pancreatic acinar cell and an accumulation of zymogen granules.
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Abrahim I Orabi, Yuhuan Luo, Mahwish U Ahmad, Ahsan U Shah, Zahir Mannan, Dong Wang, Sheharyar Sarwar, Kamaldeen A Muili, Christine Shugrue, Thomas R Kolodecik, Vijay P Singh, Mark E Lowe, Edwin Thrower, Ju Chen, and Sohail Z Husain
- Subjects
Medicine ,Science - Abstract
Acute pancreatitis is a painful, life-threatening disorder of the pancreas whose etiology is often multi-factorial. It is of great importance to understand the interplay between factors that predispose patients to develop the disease. One such factor is an excessive elevation in pancreatic acinar cell Ca(2+). These aberrant Ca(2+) elevations are triggered by release of Ca(2+) from apical Ca(2+) pools that are gated by the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3. In this study, we examined the role of IP3R type 2 (IP3R2) using mice deficient in this Ca(2+) release channel (IP3R2(-/-)). Using live acinar cell Ca(2+) imaging we found that loss of IP3R2 reduced the amplitude of the apical Ca(2+) signal and caused a delay in its initiation. This was associated with a reduction in carbachol-stimulated amylase release and an accumulation of zymogen granules (ZGs). Specifically, there was a 2-fold increase in the number of ZGs (P
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- 2012
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25. Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE
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Maria R. Mascarenhas, Bridget Zimmerman, Steven D. Freedman, Douglas S. Fishman, David A. Piccoli, Isabelle Scheers, Chee Y. Ooi, Mark E. Lowe, Steven L. Werlin, Tanja Gonska, Uzma Shah, Sarah Jane Schwarzenberg, John F. Pohl, Emily R. Perito, Ryan Himes, Matthew J. Giefer, David M. Troendle, Quin Liu, Maisam Abu-El-Haija, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Cheryl E. Gariepy, Veronique D. Morinville, Tom K. Lin, Bradley A. Barth, Michael Wilschanski, and Joseph J. Palermo
- Subjects
medicine.medical_specialty ,education ,pancreatitis ,MEDLINE ,lymphoplasmacytic sclerosing pancreatitis ,Medical and Health Sciences ,Article ,Autoimmune Diseases ,idiopathic duct-centric pancreatitis ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,children ,medicine ,Humans ,Child ,Intensive care medicine ,Autoimmune pancreatitis ,Pediatric ,Pancreas disorder ,Gastroenterology & Hepatology ,Extramural ,business.industry ,Gastroenterology ,medicine.disease ,autoimmune pancreatitis ,Pancreatitis ,030220 oncology & carcinogenesis ,recommendations ,Pediatrics, Perinatology and Child Health ,030211 gastroenterology & hepatology ,Digestive Diseases ,business - Abstract
OBJECTIVES:Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field. METHODS:A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements. RESULTS:We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP. CONCLUSIONS:The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.
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- 2018
26. Factors Associated With Frequent Opioid Use in Children With Acute Recurrent and Chronic Pancreatitis
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Steven L. Werlin, Tonya M. Palermo, Matthew J. Giefer, Sarah Jane Schwarzenberg, Sohail Z. Husain, Tom K. Lin, Uzma Shah, David M. Troendle, Michael Wilschanski, Asim Maqbool, Emily R. Perito, Tanja Gonska, Cheryl E. Gariepy, Sue Rhee, Brian A. McFerron, Chee Y. Ooi, Maria R. Mascarenhas, Ryan Himes, Miriam B. Zimmerman, Veronique D. Morinville, Bradley A. Barth, Steven D. Freedman, Jaime D. Nathan, Quin Liu, Mark E. Lowe, Douglas S. Fishman, John F. Pohl, Melvin B. Heyman, Aliye Uc, Melena D. Bellin, Yuhua Zheng, and Maisam Abu-El-Haija
- Subjects
Male ,Multivariate analysis ,pancreatitis ,Psychological intervention ,Medical and Health Sciences ,0302 clinical medicine ,Recurrence ,Odds Ratio ,Child ,Pediatric ,Analgesics ,Emergency Service ,Pain Research ,Gastroenterology ,Chronic pain ,Analgesics, Opioid ,Hospitalization ,Phenotype ,Cohort ,Acute Disease ,030211 gastroenterology & hepatology ,Female ,Chronic Pain ,Emergency Service, Hospital ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Opioid ,Article ,Hospital ,03 medical and health sciences ,Clinical Research ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Pain Management ,Gastroenterology & Hepatology ,business.industry ,Prevention ,opioids ,Odds ratio ,Patient Acceptance of Health Care ,medicine.disease ,Confidence interval ,Abdominal Pain ,Good Health and Well Being ,Cross-Sectional Studies ,Pancreatitis ,pain medication ,Pediatrics, Perinatology and Child Health ,Chronic Disease ,business - Abstract
ObjectivesThe aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP).MethodsCross-sectional study of children
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- 2019
27. 576 PREDICTORS OF HIGH DISEASE BURDEN IN CHILDREN WITH ACUTE RECURRENT OR CHRONIC PANCREATITIS*
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Aliye Uc, Laura Rubin, Ying Yuan, Gretchen A. Cress, and Mark E. Lowe
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medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,Medicine ,Pancreatitis ,business ,medicine.disease ,Disease burden - Published
- 2021
28. Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group
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Tanja Gonska, Michael Wilschanski, Bradley A. Barth, Ryan Himes, Mark E. Lowe, Steven D. Freedman, Melvin B. Heyman, John F. Pohl, Aliye Uc, Sarah Jane Schwarzenberg, Veronique D. Morinville, Steven L. Werlin, Douglas S. Fishman, Elizabeth H. Yen, Sohail Z. Husain, Chee Y. Ooi, David M. Troendle, Cheryl E. Gariepy, and Matthew J. Giefer
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Pediatrics ,medicine.medical_specialty ,Consensus ,Delphi Technique ,Medical and Health Sciences ,Article ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Clinical Research ,Pancreatitis, Chronic ,medicine ,Humans ,PRSS1 ,Chronic ,CFTR ,Child ,Autoimmune pancreatitis ,Pediatric ,Hereditary pancreatitis ,hereditary pancreatitis ,Gastroenterology & Hepatology ,business.industry ,Gastroenterology ,pancreatic insufficiency ,medicine.disease ,autoimmune pancreatitis ,Pancreatitis ,030220 oncology & carcinogenesis ,Acute Disease ,Pediatrics, Perinatology and Child Health ,Acute recurrent pancreatitis ,030211 gastroenterology & hepatology ,Digestive Diseases ,business - Abstract
ObjectivesAcute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have been diagnosed in children at increasing rates during the past decade. As pediatric ARP and CP are still relatively rare conditions, little quality evidence is available on which to base the diagnosis and determination of etiology. The aim of the study was to review the current state of the literature regarding the etiology of these disorders and to developed a consensus among a panel of clinically active specialists caring for children with these disorders to help guide the diagnostic evaluation and identify areas most in need of future research.MethodsA systematic review of the literature was performed and scored for quality, followed by consensus statements developed and scored by each individual in the group for level of agreement and strength of the supporting data using a modified Delphi method. Scores were analyzed for the level of consensus achieved by the group.ResultsThe panel reached consensus on 27 statements covering the definitions of pediatric ARP and CP, evaluation for potential etiologies of these disorders, and long-term monitoring. Statements for which the group reached consensus to make no recommendation or could not reach consensus are discussed.ConclusionsThis consensus helps define the minimal diagnostic evaluation and monitoring of children with ARP and CP. Even in areas in which we reached consensus, the quality of the evidence is weak, highlighting the need for further research. Improved understanding of the underlying cause will facilitate treatment development and targeting.
