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Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue.
Xu H, Fu JL, Miao YF, Wang CJ, Han QF, Li S, Huang SZ, Du SN, Qiu YX, Yang JC, Gustafsson JÅ, Breyer RM, Zheng F, Wang NP, Zhang XY, Guan YF
(2016) J Mol Cell Biol 8: 518-529
MeSH Terms: Adipocytes, Adipogenesis, Adipose Tissue, White, Animals, Cell Differentiation, Gene Deletion, Inflammation, Insulin Resistance, Lipolysis, Lipoproteins, VLDL, Mice, Mice, Obese, Obesity, Phenotype, Protein Isoforms, Rats, Sprague-Dawley, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Triglycerides
Show Abstract · Added February 7, 2019
Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3 mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3 and EP3β mice. Moreover, both EP3 and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.
© The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
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MeSH Terms
S-Adenosylmethionine increases circulating very-low density lipoprotein clearance in non-alcoholic fatty liver disease.
Martínez-Uña M, Varela-Rey M, Mestre D, Fernández-Ares L, Fresnedo O, Fernandez-Ramos D, Gutiérrez-de Juan V, Martin-Guerrero I, García-Orad A, Luka Z, Wagner C, Lu SC, García-Monzón C, Finnell RH, Aurrekoetxea I, Buqué X, Martínez-Chantar ML, Mato JM, Aspichueta P
(2015) J Hepatol 62: 673-81
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Diet, High-Fat, Disease Models, Animal, Female, Glycine N-Methyltransferase, Humans, Lipoproteins, VLDL, Liver, Male, Membrane Proteins, Mice, Mice, Knockout, Middle Aged, Models, Biological, Non-alcoholic Fatty Liver Disease, Perilipin-2, S-Adenosylmethionine, Triglycerides, Young Adult
Show Abstract · Added January 20, 2015
BACKGROUND & AIMS - Very-low-density lipoproteins (VLDLs) export lipids from the liver to peripheral tissues and are the precursors of low-density-lipoproteins. Low levels of hepatic S-adenosylmethionine (SAMe) decrease triglyceride (TG) secretion in VLDLs, contributing to hepatosteatosis in methionine adenosyltransferase 1A knockout mice but nothing is known about the effect of SAMe on the circulating VLDL metabolism. We wanted to investigate whether excess SAMe could disrupt VLDL plasma metabolism and unravel the mechanisms involved.
METHODS - Glycine N-methyltransferase (GNMT) knockout (KO) mice, GNMT and perilipin-2 (PLIN2) double KO (GNMT-PLIN2-KO) and their respective wild type (WT) controls were used. A high fat diet (HFD) or a methionine deficient diet (MDD) was administrated to exacerbate or recover VLDL metabolism, respectively. Finally, 33 patients with non-alcoholic fatty-liver disease (NAFLD); 11 with hypertriglyceridemia and 22 with normal lipidemia were used in this study.
RESULTS - We found that excess SAMe increases the turnover of hepatic TG stores for secretion in VLDL in GNMT-KO mice, a model of NAFLD with high SAMe levels. The disrupted VLDL assembly resulted in the secretion of enlarged, phosphatidylethanolamine-poor, TG- and apoE-enriched VLDL-particles; special features that lead to increased VLDL clearance and decreased serum TG levels. Re-establishing normal SAMe levels restored VLDL secretion, features and metabolism. In NAFLD patients, serum TG levels were lower when hepatic GNMT-protein expression was decreased.
CONCLUSIONS - Excess hepatic SAMe levels disrupt VLDL assembly and features and increase circulating VLDL clearance, which will cause increased VLDL-lipid supply to tissues and might contribute to the extrahepatic complications of NAFLD.
Copyright © 2014 European Association for the Study of the Liver. All rights reserved.
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22 MeSH Terms
Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33.
Allen RM, Marquart TJ, Jesse JJ, Baldán A
(2014) Circ Res 115: 10-22
MeSH Terms: Animals, Apolipoproteins B, Carrier Proteins, Hepatocytes, Lipoproteins, VLDL, Male, Mice, Mice, Inbred C57BL, MicroRNAs, N-Ethylmaleimide-Sensitive Proteins, Receptors, LDL, Sterol Regulatory Element Binding Protein 2, Triglycerides
Show Abstract · Added February 12, 2016
RATIONALE - Several reports suggest that antisense oligonucleotides against miR-33 might reduce cardiovascular risk in patients by accelerating the reverse cholesterol transport pathway. However, conflicting reports exist about the impact of anti-miR-33 therapy on the levels of very low-density lipoprotein-triglycerides (VLDL-TAG).
OBJECTIVE - We test the hypothesis that miR-33 controls hepatic VLDL-TAG secretion.
