Colloid Carcinoma of the Pancreas: A Rare Initial Presentation of Lynch Syndrome.

Patients with Lynch syndrome, most commonly associated with colorectal cancer, have an increased risk of developing other tumors including pancreatic ductal adenocarcinoma and precursor lesions, such as intraductal papillary mucinous neoplasms. Here, we present a case of a man in his early 20s who presented with a retroperitoneal mass involving the head of the pancreas. Following a pancreaticoduodenectomy combined with para-aortic lymphadenectomy, a pathologic diagnosis of colloid carcinoma, also known as mucinous noncystic carcinoma, of the pancreas was reported. Further testing established the diagnosis of Lynch syndrome. This case is unique because colloid carcinoma of the pancreas is rare and has never been reported as an initial presentation of Lynch syndrome.

Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.

OBJECTIVE: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts (CAFs) and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not adequately defined. METHODS: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas (TCGA) RNA-sequencing data and characterized the expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies. RESULTS: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts (P < 0.05). Immunohistochemistry detected Grem1 protein in PDAC tumor cells and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in CAFs suppressed transforming growth factor (TGF)-ß-induced extracellular matrix proteins (P < 0.05). Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages (P < 0.05). CONCLUSIONS: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.

Aging- and alcohol-associated spatial transcriptomic signature in mouse acute pancreatitis reveals heterogeneity of inflammation and potential pathogenic factors.

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP.

Intraintestinal Heterogeneity of Drug Target Expression in Inflammatory Bowel Disease.

OBJECTIVE: There has been no significant improvement in remission rate in inflammatory bowel disease (IBD) despite several new drugs being introduced in the past two decades. Post-treatment biopsies sometimes show histologic healing in some areas of the intestine while other areas within the same intestine continue to show active inflammation. The aim of this short descriptive study was to determine whether heterogeneous treatment response in IBD may be caused by heterogeneous expression of treatment targets within the same intestine. METHODS: Six cases of Crohn's disease and five cases of ulcerative colitis in which moderate to severe active inflammation was present in at least two biopsies from the same intestine obtained during the same endoscopy procedure were entered in the study. Sections were stained for TNFα and phospho-JAK1 (p-JAK1) using immunohistochemistry. Expression of TNFα and p-JAK1 was recorded as high when the staining intensity was moderate or high, or low when there was no or week staining. The number of eosinophils per high power field was counted in the area of peak density. RESULTS: Different sites within the same intestine from IBD patients with moderate to severe active inflammation may express different levels of TNFα and p-JAK1. For example, in one patient with Crohn's disease with histologically moderate to severe activity in biopsies from the ileum (site 1) and cecum (site 2), there was high expression of p-JAK1 and low TNFα in the ileum biopsy with the exact opposite in the cecum biopsy (low p-JAK1 and high TNFα expression). In this example neither small molecule drug targeting JAK1 nor anti-TNFα biologic given as single agent therapy would be expected to induce histologic remission in both actively inflamed sites in this patient. CONCLUSIONS: The heterogeneous expression of treatment targets within the same intestine may explain why some patients with IBD may not have complete remission on single drug. Studies are needed to determine whether assay for target expression in mucosal biopsies from IBD patients can help to optimize treatment selection.

Incomplete Intestinal Metaplasia of the Stomach Is more Related to Bile Reflux than Chronic Gastritis.