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- 2017
29. Predicting Severity in Acute Pancreatitis in Children: What Can a Quantitative Score Add to Clinical Judgement?
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Mark E. Lowe, Emily R. Perito, and Sarah Jane Schwarzenberg
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medicine.medical_specialty ,Text mining ,business.industry ,Clinical judgement ,Pediatrics, Perinatology and Child Health ,Gastroenterology ,MEDLINE ,Medicine ,Acute pancreatitis ,business ,Intensive care medicine ,medicine.disease - Published
- 2020
30. Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation
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Biswajit Khatua, Dora Lam-Himlin, Douglas O. Faigel, Norio Fukami, Andre Guerra, Georgios I. Papachristou, Shubham Trivedi, Krutika Patel, Arup Bag, Melissa N. Martinez, Sarah Navina, Pawan Noel, Vijay P. Singh, Cristiane de Oliveira, Ann E. McCullough, Mark E. Lowe, Erin E. Kershaw, Sergiy Kostenko, Anna E. Phillips, Rahul Pannala, and Bijinu Balakrishnan
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Adipose tissue ,Fatty Acids, Nonesterified ,Intra-Abdominal Fat ,Systemic inflammation ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,Adipocyte ,medicine ,Adipocytes ,Lipolysis ,Animals ,Humans ,Inflammation ,Mice, Knockout ,Triglyceride lipase ,Triglyceride ,business.industry ,General Medicine ,Lipase ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,Pancreatitis ,030220 oncology & carcinogenesis ,Acute Disease ,Acute pancreatitis ,Female ,medicine.symptom ,business ,Signal Transduction ,Research Article - Abstract
Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.
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- 2019
31. Risk Factors for Rapid Progression From Acute Recurrent to Chronic Pancreatitis in Children: Report From INSPPIRE
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Brian A. McFerron, Veronique D. Morinville, Michael Wilschanski, Chee Y. Ooi, Ryan Himes, John F. Pohl, Steven L. Werlin, Tom K. Lin, M. Bridget Zimmerman, David M. Troendle, Mark E. Lowe, Bradley A. Barth, Maisam Abu-El-Haija, Matthew J. Giefer, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Emily R. Perito, Jaimie D. Nathan, Asim Maqbool, Maria R. Mascarenhas, Douglas S. Fishman, Cheryl E. Gariepy, Sarah Jane Schwarzenberg, Uzma Shah, Sue Rhee, Quin Y. Liu, Steven D. Freedman, Tanja Gonska, and Melena D. Bellin
- Subjects
Male ,Medical and Health Sciences ,Cohort Studies ,0302 clinical medicine ,Recurrence ,Risk Factors ,PRSS1 ,Chronic ,Israel ,Child ,Pediatric ,screening and diagnosis ,Diabetes ,Gastroenterology ,Age Factors ,Natural history ,Detection ,natural history ,Child, Preschool ,diabetes mellitus ,Disease Progression ,Regression Analysis ,030211 gastroenterology & hepatology ,Female ,Cohort study ,medicine.medical_specialty ,Canada ,Article ,03 medical and health sciences ,Clinical Research ,030225 pediatrics ,Diabetes mellitus ,Internal medicine ,Pancreatitis, Chronic ,pediatric pancreatitis ,medicine ,Humans ,Preschool ,Survival analysis ,Proportional Hazards Models ,Gastroenterology & Hepatology ,business.industry ,Proportional hazards model ,Prevention ,Australia ,pancreatic insufficiency ,medicine.disease ,Survival Analysis ,United States ,4.1 Discovery and preclinical testing of markers and technologies ,Multicenter study ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,Acute recurrent pancreatitis ,business ,Digestive Diseases - Abstract
ObjectiveThe aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.Study designData were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan-Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log-rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable.ResultsOf 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%).ConclusionsChildren with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.
