62 PubMed-indexed references supporting the mechanistic map (zes_qsp_model.dot), the mrgsolve model (zes_mrgsolve_model.R) and the Shiny dashboard (zes_shiny_app.R).

Every PMID below was resolved against the NCBI E-utilities esummary endpoint while this model was being built, so first author, journal and year are as PubMed records them. Where a reference supplies a number the model actually uses, that number is stated next to it, together with the parameter or anchor it feeds.

The quantitative backbone of this model is the National Institutes of Health prospective ZES cohort, which is the only series large enough to give distributions rather than case reports for fasting gastrin and basal acid output.

1. Berna MJ et al. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore) 2006. PMID 17108778 → anchor A4 (untreated fasting serum gastrin ≈ 900 pg/mL; the model's KSECT0 is fitted to this). Also the source of the observation that fasting gastrin is not > 1000 pg/mL in most patients, which is why the model treats the acid brake and not the gastrin level as diagnostic.

2. Berna MJ et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. Medicine (Baltimore) 2006. PMID 17108779 → the secretin-test Δ > 120 pg/mL criterion used in secretin_test() and validation item A7.

3. Gibril F et al. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore) 2004. PMID 14747767 → MEN1 accounts for 20–25% of ZES; multiplicity and duodenal predominance of MEN1 gastrinomas (ZES_MEN1 phenotype: smaller TUM0, lower GRADEF).

4. Gibril F et al. Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. J Clin Endocrinol Metab 2001. PMID 11701693 → the bimodal growth behaviour that motivates GRADEF as a phenotype input rather than a fixed constant.

5. Gibril F, Jensen RT. Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Curr Gastroenterol Rep 2004. PMID 15527675

6. Chatzipanagiotou O et al. Gastrinoma and Zollinger-Ellison syndrome: A thorough update. J Neuroendocrinol 2023. PMID 37042078 → contemporary diagnostic algorithm; the requirement for gastric pH < 2 alongside hypergastrinaemia, which the model reproduces as an emergent discriminator (see A7).

7. Qiu C et al. Clinicopathological characteristics and prognosis analysis of gastrinoma based on the SEER database. PLoS One 2025. PMID 41406116 → survival stratification by grade and metastatic status; supports treating tumour burden, not acid, as the survival driver once acid is controlled.

8. Pellicano R et al. Zollinger-Ellison syndrome in 2006: concepts from a clinical point of view. Panminerva Med 2006. PMID 16633330

9. Wilcox CM, Seay T, Arcury JT, et al. Treatment strategies for Zollinger-Ellison syndrome. Expert Opin Pharmacother 2009. PMID 19351273 → the "titrate until basal acid output is below 10 mEq/h (below 5 after previous gastric surgery)" algorithm implemented in titrate_ppi().

10. Tomassetti P et al. Optimal treatment of Zollinger-Ellison syndrome and related conditions in elderly patients. Drugs Aging 2003. PMID 14651442

11. Riff BP et al. Weight Gain in Zollinger-Ellison Syndrome After Acid Suppression. Pancreas 2016. PMID 26164604 → weight loss in untreated ZES is acid-driven (lipase inactivation and secretory diarrhoea), which is how DIARR and the steatorrhoea path are wired: to acid output, not to tumour burden.

12. Adam MP et al. (GeneReviews). Multiple Endocrine Neoplasia Type 1. PMID 20301710 → > 90% penetrance of primary hyperparathyroidism in MEN1, usually the first manifestation (GLANDM as the MEN1 driver).

13. Huang J et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 2012. PMID 22327296

14. Dreijerink KMA et al. Multi-omics analyses of MEN1 missense mutations identify disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity. Epigenetics Chromatin 2022. PMID 35941657

15. Agarwal SK. Multiple endocrine neoplasia type 1. Front Horm Res 2013. PMID 23652667

16. Hackeng WM et al. A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in Multiple Endocrine Neoplasia 1. Mol Cancer Res 2021. PMID 33771883 → the reference behind cluster 19 and validation item A8. This is the evidence that the calcium–gastrin coupling is causal rather than coincidental, and therefore that ECA (CaSR secretagogue gain) and ACAW (the calcium arm of DRIVE) belong in the model as edges.

