Exocrine Pancreatic Tissue Research Articles

Histochemical Analysis of DNA and RNA Identified by Methyl Green - Pyronin ‘Y’ Method and Feulgen’s Reaction Staining in Liver of Channa Punctatus

The light microscopy was to identify cells, storage products, tissue deposits, and microbial pathogens. The Assessment of surrounding tissue with special stains may reveal aspects of interest for the tissue. We illustrate the expected staining characteristics of control Channa punctatus liver tissue with Methyl Green -Pyronin ‘Y’ and Feulgen’s Reaction stains. The aim of this study was to characterize the normal structure of the liver of Channa punctatus, a carnivorous freshwater fish found in Hasanparthy Lake, using gross anatomy, histology and histochemistry. Anatomically, the liver presents C-shaped and only two lobes smaller right and bigger left. The gallbladder is located in right lobe and shows elongated shaped. Histological analysis demonstrated that the hepatic parenchyma is made of two hepatocytes plates surrounded by sinusoids. The fish moreover pancreatic tissue was observed in visceral portion of liver, formed by exocrine pancreatic tissue and islet organ, constituting an extrahepatic pancreas. The nucleic acids content in different tissues in the freshwater fish of Channa punctatus. The fish were scarified and the tissues such as liver and Pancreas removed and processed for determination of nucleic acids. The results obtained in the present study may provide a contribution to the knowledge of the characteristics of nucleic acid as parameters of estimation of DNA and RNA levels in Liver of the fish.

Reduced Nephrin Tyrosine Phosphorylation Enhances Insulin Secretion and Increases Glucose Tolerance With Age.

Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function.

Exosomal ROR1 in peritoneal fluid identifies peritoneal disseminated PDAC and is associated with poor survival.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters. Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed. PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482). With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.

Understanding molecular differences in endocrine and exocrine pancreatic tissue in healthy and unhealthy metabolic states

Type II diabetes (T2D) is a metabolic disorder characterized by hyperglycemia largely due the development of insulin-resistance, and in some cases, due to insuffcient insulin secretion. The endocrine portion of the pancreas, the islets of Langerhans, is composed of a diverse population of cells (beta, alpha, delta) that play vital roles in glucose homeostasis. Intercellular signaling events that occur within this diverse cell population play an active role in T2D progression. Therefore, to properly understand the progression of T2D it is critical to understand the how both the cellular neighborhoods and cell-cell communications within the islet of Langerhans and the surrounding exocrine (non-Islet) tissue contribute to the development of T2D. As the pancreas is a heterogenous organ, techniques allowing for the identification of cellular subpopulations within the tissue, such as single-cell RNA sequencing (scRNAseq), have been critical to answering questions about the pathogenesis of T2D. However, these techniques provide no insight into the anatomical and spatial context of cells, and therefore lack the ability to determine the influence of cellular neighborhoods in T2D pathogenesis. To begin to fill the gap in our understanding of how cellular neighborhoods and cell-cell communication impacts the progression of T2D, we utilized cutting edge technology that allows for the identification of RNA and protein within tissue at cellular and subcellular level, the Nanostring CosMx Spatial Molecular Imager. In this study, we aimed to determine if the location of individual cells within the islet (exocrine adjacent versus endocrine adjacent) contributes to gene expression changes that direct disease progression. To answer this question, we collected 200 human donor pancreases and analyzed them for 1000 RNA targets using the CosMX Spatial Molecular Imager. Ig. We then performed an analysis of RNA expression of exocrine cells bordering the islets of Langerhans and endocrine cells surrounding pancreatic vasculature was compared between healthy, metabolically heathy obese (MHO), and obese T2D groups. Preliminary analysis of these data yield novel insights into the transcriptomic profile of metabolically unhealthy tissues that may play a role in the progression of T2D. In particular, we observed an upregulation of mRNA transcripts associated with pro-inflammatory IL-21 and IL-22 signaling in the alpha cells from MHO donor pancreases. Furthermore, this upregulation is primarily observed in alpha cells in close proximity to acinar cells. Overall, these data will help pave the way to addressing previously unanswered questions in the context of T2D pathogenesis and unexplored cell-cell interactions that occur between the endocrine and exocrine spaces of the pancreas. Funding: Saint Louis University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl2) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway.