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- 2019
32. Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors
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Mark E. Lowe, David C Whitcomb, Matthew J. Giefer, Chris E. Forsmark, Judah Abberbock, Michelle A. Anderson, Bimaljit S. Sandhu, Maria R. Mascarenhas, Stuart Sherman, Brian A. McFerron, Melena D. Bellin, Jaimie D. Nathan, Tom K. Lin, Uzma Shah, Thiruvengadam Muniraj, Maisam Abu-El-Haija, Gregory A. Cote, Douglas S. Fishman, Melvin B. Heyman, Aliye Uc, Sue Rhee, Adam Slivka, Asim Maqbool, C. Mel Wilcox, Sarah Jane Schwarzenberg, Gong Tang, Vikesh K. Singh, Bradley A. Barth, Emily R. Perito, Veronique D. Morinville, Bridget Zimmerman, Andres Gelrud, John F. Pohl, Sohail Z. Husain, Steven D. Freedman, Ryan Himes, Stephen T. Amann, Tanja Gonska, Michael Wilschanski, Timothy B. Gardner, Randall E. Brand, Cheryl E. Gariepy, Samer Alkaade, Darwin L. Conwell, Steven L. Werlin, Peter A. Banks, Joseph Romagnuolo, Michele D. Lewis, Chee Y. Ooi, Dhiraj Yadav, David M. Troendle, Nalini M. Guda, and Quin Liu
- Subjects
Male ,Pediatrics ,Cross-sectional study ,Disease ,Medical and Health Sciences ,Oral and gastrointestinal ,environmental ,Cohort Studies ,0302 clinical medicine ,Risk Factors ,Surveys and Questionnaires ,Medicine ,2.1 Biological and endogenous factors ,pain ,Chronic ,Aetiology ,Child ,Pediatric ,diabetes ,Gastroenterology ,Middle Aged ,Natural history ,6.1 Pharmaceuticals ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Cohort study ,Adult ,medicine.medical_specialty ,Alcohol Drinking ,Adolescent ,MEDLINE ,Article ,03 medical and health sciences ,children ,Clinical Research ,Pancreatitis, Chronic ,030225 pediatrics ,Tobacco Smoking ,Humans ,Genetic Predisposition to Disease ,endoscopy ,Demography ,Gastroenterology & Hepatology ,business.industry ,Prevention ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Cross-Sectional Studies ,Good Health and Well Being ,Socioeconomic Factors ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,North America ,Age of onset ,Disease progress ,genetic ,business ,Digestive Diseases - Abstract
ObjectivesThe aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.MethodsDemographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables.ResultsAlcohol was a risk in 53% of adults and 1% of children (P
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- 2019
33. Precision Medicine in Pancreatic Disease—Knowledge Gaps and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop
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Sylvia K. Plevritis, Richard M. Caprioli, Chris E. Forsmark, Zobeida Cruz-Monserrate, Fred S. Gorelick, Mark E. Lowe, Noa Rappaport, Hanno Steen, Dana K. Andersen, Temel Tirkes, David C. Whitcomb, Joe W. Gray, Mark Haupt, Jyoti S. Choudhary, Kimberly A. Kelly, Aliye Uc, Kirill Veselkov, Aida Habtezion, Holger R. Roth, Kenneth P. Olive, S. Joshua Swamidass, Anil K. Dasyam, and The Vodafone Foundation
- Subjects
medicine.medical_specialty ,Biomedical Research ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,Datasets as Topic ,Context (language use) ,Article ,03 medical and health sciences ,Deep Learning ,0302 clinical medicine ,Endocrinology ,Pancreatic cancer ,Health care ,Internal Medicine ,medicine ,Information system ,Metabolomics ,Humans ,Medical physics ,Precision Medicine ,Gastroenterology & Hepatology ,Hepatology ,business.industry ,Research ,Computational Biology ,Pancreatic Diseases ,1103 Clinical Sciences ,medicine.disease ,Precision medicine ,Prognosis ,Clinical trial ,Pancreatitis ,030220 oncology & carcinogenesis ,Acute Disease ,030211 gastroenterology & hepatology ,Personalized medicine ,Neural Networks, Computer ,business ,Biomarkers - Abstract
A workshop on research gaps and opportunities for Precision Medicine in Pancreatic Disease was sponsored by the National Institute of Diabetes and Digestive Kidney Diseases on July 24, 2019, in Pittsburgh. The workshop included an overview lecture on precision medicine in cancer and 4 sessions: (1) general considerations for the application of bioinformatics and artificial intelligence; (2) omics, the combination of risk factors and biomarkers; (3) precision imaging; and (4) gaps, barriers, and needs to move from precision to personalized medicine for pancreatic disease. Current precision medicine approaches and tools were reviewed, and participants identified knowledge gaps and research needs that hinder bringing precision medicine to pancreatic diseases. Most critical were (a) multicenter efforts to collect large-scale patient data sets from multiple data streams in the context of environmental and social factors; (b) new information systems that can collect, annotate, and quantify data to inform disease mechanisms; (c) novel prospective clinical trial designs to test and improve therapies; and (d) a framework for measuring and assessing the value of proposed approaches to the health care system. With these advances, precision medicine can identify patients early in the course of their pancreatic disease and prevent progression to chronic or fatal illness.