17. Sundaresan S et al. Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids. Gut 2017. PMID 26860771 → genetic demonstration that losing the somatostatin brake is what produces unrestrained gastrin; the model's "missing edge" formulation.

18. van Beek DJ et al. Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG). J Surg Oncol 2019. PMID 31401809

19. Hoffmann KM et al. Patients with multiple endocrine neoplasia type 1 with gastrinomas have an increased risk of severe esophageal disease including stricture and the premalignant condition of Barrett's esophagus. J Clin Endocrinol Metab 2006. PMID 16249283 → the ESOPH → stricture / Barrett path, and the reason MEN1-ZES is run as its own long-horizon scenario (24).

20. Dimaline R, Varro A. Novel roles of gastrin. J Physiol 2014. PMID 24665102

21. Blair AJ 3rd et al. Comparison of acid secretory responsiveness to gastrin heptadecapeptide and of gastrin heptadecapeptide pharmacokinetics in duodenal ulcer patients and normal subjects. J Clin Invest 1986. PMID 3745438 → G17 disappearance kinetics; KEL17 = 6.93 /h (t½ ≈ 6 min). The much slower G34 clearance (KEL34 = 0.99 /h, t½ ≈ 42 min) is why G34 dominates fasting immunoreactivity while G17 dominates bioactivity — the reason the model carries two species and a potency weight (GBIO = G17 + G34/6) rather than one "gastrin" compartment.

22. Bramante G et al. Ferric ions inhibit proteolytic processing of progastrin. Biochem Biophys Res Commun 2011. PMID 21195058

23. Marshall KM et al. The C-terminal flanking peptide of progastrin induces gastric cell apoptosis and stimulates colonic cell division in vivo. Peptides 2013. PMID 23742999

24. Zavros Y et al. Hypergastrinemia in response to gastric inflammation suppresses somatostatin. Am J Physiol Gastrointest Liver Physiol 2002. PMID 11751171 → the D-cell somatostatin brake and its acid dependence; HBRK50, HBRKN.

25. Schmidt PT et al. Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig. Scand J Gastroenterol 2004. PMID 15074389

26. Bevilacqua M et al. Dissimilar PTH, gastrin, and calcitonin responses to oral calcium and peptones in hypocalciuric hypercalcemia, primary hyperparathyroidism, and normal subjects. J Bone Miner Res 2006. PMID 16491288 → quantitative basis for ECA, the calcium sensitivity of gastrin release.

27. Tzaneva M. Effects of duodenogastric reflux on gastrin cells, somatostatin cells and serotonin cells in human antral gastric mucosa. Pathol Res Pract 2004. PMID 15310146

The key structural claim — that gastrin's trophic action is selective — comes from reference 28, and it is why EMAXECL (3.0) exceeds EMAXPCM (2.2) in the model and why the histamine amplifier, not direct parietal CCK2R signalling, carries most of the drive (AH = 6.0 versus AG = 3.5).

28. Bakke I et al. Gastrin has a specific proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell: a study by elutriation centrifugation. Acta Physiol Scand 2000. PMID 10759608

29. Modlin IM, Kidd M, Tang LH. Pathophysiology of the fundic enterochromaffin-like (ECL) cell and gastric carcinoid tumours. Ann R Coll Surg Engl 1996. PMID 8678447

30. Freston JW et al. Effects of hypochlorhydria and hypergastrinemia on structure and function of gastrointestinal cells. A review and analysis. Dig Dis Sci 1995. PMID 7859584 → time-scales for KPCM (t½ ≈ 3 weeks) and KECL (t½ ≈ 2 weeks).

31. Chen D et al. Ultrastructure of enterochromaffin-like cells in rat stomach: effects of alpha-fluoromethylhistidine-evoked histamine depletion and hypergastrinemia. Cell Tissue Res 1996. PMID 8593676

32. Zheng B et al. Gastrin-dependent expansion of Cck2r+ corpus progenitors accelerates ulcer healing and inhibits gastric dysplasia. Gut 2026. PMID 40983503

33. Smith JP, Nadella S, Osborne N. Gastrin and Gastric Cancer. Cell Mol Gastroenterol Hepatol 2017. PMID 28560291

34. Massironi S et al. The Autoimmune Gastritis Puzzle: Emerging Cellular Crosstalk and Molecular Pathways Driving Parietal Cell Loss and ECL Cell Hyperplasia. Cells 2025. PMID 41148791 → the mirror-image disorder, and the reason ATRF exists as a parameter: the same acid-brake edge run in the opposite direction.

