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Medicine May 2023This study explored the safety and feasibility of 3D laparoscopy and intraoperative ultrasound techniques, which made minimally invasive pancreatic surgery more precise...
RATIONALE
This study explored the safety and feasibility of 3D laparoscopy and intraoperative ultrasound techniques, which made minimally invasive pancreatic surgery more precise and detailed.
PATIENT CONCERN
Case 1 was a 51-year-old man with a primary complaint of pancreatic tumor. Case 2 was a 60-year-old woman with complaints of tinnitus for 1 week. Case 3 was a 21-year-old woman with complaints of epigastric pain and abdominal distension for 1 day.
DIAGNOSIS
Case 1 and Case 2 were diagnosed with pancreatic neuroendocrine tumors, and Case 3 was diagnosed with an infected solid pseudopapillary tumor of the pancreas.
INTERVENTIONS
All 3 patients underwent laparoscopic pancreatic surgery in our hospital.
OUTCOMES
All cases received the same perioperative management and no localized stenosis or dilatation of the pancreatic duct was found during follow-up.
LESSONS
With the development of minimally invasive surgery and the application of 3D laparoscopy and intraoperative ultrasound technology, pancreatic tumors that are tightly adhered to the main pancreatic duct can successfully be removed using 3D laparoscopic operation.
Topics: Male; Female; Humans; Middle Aged; Young Adult; Adult; Pancreatectomy; Pancreas; Pancreatic Neoplasms; Laparoscopy; Pancreatic Ducts
PubMed: 37171331
DOI: 10.1097/MD.0000000000033733 -
Cell Reports Oct 2017The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both...
The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development.
Topics: Acinar Cells; Animals; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cells, Cultured; Female; Male; Mice; Mice, Inbred C57BL; Mucoproteins; Oncogene Proteins; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 29069604
DOI: 10.1016/j.celrep.2017.09.093 -
Experimental & Molecular Medicine Apr 2021The adult pancreatic ductal system was suggested to harbor facultative beta-cell progenitors similar to the embryonic pancreas, and the appearance of insulin-positive...
The adult pancreatic ductal system was suggested to harbor facultative beta-cell progenitors similar to the embryonic pancreas, and the appearance of insulin-positive duct cells has been used as evidence for natural duct-to-beta-cell reprogramming. Nevertheless, the phenotype and fate of these insulin-positive cells in ducts have not been determined. Here, we used a cell-tagging dye, CFDA-SE, to permanently label pancreatic duct cells through an intraductal infusion technique. Representing a time when significant increases in beta-cell mass occur, pregnancy was later induced in these CFDA-SE-treated mice to assess the phenotype and fate of the insulin-positive cells in ducts. We found that a small portion of CFDA-SE-labeled duct cells became insulin-positive, but they were not fully functional beta-cells based on the in vitro glucose response and the expression levels of key beta-cell genes. Moreover, these insulin-positive cells in ducts expressed significantly lower levels of genes associated with extracellular matrix degradation and cell migration, which may thus prevent their budding and migration into preexisting islets. A similar conclusion was reached through analysis of the Gene Expression Omnibus database for both mice and humans. Together, our data suggest that the contribution of duct cells to normal beta-cells in adult islets is minimal at best.
Topics: Animals; Biomarkers; Cell Differentiation; Cell Movement; Computational Biology; Extracellular Matrix; Female; Fluorescent Antibody Technique; Gene Expression Profiling; Gene Expression Regulation; Humans; Immunophenotyping; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Transgenic; Pancreatic Ducts; Pregnancy
PubMed: 33820959
DOI: 10.1038/s12276-021-00593-z -
Pancreas Oct 2019Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the United States. Improved characterized models of PDAC are needed for drug...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the United States. Improved characterized models of PDAC are needed for drug screening.
METHODS
We grew 4 established pancreatic cancer cell lines in hanging drop cultures to produce spheroids. We also grew organoids from explanted xenografted PDAC and surgically resected primary PDAC. We performed transmission and scanning electron microscopy and compared findings with those of the normal pancreatic duct. We also performed single-cell cloning to determine the potential options for differentiation.
RESULTS
Spheroids contained tight junctions and desmosomes but lacked zymogen granules, as expected. The former features were present in normal pancreatic duct but absent from PDAC cell lines grown in standard 2-dimensional culture. Spheroids functionally excluded macromolecules in whole mounts. Cells on the surface of PDAC spheroids were carpeted by microvilli except for rare cells with prominent stereocilia. Carpets of microvilli were also seen in low passage organoids produced from xenografts and surgically resected human PDAC, in addition to normal human pancreatic duct. We performed single-cell cloning and resulting spheroids produced both cell phenotypes at the same approximate ratios as those from bulk cultures.