- Published
- 2019
34. The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis
- Author
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Andrea Szentesi, Balázs Németh, Zsofia Gabriella Pesei, Miklós Sahin-Tóth, Péter Hegyi, Ákos Szücs, Eszter Hegyi, and Mark E. Lowe
- Subjects
0301 basic medicine ,Male ,Heredity ,Hydrolases ,lcsh:Medicine ,Social Sciences ,Artificial Gene Amplification and Extension ,Acinar Cells ,Biochemistry ,Polymerase Chain Reaction ,Exon ,Gene Frequency ,Risk Factors ,Medicine and Health Sciences ,Psychology ,Lipases ,lcsh:Science ,Regulation of gene expression ,Multidisciplinary ,Genomics ,Middle Aged ,Endoplasmic Reticulum Stress ,Enzymes ,Addicts ,Genetic Mapping ,Female ,Research Article ,Adult ,medicine.medical_specialty ,Addiction ,Gastroenterology and Hepatology ,Biology ,Genome Complexity ,Research and Analysis Methods ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Internal medicine ,Complementary DNA ,Pancreatitis, Chronic ,Acinar cell ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Allele ,Alcoholics ,Molecular Biology Techniques ,Allele frequency ,Molecular Biology ,Pancreas ,Alleles ,Aged ,Endoplasmic reticulum ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Proteins ,Human Genetics ,Lipase ,medicine.disease ,Introns ,030104 developmental biology ,Endocrinology ,Pancreatitis ,Haplotypes ,Genetic Loci ,Mutation ,Enzymology ,lcsh:Q ,Mutant Proteins - Abstract
A nonsense variant (p.W358X) of human pancreatic lipase related protein 2 (PNLIPRP2) is present in different ethnic populations with a high allele frequency. In cell culture experiments, the truncated protein mainly accumulates inside the cells and causes endoplasmic reticulum stress. Here, we tested the hypothesis that variant p.W358X might increase risk for chronic pancreatitis through acinar cell stress. We sequenced exon 11 of PNLIPRP2 in a cohort of 256 subjects with chronic pancreatitis (152 alcoholic and 104 non-alcoholic) and 200 controls of Hungarian origin. We observed no significant difference in the distribution of the truncation variant between patients and controls. We analyzed mRNA expression in human pancreatic cDNA samples and found the variant allele markedly reduced. We conclude that the p.W358X truncation variant of PNLIPRP2 is expressed poorly and has no significant effect on the risk of chronic pancreatitis.
- Published
- 2018
35. Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer
- Author
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Stephen J. Pandol, Jo Ann Rinaudo, Darwin L. Conwell, Steven J. Hughes, Douglas S. Fishman, Mark E. Lowe, Hanno Steen, Robert Y. Liu, William E. Fisher, Amer Abouhamze, Amy L. McElhany, Ziding Feng, Zobeida Cruz-Monserrate, Gregory B. Lesinski, Sudhir Srivastava, Mark Topazian, David M. Troendle, Thomas A. Mace, Zachary M. Sellers, Ria Ghosh, Robert Orr, Dhiraj Yadav, Phil A. Hart, David C. Whitcomb, Jose Serrano, Aliye Uc, Emily Y. Lu, and George Van Buren
- Subjects
medicine.medical_specialty ,Biomedical Research ,Endocrinology, Diabetes and Metabolism ,Preservation, Biological ,MEDLINE ,Guidelines as Topic ,Article ,Specimen Handling ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pancreatic cancer ,Pancreatitis, Chronic ,Internal Medicine ,Diabetes Mellitus ,Medicine ,Humans ,Intensive care medicine ,Child ,Biological Specimen Banks ,Hepatology ,business.industry ,Cancer ,medicine.disease ,Biobank ,Pancreatic Neoplasms ,Biorepository ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Pancreatitis ,030211 gastroenterology & hepatology ,business ,Pancreas ,Standard operating procedure - Abstract
High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.
- Published
- 2018
36. The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity
- Author
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Karianne Fjeld, Xunjun Xiao, Stefan Johansson, Bente B. Johansson, Miriam Cnop, Anny Gravdal, Pål R. Njølstad, Anders Molven, Khadija El Jellas, and Mark E. Lowe
- Subjects
0301 basic medicine ,Glycosylation ,single-base deletions ,Biochimie ,HEK293, human embryonic kidney 293 ,Minisatellite Repeats ,Biology ,Biochemistry ,ER, endoplasmic reticulum ,03 medical and health sciences ,FBS, fetal bovine serum ,Tandem repeat ,Humans ,DEL, deletion ,Secretion ,protein misfolding ,Molecular Biology ,Gene ,MODY8, maturity-onset diabetes of the young, type 8 ,O-glycosylation ,030102 biochemistry & molecular biology ,CEL ,Endoplasmic reticulum ,HEK 293 cells ,Biologie moléculaire ,MODY8 ,VNTR, variable number of tandem repeat ,Lipase ,unfolded protein response ,Cell Biology ,Endoplasmic Reticulum Stress ,LDS, lithium dodecyl sulphate ,Molecular biology ,Variable number tandem repeat ,HEK293 Cells ,030104 developmental biology ,Proteotoxicity ,Mutation ,Proteostasis ,Unfolded protein response ,Biologie cellulaire ,Research Article - Abstract
Variable number of tandem repeat (VNTR) sequences in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which is specifically expressed in pancreatic acinar cells and encodes the digestive enzyme carboxyl ester lipase. Rare single-base deletions (DELs) within the first (DEL1) or fourth (DEL4) VNTR segment of CEL cause maturity-onset diabetes of the young, type 8 (MODY8), an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Studies on the DEL1 variant have suggested that MODY8 is initiated by CEL protein misfolding and aggregation. However, it is unclear how the position of single-base deletions within the CEL VNTR affects pathogenic properties of the protein. Here, we investigated four naturally occurring CEL variants, arising from single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, and DEL13). When the four variants were expressed in human embryonic kidney 293 cells, only DEL1 and DEL4 led to significantly reduced secretion, increased intracellular aggregation, and increased endoplasmic reticulum stress compared with normal CEL protein. The level of O-glycosylation was affected in all DEL variants. Moreover, all variants had enzymatic activity comparable with that of normal CEL. We conclude that the longest aberrant protein tails, resulting from single-base deletions in the proximal VNTR segments, have highest pathogenic potential, explaining why DEL1 and DEL4 but not DEL9 and DEL13 have been observed in patients with MODY8. These findings further support the view that CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to endoplasmic reticulum stress and activation of the unfolded protein response., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2021
37. Lipase Genetic Variants in Chronic Pancreatitis: When the End Is Wrong, All’s Not Well
- Author