Cluster 8 of the map and the four-state pump pool (PUMPI/PUMPA/PUMPB/ PUMPR) rest on this block.

35. Engevik AC, Kaji I, Goldenring JR. The Physiology of the Gastric Parietal Cell. Physiol Rev 2020. PMID 31670611 → tubulovesicle-to-canalicular trafficking as the physiological switch; KACT0, KACT1, KINACT.

36. Shin JM, Munson K, Sachs G. Gastric H+,K+-ATPase. Compr Physiol 2011. PMID 23733700

37. Sachs G, Shin JM, Vagin O, et al. The gastric H,K ATPase as a drug target: past, present, and future. J Clin Gastroenterol 2007. PMID 17575528

38. Shin JM, Sachs G. Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 2002. PMID 12404233 → the single most load-bearing reference in the file. Pump protein half-life ≈ 50 h sets KDEGP = 0.01386 /h, and the de novo synthesis rate is what makes the dosing interval, rather than the daily dose, the thing that fails first in ZES.

39. Shin JM, Cho YM, Sachs G. Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors. J Am Chem Soc 2004. PMID 15212527 → acid-catalysed conversion of the prodrug to the sulfenamide, i.e. the acid-activation trap encoded as dPPICAN/dt = KACTP·C·PUMPA/(PUMPA + KMPA) − KOUTCAN·PPICAN.

40. Besancon M et al. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997. PMID 9278394 → Cys813/Cys892 adduct formation; irreversibility, hence PUMPB as a separate pool that only leaves by degradation (KDEGP) or slow glutathione reduction (KGSH).

41. Shin JM, Kim N. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep 2008. PMID 19006606

42. Niyomugabo AP et al. Gastric Proton Pumpopathy Associated with Protein Sorting Machinery: A Narrative Review. Clin Exp Gastroenterol 2026. PMID 41889561

43. Li S et al. Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling. Pharm Res 2023. PMID 37226024 → the closest published analogue of this file's PPI submodel; source of VPPI, CLPPI0 and anchor A5 (≈ 66% acid inhibition at steady state on omeprazole 20 mg once daily).

44. Na JY et al. Influence of CYP2C19 Polymorphisms on the Pharmacokinetics of Omeprazole in Elderly Subjects. Clin Pharmacol Drug Dev 2021. PMID 34337876 → the CYPF grid (UM 1.9 / NM 1.0 / IM 0.5 / PM 0.28) used in scenarios 10–11 and validation item A5.

45. Kagami T et al. Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther 2016. PMID 26991399 → the pH > 4 holding-time contrast the model must reproduce, and the evidence that a P-CAB is far less CYP2C19-sensitive (VON2C19 in the map, CLVON route in the model).

46. Zerbetto De Palma G et al. Protonation of Key Acidic Residues Reveals Binding Features of PCABs to Gastric H,K-ATPase. J Membr Biol 2026. PMID 42217047 → K+-competitive, reversible binding without acid activation, and the accessibility of resting pumps that FRESTV encodes.

47. Wehbe H, Fass R. Potassium-competitive acid blockers: Clinical pearls and practical insights. Cleve Clin J Med 2026. PMID 42225381

48. Yoon DY et al. Effect of meal timing on pharmacokinetics and pharmacodynamics of tegoprazan in healthy male volunteers. Clin Transl Sci 2021. PMID 33382926 → the meal-timing dependence a PPI has and a P-CAB largely does not; in the model this difference is not a rule but a consequence of FRESTV and of the PUMPA/(PUMPA+KMPA) activation term.

49. Galmiche JP et al. Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers. Aliment Pharmacol Ther 2004. PMID 15023167 → the cleanest demonstration that prolonging plasma exposure, not raising the dose, is what fixes the trough.

50. Weigt J et al. Nocturnal gastric acid breakthrough is not associated with night-time gastroesophageal reflux in GERD patients. Dig Dis 2009. PMID 19439964 → definition of nocturnal acid breakthrough used by nab_hours().