Structural and immunohistochemical characterization of pancreas of Molly fish (Poecilia sphenops), with a special reference to its immune role.

Recently, teleost species have been considered important model systems for investigating different research areas including immunologic one. The available literature provides poor data about the localization and the structure of pancreas in Molly fish. Moreover, little attention has been paid to the immunologic role of pancreatic tissue of teleost, particularly Molly fish; therefore, this study aimed to highlights the description of pancreatic tissue in Molly fish using light- and electron- microscopy, focusing on the role of pancreatic immune cells and pancreatic acinar cells in immune responses. Microscopic analysis revealed that the pancreas of Molly fish was composed of intrahepatic, disseminated and compact parts. Exocrine pancreatic tissue was diffusely extended within the hepatic tissue forming hepatopancreas. The disseminated pancreas appeared as several irregular nodules of pancreatic tissue localized within the mesenteric adipose tissue. The compact pancreas appeared as an oval shaped body embedded within the mesenteric adipose tissue between the spleen and the intestinal loops. Several telocytes and melanomacrophages were detected within the disseminated pancreatic nodules. Moreover, dendritic cells were found in a close association to the exocrine pancreatic acini. The pancreatic acinar cells showed strong immunoreactivity to APG5, TGF-β, IL-1β, NF-κB, Nrf2, and SOX9 in both hepatopancreas and disseminated pancreas of Molly fish. S100 protein revealed a strong expression in the exocrine pancreatic acinar cells of disseminated pancreas and also in the endocrine cells of the compact pancreas. In conclusion, findings of this study suggest the potential role of the pancreas of the Molly fish in cell proliferation and differentiation, proinflammatory cytokines stimulation, and regulation of both innate and adaptive immunity. RESEARCH HIGHLIGHTS: Telocytes and melanomacrophages were detected in the disseminated pancreatic nodules of the Molly fish. In Molly fish, dendritic cells were found in a close association to the exocrine pancreatic acini. Strong immunoreactivity of the pancreatic acinar cells of the Molly fish to APG5, TGF-β, IL-1β, NF-κB, Nrf2, SOX9, and S100.

Rare Solid Pancreatic Lesions on Cross-Sectional Imaging.

Several solid lesions can be found within the pancreas mainly arising from the exocrine and endocrine pancreatic tissue. Among all pancreatic malignancies, the most common subtype is pancreatic ductal adenocarcinoma (PDAC), to a point that pancreatic cancer and PDAC are used interchangeably. But, in addition to PDAC, and to the other most common and well-known solid lesions, either related to benign conditions, such as pancreatitis, or not so benign, such as pancreatic neuroendocrine neoplasms (pNENs), there are solid pancreatic lesions considered rare due to their low incidence. These lesions may originate from a cell line with a differentiation other than exocrine/endocrine, such as from the nerve sheath as for pancreatic schwannoma or from mesenchymal cells as for solitary fibrous tumour. These rare solid pancreatic lesions may show a behaviour that ranges in a benign to highly aggressive malignant spectrum. This review includes cases of an intrapancreatic accessory spleen, pancreatic tuberculosis, solid serous cystadenoma, solid pseudopapillary tumour, pancreatic schwannoma, purely intraductal neuroendocrine tumour, pancreatic fibrous solitary tumour, acinar cell carcinoma, undifferentiated carcinoma with osteoclastic-like giant cells, adenosquamous carcinoma, colloid carcinoma of the pancreas, primary leiomyosarcoma of the pancreas, primary and secondary pancreatic lymphoma and metastases within the pancreas. Therefore, it is important to determine the correct diagnosis to ensure optimal patient management. Because of their rarity, their existence is less well known and, when depicted, in most cases incidentally, the correct diagnosis remains challenging. However, there are some typical imaging features present on cross-sectional imaging modalities that, taken into account with the clinical and biological context, contribute substantially to achieve the correct diagnosis.