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Mark E. Lowe, Anders Molven, and Karianne Fjeld
- Subjects
0301 basic medicine ,Hepatology ,biology ,business.industry ,Gastroenterology ,MEDLINE ,Genetic variants ,Bioinformatics ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,Text mining ,Genetic variation ,biology.protein ,medicine ,Pancreatitis ,Lipase ,business - Published
- 2016
38. Next Generation of Pancreatic Enzyme Replacement Therapy: Recombinant Microbial Enzymes and Finding the Perfect Lipase
- Author
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David C. Whitcomb and Mark E. Lowe
- Subjects
Lipolysis ,Yarrowia ,Intestinal absorption ,law.invention ,Fungal Proteins ,law ,medicine ,Animals ,Humans ,Enzyme Replacement Therapy ,Lipase ,Exocrine pancreatic insufficiency ,Triglycerides ,Fungal protein ,Lipoprotein lipase ,Hepatology ,biology ,Gastroenterology ,Enzyme replacement therapy ,medicine.disease ,biology.organism_classification ,Intestinal Absorption ,Biochemistry ,biology.protein ,Recombinant DNA ,Exocrine Pancreatic Insufficiency ,Carboxylic Ester Hydrolases - Published
- 2015
39. The β5-Loop and Lid Domain Contribute to the Substrate Specificity of Pancreatic Lipase-related Protein 2 (PNLIPRP2)
- Author
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Xunjun Xiao and Mark E. Lowe
- Subjects
Triglyceride lipase ,Galactolipid ,biology ,Triglyceride ,Recombinant Fusion Proteins ,Active site ,Lipase ,Cell Biology ,Lipids ,Biochemistry ,Protein Structure, Secondary ,Protein Structure, Tertiary ,Substrate Specificity ,chemistry.chemical_compound ,Protein structure ,chemistry ,biology.protein ,Humans ,Site-directed mutagenesis ,Molecular Biology ,Galactolipase activity - Abstract
Pancreatic triglyceride lipase (PNLIP) is essential for dietary fat digestion in children and adults, whereas a homolog, pancreatic lipase-related protein 2 (PNLIPRP2), is critical in newborns. The two lipases are structurally similar, yet they have different substrate specificities. PNLIP only cleaves neutral fats. PNLIPRP2 cleaves neutral and polar fats. To test the hypothesis that the differences in activity between PNLIP and PNLIPRP2 are governed by surface loops around the active site, we created multiple chimeras of both lipases by exchanging the surface loops singly or in combination. The chimeras were expressed, purified, and tested for activity against various substrates. The structural determinants of PNLIPRP2 galactolipase activity were contained in the N-terminal domain. Of the surface loops tested, the lid domain and the β5-loop influenced activity against triglycerides and galactolipids. Any chimera on PNLIP with the PNLIPRP2 lid domain or β5-loop had decreased triglyceride lipase activity similar to that of PNLIPRP2. The corresponding chimeras of PNLIPRP2 did not increase activity against neutral lipids. Galactolipase activity was abolished by the PNLIP β5-loop and decreased by the PNLIP lid domain. The source of the β9-loop had minimal effect on activity. We conclude that the lid domain and β5-loop contribute to substrate specificity but do not completely account for the differing activities of PNLIP and PNLIPRP2. Other regions in the N-terminal domain must contribute to the galactolipase activity of PNLIPRP2 through direct interactions with the substrate or by altering the conformation of the residues surrounding the hydrophilic cavity in PNLIPRP2.
- Published
- 2015
40. 1081 SEX DIFFERENCES IN PEDIATRIC ACUTE RECURRENT AND CHRONIC PANCREATITIS
- Author
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Mark E. Lowe, Aliye Uc, Ying Yuan, Savitri Appana, and Gretchen A. Cress
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,medicine ,Pancreatitis ,medicine.disease ,business - Published
- 2020
41. Su1505 HEALTH-RELATED QUALITY OF LIFE, EMOTIONAL, AND BEHAVIORAL FUNCTIONING IN CHILDREN WITH ACUTE RECURRENT OR CHRONIC PANCREATITIS
- Author
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Cheryl E. Gariepy, Aliye Uc, Mark E. Lowe, Tonya M. Palermo, Savitri Appana, Ying Yuan, Gretchen A. Cress, and See Wan Tham
- Subjects
Health related quality of life ,medicine.medical_specialty ,Hepatology ,business.industry ,Gastroenterology ,medicine ,Pancreatitis ,Intensive care medicine ,business ,medicine.disease - Published
- 2020
42. Web-based cognitive-behavioral intervention for pain in pediatric acute recurrent and chronic pancreatitis: Protocol of a multicenter randomized controlled trial from the study of chronic pancreatitis, diabetes and pancreatic cancer (CPDPC)
- Author
-
Brian A. McFerron, Sarah Jane Schwarzenberg, Matthew J. Giefer, Douglas S. Fishman, Zachary M. Sellers, Sohail Z. Husain, Cheryl E. Gariepy, Emily R. Perito, Tanja Gonska, Maria R. Mascarenhas, Tom K. Lin, Veronique D. Morinville, David Troendle, Asim Maqbool, Bradley A. Barth, Ying Yuan, Uzma Shah, Jaimie D. Nathan, Mark E. Lowe, Quin Y. Liu, Kate M Ellery, Homer Aalfs, Chee Y. Ooi, Caitlin B. Murray, Melena D. Bellin, Yuhua Zheng, Maisam Abu-El-Haija, Melvin B. Heyman, Aliye Uc, Jose Serrano, John F. Pohl, Tonya M. Palermo, and Praveen S. Goday
- Subjects
Abdominal pain ,Medical and Health Sciences ,Oral and gastrointestinal ,law.invention ,Randomized controlled trial ,Recurrence ,law ,Multicenter Studies as Topic ,Pharmacology (medical) ,Chronic ,Child ,Consortium for the Study of Chronic Pancreatitis ,Children ,General Clinical Medicine ,Pain Measurement ,Randomized Controlled Trials as Topic ,Cancer ,Pediatric ,Analgesics ,Diabetes and Pancreatic Cancer ,Pain Research ,Chronic pain ,General Medicine ,Health Services ,Analgesics, Opioid ,Public Health ,Chronic Pain ,medicine.symptom ,Chronic pancreatitis ,Psychosocial ,Internet-Based Intervention ,medicine.medical_specialty ,Cognitive-behavioral therapy ,Adolescent ,Acute recurrent pancreatitis ,Clinical Trials and Supportive Activities ,Pain ,Opioid ,Article ,Clinical Research ,Pancreatitis, Chronic ,Multicenter trial ,Behavioral and Social Science ,medicine ,Humans ,Pain Management ,Cognitive Behavioral Therapy ,business.industry ,Prevention ,Neurosciences ,medicine.disease ,Abdominal Pain ,Clinical trial ,Internet intervention ,Good Health and Well Being ,Pancreatitis ,Psychological pain ,Quality of Life ,Physical therapy ,Digestive Diseases ,business ,Mind and Body - Abstract
Introduction Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response. Methods This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10–18) with ARP/CP and their parents from twenty-one INSPPIRE ( IN ternational S tudy Group of P ediatric P ancreatitis: I n search for a cu RE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization. Conclusions This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.