51. Gillen D, McColl KE. Problems related to acid rebound and tachyphylaxis. Best Pract Res Clin Gastroenterol 2001. PMID 11403541

52. Clark JH et al. Histamine 2-Receptor Antagonists Tachyphylaxis: A Scoping Review. Laryngoscope 2026. PMID 41459837 → RH2, TACHM, KTACH: H2-receptor up-regulation under blockade, and hence the escape seen in scenarios 14–15.

53. Namikawa K et al. Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment — Are PPIs Addictive? Int J Mol Sci 2024. PMID 38791497 → validation item A9. In the model rebound is not a parameter: it is the enlarged PUMPI pool discharging onto the enlarged PCM.

54. Metz DC et al. Three-year oral pantoprazole administration is effective for patients with Zollinger-Ellison syndrome and other hypersecretory conditions. Aliment Pharmacol Ther 2006. PMID 16423003 → anchor A6: the maintenance regimen that holds basal acid output below 10 mEq/h, and the observation that most patients need twice-daily dosing at a total dose well above the reflux dose.

55. Metz DC et al. Maintenance oral pantoprazole therapy is effective for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion. Am J Gastroenterol 2003. PMID 12591045

56. Hirschowitz BI, Simmons J, Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors: a prospective 10-year study. Aliment Pharmacol Ther 2001. PMID 11683694 → the ten-year stability of the required dose, which the model reproduces as a consequence of PCM and ECL reaching a plateau rather than of any explicit tolerance term.

57. Hirschowitz BI, Mohnen J, Shaw S. Long-term treatment with lansoprazole for patients with Zollinger-Ellison syndrome. Aliment Pharmacol Ther 1996. PMID 8853754

58. Corleto V et al. Efficacy of long-term therapy with low doses of omeprazole in the control of gastric acid secretion in Zollinger-Ellison syndrome patients. Aliment Pharmacol Ther 1993. PMID 8485270 → the counter-observation that a substantial minority are controlled on low doses; the model's A13 virtual population is the mechanism it proposes (variability in the two trophic gains, not in drug handling).

59. Lew EA et al. Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Gastroenterology 2000. PMID 10734021 → ev_ppi_iv().

60. Pisegna JR et al. Inhibition of pentagastrin-induced gastric acid secretion by intravenous pantoprazole: a dose-response study. Am J Gastroenterol 1999. PMID 10520836 → the pentagastrin-stimulation protocol reproduced by mao_of().

61. Saeed ZA et al. Parenteral antisecretory drug therapy in patients with Zollinger-Ellison syndrome. Gastroenterology 1989. PMID 2565842 → the historical H2-antagonist doses (famotidine up to several hundred milligrams a day) that scenario 15 tests.

62. Hirschowitz BI, Simmons J, Mohnen J. Risk factors for esophagitis in extreme acid hypersecretors with and without Zollinger-Ellison syndrome. Clin Gastroenterol Hepatol 2004. PMID 15017606

63. Strader DB et al. Esophageal function and occurrence of Barrett's esophagus in Zollinger-Ellison syndrome. Digestion 1995. PMID 8549876

64. Bhattacharya S et al. Validity of Secretin Stimulation Testing on Proton Pump Inhibitor Therapy for Diagnosis of Zollinger-Ellison Syndrome. Am J Gastroenterol 2021. PMID 34515664 → the clinical statement of the problem that validation item A7 poses mechanistically: a PPI raises gastrin by lifting the D-cell acid brake, so a healthy subject on a PPI can look like a gastrinoma.

65. Proye C et al. Intraoperative gastrin measurements during surgical management of patients with gastrinomas: experience with 20 cases. World J Surg 1998. PMID 9606276

66. Norton JA et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? Ann Surg 2004. PMID 15082965 → the cure rates behind scenario 18's TUMCUT state edit.

67. Norton JA, Jensen RT. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol 2005. PMID 16253901

68. Norton JA. Surgery and prognosis of duodenal gastrinoma as a duodenal neuroendocrine tumor. Best Pract Res Clin Gastroenterol 2005. PMID 16253894

69. Albers MB, Manoharan J, Bartsch DK. Contemporary surgical management of the Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1. Best Pract Res Clin Endocrinol Metab 2019. PMID 31521501 → the sequencing rule (parathyroids first) that scenario 17 tests without being told.