METHODS AND RESULTS - Using therapeutic silencing of miR-33 and adenoviral overexpression of miR-33, we show that miR-33 limits hepatic secretion of VLDL-TAG by targeting N-ethylmaleimide-sensitive factor (NSF), both in vivo and in primary hepatocytes. We identify conserved sequences in the 3'UTR of NSF as miR-33 responsive elements and show that Nsf is specifically recruited to the RNA-induced silencing complex following induction of miR-33. In pulse-chase experiments, either miR-33 overexpression or knock-down of Nsf lead to decreased secretion of apolipoproteins and TAG in primary hepatocytes, compared with control cells. Importantly, Nsf rescues miR-33-dependent reduced secretion. Finally, we show that overexpression of Nsf in vivo increases global hepatic secretion and raises plasma VLDL-TAG.
CONCLUSIONS - Together, our data reveal key roles for the miR-33-NSF axis during hepatic secretion and suggest that caution should be taken with anti-miR-33-based therapies because they might raise proatherogenic VLDL-TAG levels.
© 2014 American Heart Association, Inc.
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13 MeSH Terms
Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats.
Rojas JM, Stafford JM, Saadat S, Printz RL, Beck-Sickinger AG, Niswender KD
(2012) Am J Physiol Endocrinol Metab 303: E1479-88
MeSH Terms: Animals, Appetite Regulation, Behavior, Animal, Central Nervous System, Humans, Hyperphagia, Infusions, Intraventricular, Lipoproteins, VLDL, Liver, Male, Nerve Tissue Proteins, Neurons, Neuropeptide Y, Obesity, Protein Isoforms, Rats, Rats, Long-Evans, Receptors, Neuropeptide Y, Recombinant Proteins, Signal Transduction, Triglycerides
Show Abstract · Added December 10, 2013
Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed Long-Evans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed Long-Evans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.
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21 MeSH Terms
Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones.
Martinez MN, Emfinger CH, Overton M, Hill S, Ramaswamy TS, Cappel DA, Wu K, Fazio S, McDonald WH, Hachey DL, Tabb DL, Stafford JM
(2012) J Lipid Res 53: 379-89
MeSH Terms: Animals, Apolipoprotein C-II, Apolipoproteins A, Blotting, Western, Cholesterol, Cholesterol Ester Transfer Proteins, Chromatography, High Pressure Liquid, Computational Biology, Diet, High-Fat, Female, Hyperinsulinism, Insulin, Lipoproteins, HDL, Lipoproteins, VLDL, Mice, Mice, Transgenic, Obesity, Ovariectomy, Triglycerides, Weight Gain
Show Abstract · Added December 10, 2013
Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function.
1 Communities
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20 MeSH Terms
High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study.
Wojczynski MK, Glasser SP, Oberman A, Kabagambe EK, Hopkins PN, Tsai MY, Straka RJ, Ordovas JM, Arnett DK
(2011) Lipids Health Dis 10: 181
MeSH Terms: Adult, Aged, Cardiovascular Diseases, Cholesterol, VLDL, Cohort Studies, Dietary Fats, Family Health, Female, Humans, Hypertriglyceridemia, Lipoproteins, HDL, Lipoproteins, IDL, Lipoproteins, LDL, Lipoproteins, VLDL, Magnetic Resonance Spectroscopy, Male, Middle Aged, Particle Size, Postprandial Period, Risk Factors, Sex Characteristics, Triglycerides, United States
Show Abstract · Added April 23, 2015
BACKGROUND - Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.
RESULTS - Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.
CONCLUSIONS - We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
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23 MeSH Terms
Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS.
Wood AC, Glasser S, Garvey WT, Kabagambe EK, Borecki IB, Tiwari HK, Tsai MY, Hopkins PN, Ordovas JM, Arnett DK
(2011) Lipids Health Dis 10: 143
MeSH Terms: Adult, Aged, Amino Acid Substitution, Cluster Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Insulin Resistance, Lipoprotein Lipase, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Male, Metabolic Syndrome, Middle Aged, Particle Size, Pedigree, Polymorphism, Genetic, Polymorphism, Single Nucleotide, United States
Show Abstract · Added April 23, 2015
BACKGROUND - Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328).
FINDINGS - Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04).
CONCLUSIONS - This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.
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22 MeSH Terms
Lipoprotein subclasses determined by nuclear magnetic resonance spectroscopy and coronary atherosclerosis in patients with rheumatoid arthritis.
Chung CP, Oeser A, Raggi P, Sokka T, Pincus T, Solus JF, Linton MF, Fazio S, Stein CM
(2010) J Rheumatol 37: 1633-8
MeSH Terms: Arthritis, Rheumatoid, Calcinosis, Coronary Angiography, Coronary Artery Disease, Female, Humans, Joints, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Magnetic Resonance Spectroscopy, Male, Middle Aged, Particle Size, Severity of Illness Index, Tomography, Spiral Computed
Show Abstract · Added December 10, 2013
OBJECTIVE - Patients with rheumatoid arthritis (RA) are at increased risk of atherosclerosis, but routine lipid measurements differ little from those of people without RA. We examined the hypothesis that lipid subclasses determined by nuclear magnetic resonance spectroscopy (NMR) differed in patients with RA compared to controls and are associated with disease activity and the presence of coronary-artery atherosclerosis.