- Published
- 2020
43. Impact of Obesity on Pediatric Acute Recurrent and Chronic Pancreatitis
- Author
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Melvin B. Heyman, Bradley A. Barth, M. Bridget Zimmerman, Joseph J. Palermo, Melena D. Bellin, Tanja Gonska, Uzma Shah, Michael Wilschanski, Matthew J. Giefer, Steven D. Freedman, Cheryl E. Gariepy, Veronique D. Morinville, Maisam Abu-El-Haija, Sue Rhee, Sohail Z. Husain, Ryan Himes, Aliye Uc, Emily R. Perito, Chee Y. Ooi, Mark E. Lowe, Tom K. Lin, Quin Liu, John F. Pohl, Douglas S. Fishman, Steven L. Werlin, Brian A. McFerron, Sarah Jane Schwarzenberg, and David M. Troendle
- Subjects
Male ,Pediatrics ,Endocrinology, Diabetes and Metabolism ,pancreatitis ,Cardiovascular ,Severity of Illness Index ,Oral and gastrointestinal ,Body Mass Index ,Cohort Studies ,0302 clinical medicine ,Endocrinology ,Recurrence ,Chronic ,Child ,Cancer ,Pediatric ,Diabetes ,Stroke ,Cohort ,Acute Disease ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Cohort study ,medicine.medical_specialty ,Clinical Sciences ,body mass index ,Article ,03 medical and health sciences ,children ,Clinical Research ,030225 pediatrics ,Pancreatitis, Chronic ,Severity of illness ,Internal Medicine ,medicine ,Humans ,Obesity ,Metabolic and endocrine ,Nutrition ,Hepatology ,Gastroenterology & Hepatology ,business.industry ,Prevention ,Disease progression ,nutritional and metabolic diseases ,Overweight ,medicine.disease ,Pancreatitis ,Acute recurrent pancreatitis ,business ,Digestive Diseases ,Body mass index - Abstract
ObjectiveThe aim of this study was to assess the impact of obesity on pediatric acute recurrent pancreatitis or chronic pancreatitis (CP).MethodsWe determined body mass index (BMI) status at enrollment in INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort using CDC criteria for pediatric-specific BMI percentiles. We used the Cochran-Armitage test to assess trends and the Jonckheere-Terpstra test to determine associations.ResultsOf 446 subjects (acute recurrent pancreatitis, n = 241; CP, n = 205), 22 were underweight, 258 normal weight, 75 overweight, and 91 were obese. The BMI groups were similar in sex, race, and age at presentation. Hypertriglyceridemia was more common in overweight or obese. Obese children were less likely to have CP and more likely to have acute inflammation on imaging. Compared with children with normal weight, obese or overweight children were older at first acute pancreatitis episode and diagnosed with CP at an older age. Obese or overweight children were less likely to undergo medical or endoscopic treatment, develop exocrine pancreatic insufficiency, and require total pancreatectomy with islet autotransplantation. Diabetes was similar among all groups.ConclusionsObesity or overweight seems to delay the initial acute pancreatitis episode and diagnosis of CP compared with normal weight or underweight. The impact of obesity on pediatric CP progression and severity deserves further study.
- Published
- 2018
44. Pancreas Divisum in Pediatric Acute Recurrent and Chronic Pancreatitis: Report From INSPPIRE
- Author
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Veronique D. Morinville, Aliye Uc, Tom K. Lin, Sarah Jane Schwarzenberg, Tanja Gonska, M. Bridget Zimmerman, Matthew J. Giefer, Chee Y. Ooi, Brian A. McFerron, Melena D. Bellin, Mark E. Lowe, Joseph P. Palermo, Steven L. Werlin, Michael Wilschanski, Bradley A. Barth, Maisam Abu-El-Haija, Uzma Shah, Douglas S. Fishman, Quin Liu, Cheryl E. Gariepy, Sue Rhee, Melvin B. Heyman, Steven D. Freedman, David M. Troendle, Ryan Himes, Maria R. Mascarenhas, Sohail Z. Husain, John F. Pohl, Asim Maqbool, Emily R. Perito, and Jaimie D. Nathan
- Subjects
Male ,pancreatitis ,Gastroenterology ,Oral and gastrointestinal ,Cohort Studies ,Endoscopic Retrograde ,Sex factors ,Recurrence ,Risk Factors ,Prevalence ,2.1 Biological and endogenous factors ,Chronic ,Aetiology ,Child ,Cancer ,Pediatric ,Cholangiopancreatography, Endoscopic Retrograde ,medicine.diagnostic_test ,MRCP ,Cholangiopancreatography ,Child, Preschool ,Female ,Cohort study ,medicine.medical_specialty ,Adolescent ,Clinical Sciences ,MEDLINE ,Article ,Pancreatic Cancer ,ERCP ,Rare Diseases ,Sex Factors ,children ,Clinical Research ,Internal medicine ,Pancreatitis, Chronic ,medicine ,Humans ,endoscopy ,Risk factor ,Preschool ,Pancreas ,Pancreas divisum ,Gastroenterology & Hepatology ,business.industry ,Pancreatic Ducts ,Infant ,medicine.disease ,Endoscopy ,Pancreatitis ,Mutation ,Digestive Diseases ,business - Abstract
IntroductionThe significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact.Patients and methodsWe compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables.ResultsPD was found in 52 of 359 (14.5%) subjects, a higher prevalence than the general population (∼7%). Females more commonly had PD (71% vs. 55%; P=0.02). Children with PD did not have a higher incidence of mutations in SPINK1, CFTR, CTRC compared with children with no PD. Children with PD were less likely to have PRSS1 mutations (10% vs. 34%; P
- Published
- 2018
45. The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2
- Author
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Khadija, El Jellas, Bente B, Johansson, Karianne, Fjeld, Aristotelis, Antonopoulos, Heike, Immervoll, Man H, Choi, Dag, Hoem, Mark E, Lowe, Dominique, Lombardo, Pål R, Njølstad, Anne, Dell, Eric, Mas, Stuart M, Haslam, and Anders, Molven
- Subjects
Protein Domains ,Polysaccharides ,Cell Line, Tumor ,Humans ,Molecular Bases of Disease ,Pancreas ,Gene Expression Regulation, Enzymologic ,ABO Blood-Group System ,Carboxylesterase - Abstract
Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-α1,3(Fuc-α1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject's FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.