70. Gaujoux S et al. Surgical Management of Zollinger-Ellison Syndrome in Multiple Endocrine Neoplasia Type 1: an AFCE and GTE Cohort Study. World J Surg 2026. PMID 41862416

71. Kong W et al. Pancreaticoduodenectomy Is the Best Surgical Procedure for Zollinger-Ellison Syndrome Associated with Multiple Endocrine Neoplasia Type 1. Cancers (Basel) 2022. PMID 35454834

72. Krampitz GW, Norton JA. Current management of the Zollinger-Ellison syndrome. Adv Surg 2013. PMID 24298844

73. Kunz PL et al. Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211). J Clin Oncol 2023. PMID 36260828 → the CAPTEM arm (scenario 30); median progression-free survival 22.7 months for temozolomide + capecitabine.

74. Evans MG et al. Loss of O6-Methylguanine-DNA Methyltransferase Protein Expression by Immunohistochemistry Is Associated With Response to Capecitabine and Temozolomide. World J Surg 2025. PMID 39825572 → MGMTM and EMGMT: the model's alkylator kill is multiplied by MGMT status rather than assumed uniform.

75. Fazio N et al. Relationship between metabolic toxicity and efficacy of everolimus in patients with neuroendocrine tumors: A pooled analysis from the randomized, phase 3 RADIANT-3 and RADIANT-4 trials. Cancer 2021. PMID 33857327 → the everolimus arm (scenario 28) and its EVEADV toxicity node.

76. Chan DL et al. Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies. Pancreas 2021. PMID 33560090

77. Baudin E et al. [177Lu]Lu-DOTA-TATE versus sunitinib in patients with metastatic progressive neuroendocrine tumours of the pancreas (OCLURANDOM): a randomised, controlled, phase 2 trial. Lancet Oncol 2026. PMID 42225102 → the head-to-head that scenarios 29 and 31 reproduce, and the reason those two arms are run from an identical baseline state.

78. Strosberg JR et al. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results. Lancet Oncol 2021. PMID 34793718 → the 7.4 GBq × 4 every-8-weeks schedule in ev_prrt().

79. Bodei L et al. Dosimetry of [177Lu]Lu-DOTATATE in Patients with Advanced Midgut Neuroendocrine Tumors: Results from a Substudy of the Phase III NETTER-1 Trial. J Nucl Med 2025. PMID 39947918 → SDOSET, SDOSEK: absorbed dose per unit of retained activity, and the 23 Gy renal constraint that scenario 33 breaches when amino-acid protection is withheld.

80. Kobayashi N et al. Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor positive tumours. Ann Nucl Med 2021. PMID 34533700 → AALYS, FPROT.

81. Park EA et al. The Impact of Radiopharmaceutical Therapy on Renal Function. Semin Nucl Med 2022. PMID 35314056

82. Pavel M et al. Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results. Eur J Cancer 2021. PMID 34597974

83. Pusceddu S et al. Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study. Cancers (Basel) 2021. PMID 35008233

84. Mujica-Mota R et al. Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis. Health Technol Assess 2018. PMID 30209002 → the cross-trial progression-free-survival table used to sanity-check the relative ordering of scenarios 27–31.

85. Gaztambide S, Vazquez JA. Short- and long-term effect of a long-acting somatostatin analogue, lanreotide (SR-L) on metastatic gastrinoma. J Endocrinol Invest 1999. PMID 10195383 → the antisecretory arm ESSAS: a somatostatin analogue lowers tumour gastrin output, which is the only licensed way to move factors 1 and 3.

86. Plöckinger U et al. Effect of the somatostatin analog octreotide on gastric mucosal function and histology during 3 months of preoperative treatment in patients with acromegaly. Eur J Endocrinol 1998. PMID 9820614 → ESSAE, ESSAP: direct SSTR2 effects on ECL mass and on the parietal cell, separate from the antisecretory effect on the tumour.

87. Faggiano A et al. The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer. Endocrine 2018. PMID 29572709

88. Sawicka-Gutaj N et al. Pasireotide — Mechanism of Action and Clinical Applications. Curr Drug Metab 2018. PMID 29595102

89. Boyce M et al. Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis. Br J Clin Pharmacol 2017. PMID 27704617 → KINET; scenario 19. This is the only agent in the file that blocks the gastrin signal itself rather than its consequences.