METHODS - We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large low-density lipoprotein (LDL; diameter range 21.2-27.0 nm), small LDL (18.0-21.2 nm), large high-density lipoprotein (HDL; 8.2-13.0 nm), small HDL (7.3-8.2 nm), and total very low-density lipoprotein (VLDL; >or= 27 nm). All subjects underwent an interview and examination; disease activity was quantified by the 28-joint Disease Activity Score (DAS28) and coronary artery calcification (CAC) was measured with electron-beam computed tomography.
RESULTS - Concentrations of small HDL particles were lower in patients with RA (18.2 +/- 5.4 nmol/l) than controls (20.0 +/- 4.4 nmol/l; p = 0.003). In patients with RA, small HDL concentrations were inversely associated with DAS28 (rho = -0.18, p = 0.04) and C-reactive protein (rho = -0.25, p = 0.004). Concentrations of small HDL were lower in patients with coronary calcification (17.4 +/- 4.8 nmol/l) than in those without (19.0 +/- 5.8 nmol/l; p = 0.03). This relationship remained significant after adjustment for the Framingham risk score and DAS28 (p = 0.025). Concentrations of small LDL particles were lower in patients with RA (1390 +/- 722 nmol/l) than in controls (1518 +/- 654 nmol/l; p = 0.05), but did not correlate with DAS28 or CAC.
CONCLUSION - Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA.
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17 MeSH Terms
Impaired-inactivation of FoxO1 contributes to glucose-mediated increases in serum very low-density lipoprotein.
Wu K, Cappel D, Martinez M, Stafford JM
(2010) Endocrinology 151: 3566-76
MeSH Terms: Adenoviridae, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Nucleus, Forkhead Transcription Factors, Glucose, Glucose Clamp Technique, Hyperinsulinism, Insulin, Lipid Metabolism, Lipoproteins, VLDL, Liver, Male, Nerve Tissue Proteins, Rats, Rats, Long-Evans, Rats, Transgenic, Transduction, Genetic, Up-Regulation
Show Abstract · Added October 8, 2015
For patients with diabetes, insulin resistance and hyperglycemia both contribute to increased serum triglyceride in the form of very low-density lipoprotein (VLDL). Our objective was to define the insulin conditions in which hyperglycemia promotes increased serum VLDL in vivo. We performed hyperglycemic-hyperinsulinemic clamp studies and hyperglycemic-hypoinsulinemic clamp studies in rats, with metabolic tracers for glucose flux and de novo fatty acid synthesis. When blood glucose was clamped at hyperglycemia (17 mm) for 2 h under hyperinsulinemic conditions (4 mU/kg . min), serum VLDL levels were not increased compared with baseline. We speculated that hyperinsulinemia minimized glucose-mediated VLDL changes and performed hyperglycemic-hypoinsulinemic clamp studies in which insulin was clamped near fasting levels with somatostatin (17 mm blood glucose, 0.25 mU/kg . min insulin). Under low-insulin conditions, serum VLDL levels were increased 4.7-fold after hyperglycemia, and forkhead box O1 (FoxO1) was not excluded from the nucleus of liver cells. We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL. We found that, when the ability of insulin to inactivate FoxO1 is blocked after adenoviral delivery of constitutively active FoxO1, glucose increased serum VLDL triglyceride when given both by ip glucose tolerance testing (3.5-fold increase) and by a hyperglycemic clamp (4.6-fold). Under both experimental conditions in which insulin signaling to FoxO1 was impaired, we found increased activation of carbohydrate response element binding protein. These data suggest that glucose more potently promotes increased serum VLDL when insulin action is impaired, with either low insulin levels or disrupted downstream signaling to the transcription factor FoxO1.
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19 MeSH Terms
Diabetes and obesity: therapeutic targeting and risk reduction - a complex interplay.
Niswender K
(2010) Diabetes Obes Metab 12: 267-87
MeSH Terms: Antihypertensive Agents, Cholesterol, HDL, Coronary Artery Disease, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Humans, Hypoglycemic Agents, Lipoproteins, VLDL, Obesity, Risk Reduction Behavior, Triglycerides
Show Abstract · Added February 15, 2016
Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off-target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non-pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co-morbid hypertension and dyslipidaemia. Additional long-term studies, including CVD end-point studies, will be necessary to determine the appropriate places for incretin-based therapies in treatment algorithms.
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11 MeSH Terms