OBJECTIVE: Incomplete intestinal metaplasia (IIM) of the stomach is associated with higher risk of progression to dysplasia and gastric cancer than complete intestinal metaplasia (CIM). Whether the causative factors underlying IIM are different from those underlying CIM is currently unknown. In a recent study, bile acids were found to induce gastric intestinal metaplasia (IM) in mice by activating STAT3 signaling and accelerated the development of dysplasia. The aim of this study was to determine whether there are differences in associations between IIM and CIM and clinicopathologic features known to be associated with intestinal metaplasia, bile reflux, and activated STAT3. METHODS: Fifty-two consecutive gastric biopsies with IM were examined for the type of metaplasia, presence of inflammation, and Helicobacter pylori (H. pylori) status. Immunohistochemical staining was performed for phospho-STAT3 (p-STAT3) and evaluated by image analysis. The type of IM was then correlated with relevant clinicopathologic variables and p-STAT3 expression. RESULTS: Seven cases had IIM only, 31 had CIM only, and 14 had both CIM and IIM (CIIM). Significantly fewer cases with IIM had chronic gastritis than either CIM or CIIM (43%, 93%, 79%, respectively, p=0.005). H. pylori was not detected in any of the IIM cases but was positive in 29% of CIM and 29% of CIIM. Fifty-seven percent of patients with IIM had a history of cholecystectomy compared to 25% of those with CIM and 23% of those with CIIM. The mean BMI was 32.3 kg/m2 for patients with IIM compared to 28 kg/m2 for those with CIM and 31.2 kg/m2 for those with CIIM. Median p-STAT3 for biopsies with was IIM was 6.36 compared to 3.54 for CIM and 6.27 for CIIM. Reactive gastropathy was present in 57% of biopsies with IIM, 39% of CIM and 50% of CIIM. CONCLUSION: In contrast to CIM, IIM is significantly less likely to be associated with chronic gastritis. CIIM also tended to be less associated with H. pylori infection and more associated with reactive gastropathy, history of cholecystectomy, higher BMI, and higher median p-STAT3. These results tend to suggest that IIM is probably more likely to be associated with bile reflux than H. pylori-associated gastritis. Larger studies are needed to confirm these findings.Presented in part at Digestive Disease Week 2023, Chicago, IL, May 6, 2023.

A Common Infection in a Highly Atypical Patient: Hematochezia From a Cytomegalovirus Colonic Ulcer in a Young and Healthy Immunocompetent Patient.

Gastrointestinal (GI) cytomegalovirus (CMV) infections are far more common in immunocompromised as opposed to immunocompetent patients. Immunocompetent patients who develop GI tract CMV infections are typically older with medical comorbidities. As such, descriptions of GI CMV infections in younger immunocompetent patients are lacking. Here, we present a case of a GI CMV infection in a young and healthy immunocompetent patient. A 41-year-old male with hyperlipidemia and hypothyroidism presented with painless, intermittent hematochezia. He denied changes in bowel habits or appetite, abdominal pain, fevers, chills, fatigue, or weight loss. His history was pertinent for insertive and receptive intercourse with one male partner. Medications were emtricitabine/tenofovir for pre-exposure prophylaxis, levothyroxine, and atorvastatin. A colonoscopy revealed a cecal ulcer surrounded by nodular-appearing mucosa that felt firm and friable when biopsied. The remaining colon and terminal ileum were normal. There was no diverticulosis or hemorrhoids. Pathology was positive for CMV. A subsequent serological evaluation revealed a normal complete blood count and comprehensive metabolic panel. Tests for human immunodeficiency virus, syphilis, viral hepatitis, chlamydia, and gonorrhea were negative. He was treated with valganciclovir 900 mg twice daily for 21 days. A subsequent test for CMV deoxyribonucleic acid polymerase chain was negative. Hematochezia resolved. A repeat colonoscopy revealed normal mucosa in the cecum. GI CMV infections in immunocompetent patients are rare and typically occur in older patients with medical comorbidities. Further, such case reports are needed to inform clinicians about risk factors and the presentation of GI CMV infections in young healthy immunocompetent patients.

Overexpression of Gremlin1 in Crohn's Disease-Associated Bowel Strictures.