- Published
- 2018
46. EPC/HPSG evidence-based guidelines for the management of pediatric pancreatitis
- Author
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Ib Rasmussen, László Czakó, Péter Hegyi, Andrea Párniczky, Flora Szabo, Tassos Grammatikopoulos, Mark E. Lowe, Sohail Z. Husain, Miklós Sahin-Tóth, Heiko Witt, Robert Sutton, Grzegorz Oracz, Maisam Abu-El-Haija, Aliye Uc, and Michael Wilschanski
- Subjects
medicine.medical_specialty ,Evidence-based practice ,Endocrinology, Diabetes and Metabolism ,Disease ,Recurrent acute pancreatitis ,Pediatric pancreatitis ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,03.02. Klinikai orvostan ,Child ,Intensive care medicine ,Societies, Medical ,Hepatology ,business.industry ,Incidence (epidemiology) ,Gastroenterology ,Evidence-based management ,01.06. Biológiai tudományok ,Guideline ,medicine.disease ,Evidence-based management guidelines ,Acute pancreatitis ,Europe ,Pancreatitis ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Etiology ,030211 gastroenterology & hepatology ,business ,Chronic pancreatitis - Abstract
Background Pediatric pancreatitis is an underdiagnosed disease with variable etiology. In the past 10–15 years the incidence of pediatric pancreatitis has increased, it is now 3.6–13.3 cases per 100,000 children. Up-to-date evidence based management guidelines are lacking for the pediatric pancreatitis. The European Pancreatic Club, in collaboration with the Hungarian Pancreatic Study Group organized a consensus guideline meeting on the diagnosis and management of pancreatitis in the pediatric population. Methods Pediatric Pancreatitis was divided into three main clinical categories: acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis. Fifteen relevant topics (acute pancreatitis: diagnosis; etiology; prognosis; imaging; complications; therapy; biliary tract management; acute recurrent pancreatitis: diagnosis; chronic pancreatitis: diagnosis, etiology, treatment, imaging, intervention, pain, complications; enzyme replacement) were defined. Ten experts from the USA and Europe reviewed and summarized the available literature. Evidence was classified according to the GRADE classification system. Results Within fifteen topics, forty-seven relevant clinical questions were defined. The draft of the updated guideline was presented and discussed at the consensus meeting held during the 49th Meeting of European Pancreatic Club, in Budapest, on July 1, 2017. Conclusions These evidence-based guidelines provides the current state of the art of the diagnosis and management of pediatric pancreatitis.
- Published
- 2018
47. The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants
- Author
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Eric Mas, Anders Molven, Khadija El Jellas, Bente B. Johansson, Mark E. Lowe, Pål R. Njølstad, Dominique Lombardo, Man Hung Choi, Aristotelis Antonopoulos, Heike Immervoll, Karianne Fjeld, Stuart M. Haslam, Anne Dell, and Dag Hoem
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Glycan ,biology ,Chemistry ,Tn antigen ,Cell Biology ,medicine.disease ,Biochemistry ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Pancreatic cancer ,ABO blood group system ,Pancreatic juice ,medicine ,biology.protein ,Antibody ,Pancreas ,Glycoprotein ,Molecular Biology - Abstract
Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc- 1,3(Fuc- 1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool ofCELimmunoprecipitatedfromhumanpancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject’s FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas,CELis a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum. publishedVersion
- Published
- 2018
48. Autoimmune Pancreatitis in Children: Characteristic Features, Diagnosis, and Management
- Author
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Maria R. Mascarenhas, Bridget Zimmerman, Steven D. Freedman, Veronique D. Morinville, Uzma Shah, David A. Piccoli, Tom K. Lin, Bradley A. Barth, Quin Liu, Emily R. Perito, Michael Wilschanski, Matthew J. Giefer, Isabelle Scheers, Cheryl E. Gariepy, Douglas S. Fishman, David M. Troendle, Sohail Z. Husain, Chee Y. Ooi, Ryan Himes, Joseph J. Palermo, Sarah Jane Schwarzenberg, Tanja Gonska, Maisam Abu-El-Haija, Melvin B. Heyman, Aliye Uc, Steven L. Werlin, John F. Pohl, and Mark E. Lowe
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,International Cooperation ,Clinical Sciences ,Jaundice ,Article ,Autoimmune Diseases ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Clinical Research ,Pancreatitis, Chronic ,Diagnosis ,medicine ,Humans ,Registries ,Chronic ,Child ,Preschool ,Pancreas ,Glucocorticoids ,Autoimmune pancreatitis ,Pediatric ,Disease entity ,Hepatology ,Gastroenterology & Hepatology ,business.industry ,Obstructive ,Gastroenterology ,Disease Management ,medicine.disease ,Abdominal Pain ,Jaundice, Obstructive ,Pancreatic Function Tests ,Multicenter study ,Pancreatitis ,030220 oncology & carcinogenesis ,Child, Preschool ,Immunoglobulin G ,Differential ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Digestive Diseases - Abstract
ObjectivesAutoimmune pancreatitis (AIP) is an increasingly recognized disease entity, but data in children are limited. AIP presentation and outcome in children might differ from the adult experience. We aim to determine the characteristic features of AIP in children.MethodsData about clinical symptoms, imaging, histology, and treatment were collected using two sources: (i) a systematic literature search and (ii) the INSPPIRE database, the largest international multicenter study of pancreatitis in children and the Cliniques Universitaires St-Luc (CUSL) registry.ResultsWe identified 48 AIP cases: 30 from literature review, 14 from INSPPIRE, and 4 from CUSL. The median age at diagnosis was 13 years (range 2-17 years). Abdominal pain (43/47, 91%) and/or obstructive jaundice (20/47, 42%) were the most common symptoms at diagnosis. Elevated serum IgG4 levels were only observed in 9/40 (22%) children. Cross-sectional imaging studies were abnormal in all children including hypointense global or focal gland enlargement (39/47, 83%), main pancreatic duct irregularity (30/47, 64%), and common bile duct stricture (26/47, 55%). A combination of lymphoplasmacytic inflammation, pancreatic fibrosis, and ductal granulocyte infiltration were the main histological findings (18/25, 72%). Children with AIP had a prompt clinical response to steroids. Complications of AIP included failure of exocrine (4/25, 16%) and endocrine (3/27, 11%) pancreas function.ConclusionsPediatric AIP has a distinct presentation with features similar to type 2 AIP in adults. This comprehensive report on the largest group of children with AIP to date is expected to help with the diagnosis and management of this disease and pave the way for future research studies.