Thrombospondin-1, CD47, and SIRPα display cell-specific molecular signatures in human islets and pancreata.

Thrombospondin-1 (TSP1) is a secreted protein minimally expressed in health but increased in disease and age. TSP1 binds to the cell membrane receptor CD47, which itself engages signal regulatory protein α (SIRPα), and the latter creates a checkpoint for immune activation. Individuals with cancer administered checkpoint-blocking molecules developed insulin-dependent diabetes. Relevant to this, CD47 blocking antibodies and SIRPα fusion proteins are in clinical trials. We characterized the molecular signature of TSP1, CD47, and SIRPα in human islets and pancreata. Fresh islets and pancreatic tissue from nondiabetic individuals were obtained. The expression of THBS1, CD47, and SIRPA was determined using single-cell mRNA sequencing, immunofluorescence microscopy, Western blot, and flow cytometry. Islets were exposed to diabetes-affiliated inflammatory cytokines and changes in protein expression were determined. CD47 mRNA was expressed in all islet cell types. THBS1 mRNA was restricted primarily to endothelial and mesenchymal cells, whereas SIRPA mRNA was found mostly in macrophages. Immunofluorescence staining showed CD47 protein expressed by β cells and present in the exocrine pancreas. TSP1 and SIRPα proteins were not seen in islets or the exocrine pancreas. Western blot and flow cytometry confirmed immunofluorescent expression patterns. Importantly, human islets produced substantial quantities of secreted TSP1. Human pancreatic exocrine and endocrine tissue expressed CD47, whereas fresh islets displayed cell surface CD47 and secreted TSP1 at baseline and in inflammation. These findings suggest unexpected effects on islets from agents that intersect TSP1-CD47-SIRPα.NEW & NOTEWORTHY CD47 is a cell surface receptor with two primary ligands, soluble thrombospondin-1 (TSP1) and cell surface signal regulatory protein alpha (SIRPα). Both interactions provide checkpoints for immune cell activity. We determined that fresh human islets display CD47 and secrete TSP1. However, human islet endocrine cells lack SIRPα. These gene signatures are likely important given the increasing use of CD47 and SIRPα blocking molecules in individuals with cancer.

Morphological and histological structure of hepatopancreas in rock goby Gobius paganellus on the western coast of Libya.

The rock goby, Gobius paganellus, is not a commercial species. This species has an essential role in the coastal ecosystem as a biological indicator. Therefore, it has been selected as the study's model species. Due to the insufficient studies that have described the hepatopancreas of G. paganellus, this study aimed to provide information on the anatomical and histological structure of the hepatopancreas of the alimentary canal of this species on the western coast of Libya. Fifty mature G. paganellus specimens were collected from the northwest of Libya (Tajoura, Jodaem, and Farwa Island). Total length and total weight of the samples were measured and performed by using gross anatomy and histology. Then, the histological sections (3-5 µm) were stained with hematoxylin and eosin (H and E). Morphologically, the liver has a large pyriform lobe. The dorsal surface of the liver is shiny and smooth, and the ventral surface contains shallow sulci; each sulus has a large blood vessel. Histologically, the liver is wrapped with a thin capsule of fibro-connective tissue. The hepatic parenchyma is made of hepatocytes with blood sinusoids. The hepatocytes are polygonal-shaped cells and have no hepatic lobules or portal triads. Melano-macrophage centers are distributed next to the blood vessels and bile ducts. The bile ducts are lined by columnar epithelial cells. The exocrine pancreatic tissue was observed in the liver parenchyma, and it consists of acini that are composed of pyramidal cells and contain zymogen granules. The liver of this species has both pancreatic and liver tissue, which was discovered in this investigation for the first time.

In mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3+CD25+ Treg cells suppress the type-2 immune response by a repression of GATA3+ T helper cells (Th2), GATA3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.

Symptomatic heterotopic pancreas of the jejunum: A case report

Introduction: Heterotopic pancreatic (HP) tissue defined as tissue that is found outside the anatomical location of the pancreas. It can occur anywhere in the gastrointestinal tract with the stomach and small bowel being the most common sites. The diagnosis of HP is considered difficult and usually discovered as an incidental finding in laparotomy. However, it can present as a case of intussusception or even perforation. Case Presentation: In this case, we report a 23-year-old male with a history of abdominal pain with vomiting that lasted for 7 days. Computed tomography (CT) scan was suggestive of intussusception. Laparotomy was done and a mass was found adherent to the jejunal wall. Partial resection of the jejunum was performed including the mass. The histopathological analysis confirmed it to be mixed exocrine and endocrine heterotopic pancreatic tissue. Conclusion: Heterotopic pancreatic tissue in the jejunum is rare. However, it should be considered in the differential diagnosis of jejunal masses.

Abstract 728: Tissue-specific tumorigenesis in multiple endocrine neoplasia type 1

Abstract Multiple endocrine neoplasia type 1 (MEN1) is an inherited cancer syndrome caused by a germline mutation in the MEN1 gene. While a germline heterozygous mutation in the MEN1 gene predisposes tumor formation in specific tissues such as the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in mouse pancreatic exocrine tissue does not result in tumor formation, suggesting a tissue-specific mechanism. Loss of menin activates a menin-interacting protein retinoblastoma-binding-protein 5 (RBBP5). Since RBBP5 transcriptionally regulates DNA methyltransferase 1 (DNMT1), this causes global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. We hypothesize that while RBBP5 is ubiquitously expressed, it exclusively binds to the DNMT1 promoter in MEN1-target-tissues through its recruitment by tissue-specific factors. Using ChIP-PCR, we demonstrated that Rbbp5 is bound to the Dnmt1 promoter in MEN1-target-tissues, while not in non-target tissues. In the present study, we set out to identify and validate putative endocrine-specific factors involved in Rbbp5 binding to the Dnmt1 promoter. To investigate this tissue-specific occupancy of Rbbp5 at the Dnmt1 promoter, a ChIP-Seq analysis was carried out on DNA purified from pancreatic endocrine islet cells and pancreatic exocrine cells from wild type (WT) mice. These DNA samples were analyzed to identify differentially occupied DNA binding sites of menin and Rbbp5 by a high-throughput tissue-specific ChIP-seq assay. This analysis yielded a list of endocrine-specific genes regulated by both menin and Rbbp5. In order to further identify the tissue-specific factors that may alter menin-Rbbp5 binding to the Dnmt1 promoter, we performed tissue-specific RNA-Seq on endocrine and exocrine pancreas tissues from WT mice. Integrating tissue-specific ChIP-Seq and RNA-seq data, we identified 20 endocrine tissue-specific factors that may alter the interaction of the menin-Rbbp5 complex with the Dnmt1 promoter. By carrying out this unbiased genome-wide screen, we identified endocrine-specific candidate factors that may interact with the menin-Rbbp5 complex at the Dnmt1 promoter. After screening all candidates, the stand-out candidates were identified for further validation. Criteria to be met to establish stand-out candidates included: MEN1-target-tissue-specific expression through immunohistochemical staining and high mRNA expression by qRT-PCR analysis in WT mouse pancreatic islets on samples extracted by laser capture microscopy. In conclusion, we have identified candidates for Rbbp5 recruitment to the Dnmt1 promoter that must be tested further to determine their role in the observed tissue specificity of MEN1-related tumorigenesis. Citation Format: Juliet C. Gardiner. Tissue-specific tumorigenesis in multiple endocrine neoplasia type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 728.