OBJECTIVE: One of the most serious complications of Crohn's disease is intestinal strictures that may lead to bowel obstruction. Understanding the underlying mechanisms of stricture formation is essential in order to develop more effective nonsurgical prevention and treatment modalities. The aim of this pilot study was to determine whether Gremlin1, a protein implicated in fibrogenesis and smooth muscle proliferation, is overexpressed in Crohn's-associated bowel strictures. METHODS: Paired sections from three strictured and non-strictured surgically resected bowel from patients with Crohn's disease were evaluated for Gremlin1 expression by immunohistochemistry. RESULTS: Strictured areas from all three specimens showed strong Gremlin1 staining in the hypertrophic muscularis mucosae area compared to no staining in the mucosa or muscularis propria in the same sections and in contrast to sections from non-strictured areas which were negative. CONCLUSIONS: This short report is the first to describe the overexpression of Gremlin1 in the hypertrophied muscularis mucosae of strictured small intestine from patients with Crohn's disease. Additional studies are needed to elucidate the potential role of Gremlin1 in the etiopathogenesis of Crohn's disease strictures, and to investigate whether targeting Gremlin1 may be an option for preventing or treating strictures in patients with Crohn's disease.

Collagenous Gastritis: An Atypical Presentation of a Rare Disease.

Collagenous gastritis is a rare inflammatory condition of unknown etiology defined histologically by subepithelial deposition of collagen bands ≥ 10 µm in the lamina propria. Adults typically present with diarrhea, often attributed to concurrent collagenous sprue or collagenous colitis. Children more commonly present with abdominal pain and anemia, with inflammation typically limited to the stomach. Herein, we present a case of collagenous gastritis in a 38-year-old female with a history of iron deficiency and hypothalamic amenorrhea who presented with a one-year history of microcytic anemia. Celiac disease panel, Helicobacter pylori testing, and anti-parietal cell and intrinsic factor antibodies were negative. Esophagogastroduodenoscopy revealed diffusely erythematous and nodular gastric mucosa in the antrum and pylorus. Biopsy from the gastric body showed complete loss of oxyntic glands and deposition of a thick band of collagen under the surface epithelium infiltrated by a few eosinophils, consistent with collagenous gastritis with severe atrophy. She was treated with omeprazole 40 mg daily for six weeks and iron supplementation. Our patient's symptoms and endoscopic findings are consistent with previously described pediatric, but not adult, cases of collagenous gastritis, yielding insight into the variable clinical presentation of this rare disease.

Colonic Eosinophilia: Clinicopathologic Study of Paired Right and Left Colon Biopsies from 276 Patients.

OBJECTIVE: This study evaluated differences in eosinophil (Eos) count in the right colon (RC) and left colon (LC) relative to known clinical and pathologic features. METHODS: H&E slides from 276 subjects with biopsies taken from both RC and LC were reviewed. Eos/mm2 were counted in the area with highest concentration then correlated with clinical and pathologic findings for RC and LC. RESULTS: There were higher numbers of Eos/mm2 in RC than in LC (mean 177 vs 122, respectively p<0.0001), and there was significant positive correlation between Eos numbers in the two locations (r=0.57, p<0.001). In RC, the mean Eos/mm2 was 242 with active chronic colitis, 195 with inactive chronic colitis, 160 in microscopic colitis, 144 in quiescent IBD, and 142 with normal histology (p<0.001), and was higher in males (204 vs 164, p=0.022). In LC, mean Eos/mm2 was 186 with active chronic colitis, 168 with inactive chronic colitis, 154 in microscopic colitis, 82 in quiescent IBD, and 84 with normal histology (p<0.001), and was higher in males (154 vs 107, p<0.001). In biopsies with normal histology, RC showed higher mean Eos/mm2 in Asian patients (228 vs 139, p=0.019), and patients with history of UC (205 vs 136, p=0.004), but was not significantly different in patients with or without irritable bowel syndrome with diarrhea (IBS-D) or history of Crohn's disease (CD). In LC the mean Eos/mm2 was higher in males (102 vs 77, p=0.036), and history of CD (117 vs 78, p=0.007), but was not significantly different in patients with or without IBS-D or history of UC. The number of Eos/mm2 was greater in biopsies performed in the summer than during other seasons of the year. CONCLUSION: The mean number of Eos/mm2 in colorectal biopsies varies significantly by location, histopathologic changes, clinical diagnosis, season, gender and ethnicity. Of particular interest is the association between high Eos/mm2 in RC biopsies with otherwise normal histology and clinical history of UC, and in LC biopsies with clinical history of CD. Additional larger and prospective studies that include normal healthy volunteers are needed to establish a reliable cutoff for the histopathologic diagnosis of eosinophilic colitis, taking into consideration the biopsy site within the colon and rectum, as well as patient gender and ethnicity.Presented in part at the annual American College of Gastroenterology meeting, San Antonio, TX October 2019.