90. Boyce M, Moore AR, Sagatun L, et al. Potential clinical indications for a CCK2 receptor antagonist. Curr Opin Pharmacol 2016. PMID 27710813

91. Lloyd KA et al. Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors. Cell Mol Gastroenterol Hepatol 2020. PMID 32004755

92. Lamberti G et al. Gastric neuroendocrine neoplasms. Nat Rev Dis Primers 2024. PMID 38605021 → the type-1 / type-2 / type-3 taxonomy; MENFLG gates the type-2 path in the model because a type-2 gastric NET requires hypergastrinaemia plus the MEN1 background.

93. McCarthy DM. Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids — What Is the Relationship? Int J Mol Sci 2020. PMID 31963924

94. Rais R et al. Enterochromaffin-like Cell Hyperplasia-Associated Gastric Neuroendocrine Tumors May Arise in the Setting of Proton Pump Inhibitor Use. Arch Pathol Lab Med 2022. PMID 34283890

95. Massironi S et al. Gastric carcinoids: between underestimation and overtreatment. World J Gastroenterol 2009. PMID 19437556

96. Moeinipour Y et al. The Association Between Proton Pump Inhibitor Use and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review. J Gastrointest Cancer 2025. PMID 41191220

97. Choudhury A et al. Vitamin B12 deficiency and use of proton pump inhibitors: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol 2023. PMID 37060552 → PHB12, NB12, KB12OUT.

98. Mumtaz H et al. Association of Vitamin B12 deficiency with long-term PPIs use: A cohort study. Ann Med Surg (Lond) 2022. PMID 36268318

99. Wang C et al. Safety of proton pump inhibitors: an overview of systematic reviews and meta-analyses. BMJ Evid Based Med 2026. PMID 42303374 → the umbrella review that sets the magnitude of every harm in cluster 21, and the reason FMGFL puts an acid-independent floor under magnesium absorption rather than letting it fall without limit.

100. Sundar C et al. Impact of Proton Pump Inhibitor Therapy on Bone Mineral Density: An Updated Systematic Review. Cureus 2026. PMID 42110060 → KBMD (about 3% bone loss over five years of near-complete achlorhydria).

101. Li P et al. Proton pump inhibitors use and the risk of osteoporosis and fractures: A two-sample Mendelian randomization study. Medicine (Baltimore) 2026. PMID 42499118

102. Azores-Moreno J et al. Acute Drug-Induced Tubulointerstitial Nephritis: Current Perspectives on Diagnosis and Treatment. Adv Kidney Dis Health 2025. PMID 40947149 → the AKIINT → RENALG → gastrin-clearance loop, i.e. why renal injury raises measured gastrin without any change in secretion (scenario 35).

103. Al-Fakhouri Z et al. Short-Term Daily Vonoprazan Treatment Is More Commonly Associated With Infectious Gastroenteritis Than Short-Term Daily PPI Treatment. Neurogastroenterol Motil 2026. PMID 42260324 → the ENTINF node, and a caution attached to the model's own finding that a P-CAB gives the deepest acid suppression of the three classes.

104. Uemura N et al. Vonoprazan as a Long-term Maintenance Treatment for Erosive Esophagitis: VISION, a 5-Year, Randomized, Open-label Study. Clin Gastroenterol Hepatol 2025. PMID 39209187

105. Nafea S et al. Association of Long-Term Proton Pump Inhibitor Use With Nutrient Deficiencies: A Retrospective Cross-Sectional Study. Cureus 2026. PMID 42064495

106. Elmokadem A, Riggs MM, Baron KT. mrgsolve — R package for simulation from ODE-based population PK/PD and QSP models. https://mrgsolve.org/ (model built and validated under mrgsolve 2.0.1).

107. gPKPDviz — an mrgsolve-based Shiny tool for PK/PD simulation. Paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC10941578/ · Code: https://github.com/Genentech/gPKPDviz/

Held-out (not fitted, used only to test the model): the secretin-test increment and its PPI false positive (refs 2, 64), the CYP2C19 gradient (ref 44), the vonoprazan pH-holding-time advantage (ref 45), H2-antagonist escape (refs 52, 61), withdrawal rebound (ref 53), the effect of parathyroidectomy on gastrin and acid output (refs 16, 69), and the relative ordering of the four antitumour arms (refs 73, 77, 78, 84).

Educational and research use only. Not validated for clinical or regulatory use.