Brunner's gland hyperplasia and recurrent gastric impaction in a horse

AbstractWhile Brunner's gland hyperplasia may rarely be considered as a cause of chronic gastric impaction in horses, it should be included in the differential diagnoses. A 7‐year‐old Cob cross‐breed gelding was presented with weight loss over a 3‐week period, and a diagnosis of chronic gastric impaction was made. Initial medical management was successful; however, the impaction recurred a further three times, at progressively shorter intervals, over the following 3 months. The owners subsequently elected euthanasia, and the horse was submitted for post‐mortem examination. A focal nodule within the cranial part of the duodenum was seen during the post‐mortem exam. Histopathologic evaluation of the duodenum revealed a marked increase in Brunner's glands admixed with distinct lobules of exocrine pancreatic tissue.

Transcriptional profiles of human islet and exocrine endothelial cells in subjects with or without impaired glucose metabolism

In experimental studies, pancreatic islet microvasculature is essential for islet endocrine function and mass, and islet vascular morphology is altered in diabetic subjects. Even so, almost no information is available concerning human islet microvascular endothelial cell (MVEC) physiology and gene expression. In this study, islets and exocrine pancreatic tissue were acquired from organ donors with normoglycemia or impaired glucose metabolism (IGM) immediately after islet isolation. Following single-cell dissociation, primary islet- and exocrine MVECs were obtained through fluorescence-activated cell sorting (FACS) and transcriptional profiles were generated using AmpliSeq. Multiple gene sets involved in general vascular development and extracellular matrix remodeling were enriched in islet MVEC. In exocrine MVEC samples, multiple enriched gene sets that relate to biosynthesis and biomolecule catabolism were found. No statistically significant enrichment was found in gene sets related to autophagy or endoplasmic reticulum (ER) stress. Although ample differences were found between islet- and exocrine tissue endothelial cells, no differences could be observed between normoglycemic donors and donors with IGM at gene or gene set level. Our data is consistent with active angiogenesis and vascular remodeling in human islets and support the notion of ongoing endocrine pancreas tissue repair and regeneration even in the adult human.

Ex Vivo Imaging of Ultrasound-Stimulated Metabolic Activity in Rat Pancreatic Slices

Ultrasound has previously been reported to produce a reversible stimulatory effect in cultured rat beta cells. Here, we quantified and assessed dynamic metabolic changes in an in situ pancreatic slice model evoked by ultrasound application. After plating, pancreas slices were imaged using a confocal microscope at 488 and 633 nm to image lipodamine dehydrogenase (Lip-DH) autofluorescence and a far red fluorescence, respectively. Ultrasound was applied at intensities of 0.5 and 1 W/cm2 at both 800 kHz and 1 MHz. Additionally, 800 kHz at 1 W/cm2 was applied in a pulsing scheme. No ultrasound (control) and glucose application experiments were performed. A difference in fluorescence signal before and after treatment application was the metric for analysis. Comparison of experimental groups using far red fluorescence revealed significant differences between all experimental groups and control in the islet (p < 0.05) and between all ultrasound experimental groups and control (p < 0.05) in pancreatic exocrine tissue. However, this difference in response between control and glucose did not exist in the exocrine tissue. We also observed using Lip-DH autofluorescence that glucose produces a significantly increased metabolic response in islet tissue compared with exocrine tissue (p < 0.05). Pulsed ultrasound appeared to increase metabolic activity in the pancreatic slice in a more consistent manner compared with continuous ultrasound application. Our results indicate that therapeutic ultrasound may have a stimulatory metabolic effect on the pancreatic islets similar to that of glucose.