CONCLUSIONS
Pancreatic cancer spheroids/organoids are capable of biphenotypic differentiation.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Desmosomes; Female; Heterografts; Humans; Mice, Nude; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Organoids; Pancreatic Ducts; Pancreatic Neoplasms; Spheroids, Cellular; Tight Junctions
PubMed: 31593010
DOI: 10.1097/MPA.0000000000001390 -
Shock (Augusta, Ga.) May 2020Activation of the constitutive nuclear and mitochondrial enzyme poly (ADP-ribose) polymerase (PARP) has been implicated in the pathogenesis of cell dysfunction,...
OBJECTIVE
Activation of the constitutive nuclear and mitochondrial enzyme poly (ADP-ribose) polymerase (PARP) has been implicated in the pathogenesis of cell dysfunction, inflammation, and organ failure in various forms of critical illness. The objective of our study was to evaluate the efficacy and safety of the clinically approved PARP inhibitor olaparib in an experimental model of pancreatitis in vivo and in a pancreatic cell line subjected to oxidative stress in vitro. The preclinical studies were complemented with analysis of clinical samples to detect PARP activation in pancreatitis.
METHODS
Mice were subjected to cerulein-induced pancreatitis; circulating mediators and circulating organ injury markers; pancreatic myeloperoxidase and malondialdehyde levels were measured and histology of the pancreas was assessed. In human pancreatic duct epithelial cells (HPDE) subjected to oxidative stress, PARP activation was measured by PAR Western blotting and cell viability and DNA integrity were quantified. In clinical samples, PARP activation was assessed by PAR (the enzymatic product of PARP) immunohistochemistry.
RESULTS
In male mice subjected to pancreatitis, olaparib (3 mg/kg i.p.) improved pancreatic function: it reduced pancreatic myeloperoxidase and malondialdehyde levels, attenuated the plasma amylase levels, and improved the histological picture of the pancreas. It also attenuated the plasma levels of pro-inflammatory mediators (TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-12, IP-10, KC) but not MCP-1, RANTES, or the anti-inflammatory cytokine IL-10. Finally, it prevented the slight, but significant increase in plasma blood urea nitrogen level, suggesting improved renal function. The protective effect of olaparib was also confirmed in female mice. In HPDE cells subjected to oxidative stress olaparib (1 μM) inhibited PARP activity, protected against the loss of cell viability, and prevented the loss of cellular NAD levels. Olaparib, at 1μM to 30 μM did not have any adverse effects on DNA integrity. In human pancreatic samples from patients who died of pancreatitis, increased accumulation of PAR was demonstrated.
CONCLUSION
Olaparib improves organ function and tempers the hyperinflammatory response in pancreatitis. It also protects against pancreatic cell injury in vitro without adversely affecting DNA integrity. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of pancreatitis.
Topics: Animals; Cell Culture Techniques; Cell Line; Ceruletide; Disease Models, Animal; Epithelial Cells; Female; Humans; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Pancreatic Ducts; Pancreatitis; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 31274831
DOI: 10.1097/SHK.0000000000001402 -
International Journal of Molecular... Oct 2019Adenosine regulates exocrine and endocrine secretions in the pancreas. Adenosine is considered to play a role in acini-to-duct signaling in the exocrine pancreas. To...
Adenosine regulates exocrine and endocrine secretions in the pancreas. Adenosine is considered to play a role in acini-to-duct signaling in the exocrine pancreas. To identify the molecular basis of functional adenosine receptors in the exocrine pancreas, immunohistochemical analysis was performed in the rat, mouse, and guinea pig pancreas, and the secretory rate and concentration of HCO in pancreatic juice from the rat pancreas were measured. The A adenosine receptor colocalized with ezrin, an A-kinase anchoring protein, in the luminal membrane of duct cells in the mouse and guinea pig pancreas. However, a strong signal ascribed to A adenosine receptors was detected in insulin-positive β cells in islets of Langerhans. The A adenosine receptor agonist 4-[2-[[6-Amino-9-(-ethyl-β-D-ribofuranuronamidosyl)-9-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS 21680) stimulated HCO-rich fluid secretion from the rat pancreas. These results indicate that A adenosine receptors may be, at least in part, involved in the exocrine secretion of pancreatic duct cells via acini-to-duct signaling. The adenosine receptors may be a potential therapeutic target for cancer as well as exocrine dysfunctions of the pancreas.
Topics: Animals; Bicarbonates; Cytoskeletal Proteins; Female; Guinea Pigs; Islets of Langerhans; Male; Mice; Pancreas; Pancreatic Ducts; Rats; Receptors, Purinergic P1; Rodentia
PubMed: 31717704
DOI: 10.3390/ijms20215329 -
Nature Communications Oct 2017Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos...