- Published
- 2017
49. A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding
- Author
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Mark E. Lowe, Xunjun Xiao, András Szabó, Margaret Haughney, Alyssa Spector, and Miklós Sahin-Tóth
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X-Box Binding Protein 1 ,Protein Folding ,XBP1 ,Chaperonins ,Mutant ,Mutation, Missense ,Regulatory Factor X Transcription Factors ,Biology ,medicine.disease_cause ,Lipid Metabolism, Inborn Errors ,Article ,Acinar cell ,medicine ,Animals ,Humans ,Elméleti orvostudományok ,Molecular Biology ,Mutation ,Triglyceride lipase ,Endoplasmic reticulum ,HEK 293 cells ,Lipase ,Orvostudományok ,Endoplasmic Reticulum Stress ,Molecular biology ,Rats ,DNA-Binding Proteins ,Endoplasmic reticulum stress response ,HEK293 Cells ,Unfolded protein response ,Molecular Medicine ,Fat digestion ,Transcription Factors ,Protein misfolding - Abstract
Congenital pancreatic triglyceride lipase (PNLIP) deficiency is a rare disorder with uncertain genetic background as most cases were described before gene sequencing was readily available. Recently, two brothers with PNLIP deficiency were found to carry a homozygous missense mutation, c.662C>T (p.T221M) in the PNLIP gene (J. Lipid Res. 2014. 55:307–312). Molecular modeling suggested the substitution would change the orientation of residues in the catalytic site and disrupt the function of p.T221M PNLIP. To test the effect of the p.T221M mutation on PNLIP function, we expressed wild-type and p.T221M PNLIP in human embryonic kidney (HEK) 293A cells and dexamethasone-differentiated AR42J rat acinar cells. In both cellular models, wild-type PNLIP was secreted into the conditioned medium where it was readily detectable by protein staining, immunoblot or lipase activity assays. In contrast, mutant p.T221M was not secreted into the medium, but it was present in cell lysates where it accumulated in the insoluble fraction. Intracellular retention of mutant p.T221M resulted in endoplasmic reticulum (ER) stress as measured by elevated XBP1 splicing and increased levels of ER chaperones. Our results demonstrate that the presence of methionine at position 221 in the PNLIP protein sequence causes misfolding and aggregation of the p.T221M mutant inside the cell. The consequent loss of enzyme secretion adequately explains the clinical phenotype of PNLIP deficiency reported for homozygous carriers of p.T221M. Furthermore, the ability of mutant p.T221M to induce ER stress suggests that this form of PNLIP deficiency might cause acinar cell damage as well.
- Published
- 2015
50. A case of pancreatitis, panniculitis and polyarthritis syndrome: Elucidating the pathophysiologic mechanisms of a rare condition
- Author
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Rayfel Schneider, Shant Shekherdimian, Joel S. Fish, Jacob C. Langer, Ines Loverdos, Bo Yee Ngan, Marc C. Swan, Mark E. Lowe, Tanja Gonska, Wednesday Marie A. Sevilla, Khosrow Adeli, Vijay P. Singh, and Abdulrahman Al-Rasheed
- Subjects
Pathology ,medicine.medical_specialty ,lcsh:Surgery ,panniculitis and polyarthritis syndrome ,Pediatric pancreatitis ,Article ,Pancreatitis, panniculitis and polyarthritis syndrome ,medicine ,Pancreatic lipase ,Lipolysis ,chemistry.chemical_classification ,Complicated pancreatitis ,biology ,business.industry ,lcsh:RJ1-570 ,Fatty acid ,lcsh:Pediatrics ,lcsh:RD1-811 ,medicine.disease ,Pathophysiology ,Pancreatitis ,chemistry ,Pediatrics, Perinatology and Child Health ,biology.protein ,Surgery ,Polyarthritis ,Panniculitis ,business ,Tissue inflammation - Abstract
Pancreatitis-Panniculitis-Polyarthritis (PPP) syndrome is rare and its physiopathology unclear. A 6-year old boy suffered of traumatic pancreatitis complicated by PPP syndrome. Extensive investigations demonstrated high levels of pancreatic lipase and fatty acids in the affected peripheral tissues. These findings support the sequence of peripheral lipolysis and fatty acid accumulation inducing tissue inflammation.
- Published
- 2015
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