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

A Case Of Pancreatic Hamartoma Mimicking Malignancy: An Uncommon Pitfall

Abstract Casestudy Hamartomas are benign, disordered, tumor-like growth of cellular constituents resembling the tissue of its origin. Hamartomas are usually seen in lung, heart, kidney and spleen. Pancreatic hamartomas (PH) are extremely rare, accounting for &amp;lt;1% of all hamartomas. PH occurs at any age (median: 50 years) without gender predilection. PH presents as single or multiple, solid and/or cystic mass composed of exocrine tissues. Admixed neuroendocrine cells may be seen, but well-formed islets are unusual. PH stroma is typically positive for CD34 by immunohistochemistry. We present a case of a PH resected for the clinical suspicion of malignancy, with the final diagnosis established postoperatively. The case is that of a 74-year-old male with an incidental 2.3 x 1.7 x 1.1 cm hyperenhancing solid mass of the pancreatic uncinate process, found during anemia workup. The radiologic appearance was suspicious for a neuroendocrine tumor. Biopsy of the mass showed benign-appearing pancreatic ductal and acinar tissue. Given the clinical suspicion of malignancy, the patient elected to undergo a pancreaticoduodenectomy. Macroscopically the mass was well-circumscribed with solid, tan-white, firm cut surface. Microscopic examination revealed well- circumscribed proliferation of disorderly-arranged, well-differentiated, bland exocrine pancreatic tissue. Chromogranin, synaptophysin and CD56 immunostains did not highlight significant neuroendocrine component. Ki-67 proliferation index was low (1%). CD34 and CD117 immunostains were negative in the stroma. The findings were consistent with PH. Conclusion PH may mimic a malignant process of the pancreas. The preoperative diagnosis of PH is extremely challenging due to the lack of characteristic clinical and radiological features, therefore, the diagnosis of PH is often made on resection specimen. CD34 immunostain is not always helpful for the diagnosis as it may be negative in PH stroma. Although extremely rare, pancreatic hamartoma should be considered in the differential diagnosis of a pancreatic tumor.

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f ) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rbf/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. SIGNIFICANCE: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).

Abstract 2080: Tissue-specific tumorigenesis in multiple endocrine neoplasia type I

Abstract While a germline heterozygous mutation in the Multiple Endocrine Neoplasia type 1 (MEN1) gene predisposes tumor formation in specific tissues such as the endocrine pancreas, parathyroid glands and anterior pituitary, this tissue-specific tumorigenesis is not dependent on MEN1 mutations alone. In fact, a homozygous deletion of Men1 in mouse pancreatic exocrine tissue does not result in tumor formation, suggesting a tissue-specific mechanism. Loss of menin activates a menin-interacting protein retinoblastoma-binding-protein 5 (RBBP5). Since RBBP5 transcriptionally regulates DNA methyltransferase 1 (DNMT1), this causes global DNA hypermethylation and subsequent tumorigenesis in MEN1-target endocrine tissues. We hypothesize that while RBBP5 is ubiquitously expressed, it exclusively binds to the DNMT1 promoter in MEN1-target-tissues through its recruitment by tissue-specific factors. Using chromatin immunoprecipitation, we demonstrated that Rbbp5 is bound to the Dnmt1 promoter in MEN1-target-tissues, while not in non-target tissues. Following a high-throughput genome-wide approach, we identified two candidate factors that may recruit Rbbp5 to the Dnmt1 promoter. Immunohistochemistry showed MEN1-target-tissue-specific expression of these target factors. Co-immunoprecipitation revealed MEN1-target-tissue-specific binding of Rbbp5 to the factors. In conclusion, Rbbp5 binds the Dnmt1 promoter in MEN1-target-tissues and we have identified candidates for Rbbp5 recruitment to the Dnmt1 promoter that must be tested further to determine their role in the observed tissue specificity of MEN1-related tumorigenesis. Citation Format: Juliet C. Gardiner, Steven K. Libutti. Tissue-specific tumorigenesis in multiple endocrine neoplasia type I [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2080.