Liver duct paucity is characteristic of children born with Alagille Syndrome (ALGS), a disease associated with JAGGED1 mutations. Here, we report that zebrafish embryos with compound homozygous mutations in two Notch ligand genes, jagged1b (jag1b) and jagged2b (jag2b) exhibit a complete loss of canonical Notch activity and duct cells within the liver and exocrine pancreas, whereas hepatocyte and acinar pancreas development is not affected. Further, animal chimera studies demonstrate that wild-type endoderm cells within the liver and pancreas can rescue Notch activity and duct lineage specification in adjacent cells lacking jag1b and jag2b expression. We conclude that these two Notch ligands are directly and solely responsible for all duct lineage specification in these organs in zebrafish. Our study uncovers genes required for lineage specification of the intrahepatopancreatic duct cells, challenges the role of duct cells as progenitors, and suggests a genetic mechanism for ALGS ductal paucity.The hepatopancreatic duct cells connect liver hepatocytes and pancreatic acinar cells to the intestine, but the mechanism for their lineage specification is unclear. Here, the authors reveal that Notch ligands Jagged1b and Jagged2b induce duct cell lineage in the liver and pancreas of the zebrafish.
Topics: Alagille Syndrome; Animals; Bile Ducts, Intrahepatic; Calcium-Binding Proteins; Cell Lineage; Endoderm; Gene Expression Regulation, Developmental; Jagged-2 Protein; Pancreatic Ducts; Zebrafish; Zebrafish Proteins
PubMed: 28974684
DOI: 10.1038/s41467-017-00666-6 -
Stem Cell Research Jul 2015Pancreatic duct glands (PDGs) have molecular features known to mark stem cell niches, but their function remains to be determined. To investigate the role of PDGs as a...
Pancreatic duct glands (PDGs) have molecular features known to mark stem cell niches, but their function remains to be determined. To investigate the role of PDGs as a progenitor niche, PDGs were analyzed in both humans and mice. Cells were characterized by immunohistochemistry and microarray analysis. In vivo proliferative activity and migration of PDG cells were evaluated using a BrdU tag-and-chase strategy in a mouse model of pancreatitis. In vitro migration assays were used to determine the role of trefoil factor (TFF) -1 and 2 in cell migration. Proliferative activity in the pancreatic epithelium in response to inflammatory injury is identified principally within the PDG compartment. These proliferating cells then migrate out of the PDG compartment to populate the pancreatic duct. Most of the pancreatic epithelial migration occurs within 5days and relies, in part, on TFF-1 and -2. After migration, PDG cells lose their PDG-specific markers and gain a more mature pancreatic ductal phenotype. Expression analysis of the PDG epithelium reveals enrichment of embryonic and stem cell pathways. These results suggest that PDGs are an epithelial progenitor compartment that gives rise to mature differentiated progeny that migrate to the pancreatic duct. Thus PDGs are a progenitor niche important for pancreatic epithelial regeneration.
Topics: Animals; Biomarkers; Cell Differentiation; Cell Movement; Epithelial Cells; Humans; Mice; Oligonucleotide Array Sequence Analysis; Pancreatic Ducts; Peptides; RNA; Regeneration; Stem Cells; Trefoil Factor-2; Wound Healing
PubMed: 26100232
DOI: 10.1016/j.scr.2015.05.006 -
Digestive Surgery 2019Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas comprise a heterogeneous group of intraductal mucin-producing neoplasms representing a typical... (Review)
Review
BACKGROUND
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas comprise a heterogeneous group of intraductal mucin-producing neoplasms representing a typical adenoma-to-carcinoma sequence. The involvement of the main pancreatic duct (MPD) is a feature of paramount importance, directly related to a more aggressive biology and a higher malignancy rate.
METHOD
We review and discuss the clinical management of IPMNs with a MPD involvement, recalling the different consensus guidelines and addressing recent controversies in literature, presenting the current clinical practice in Verona Pancreas Institute.
RESULTS
All the aspects of surgical management were discussed, from the indication for surgery to the intraoperative management and the follow-up strategies.
CONCLUSION
The management of presumed IPMNs involving the MPD at our Institution is in line with the International Association of Pancreatology 2012 guidelines, revised in 2016. Surgical resection proposed should achieve the complete removal of the tumor with negative margins. Despite a good prognosis in terms of survival of overall resected main duct intraductal papillary mucinous neoplasms, follow-up should not be discontinued.
Topics: Humans; Intraoperative Care; Pancreatic Ducts; Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Patient Selection; Postoperative Care
PubMed: 29421807
DOI: 10.1159/000486869 -
ELife May 2021To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing...
To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.
Topics: Animals; Cell Line; Cell Separation; DNA Damage; Databases, Genetic; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Geminin; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genetic Heterogeneity; Humans; Mice, Inbred C57BL; Mice, Transgenic; Morphogenesis; Osteopontin; Pancreatic Ducts; Pancreatitis, Chronic; Phenotype; RNA-Seq; Single-Cell Analysis; Transcriptome; Mice
PubMed: 34009124
DOI: 10.7554/eLife.67776