Expression of p-STAT3 and c-Myc correlates with P2-HNF4α expression in nonalcoholic fatty liver disease (NAFLD).

We studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α (p = 0.03). p-STAT3-positive cases were more likely to be positive for c-Myc (67% vs. 2%, p = 0.0003). Four cases were positive for P2-HNF4α, p-STAT3 and c-Myc. p-STAT3 expression was associated with hypertension (p = 0.037). All c-Myc positive biopsies were from patients with obesity, diabetes and hypertension. Only c-Myc expression was associated with advanced fibrosis; three (60%) of the c-Myc positive cases were associated with advanced fibrosis in contrast to 7 (10%) of the 44 c-Myc negative cases (p = 0.011). Based on these results, we hypothesize with the following sequence of events with progression of NAFLD: P2-HNF4α expression is followed by expression of p-STAT3 which in turn is followed by the expression of c-Myc. Additional larger studies are needed to confirm these findings.

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.

Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis.

Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.

Alterations in MAdCAM1-Positive Mucosal Capillaries and Integrin a4b7-Positive Lymphocytes in Crohn's Disease Treated with Anti-TNFα Biologics.

OBJECTIVE: To elucidate the reasons for the decreased effectiveness of Vedolizumab (VDZ) treatment in patients with Crohn's disease (CD) previously treated (CD-T) with anti-TNF-α biologics. METHODS: Immunohistochemical staining was performed on sections of formalin-fixed paraffin-embedded ileocolonic biopsies using antibodies for the mucosal addressin molecule (MAdCAM-1) and Etrolizumab. RESULTS: The mean number of MAdCAM-1 positive capillaries (MAdCAM-1-C) was 3 in controls, 8.5 in CD, 5.37 in CD-T, 5.7 in ulcerative colitis (UC), and 3.1 in lymphocytic colitis (LC) (p=0.0032). When all biopsies with inflammatory bowel disease (IBD) in this series were considered together, the number of MAdCAM-1-C increased with an increased histologic activity score (HAS) (p<0.001). The mean MAd-CAM-1-C was lower in CD-T than CD (5.37 vs. 8.5, p=0.0362), even in cases with high HAS (6.46 vs. 9.5, p=0.073). Two of 6 (33%) controls, 4 of 6 (67%) CD, 9 of 16 (56%) CD-T, 6 of 7 (86%) UC, and 0 of 8 (0%) LC showed Etrolizumab-positive lymphocytes (E-Ly, p=0.0106). IBD biopsies positive for E-Ly were associated with higher HAS (p=0.0546). MAdCAM-1-C was heterogenous in some IBD cases. CONCLUSIONS: Our results suggest that treatment with anti-TNF-α reduces the number of MAdCAM-1-C in CD, even in biopsies with high HAS. This suggests that high inflammation in such cases obviously failed to respond to anti-TNF-α, may be less dependent on the migration of a4b7-lymphocytes to the inflamed mucosa, and therefore may not optimally respond to VDZ treatment.Presented in part at the Digestive Diseases Week meeting, San Diego, CA, May 2019. Supported by Takeda Pharmaceuticals.

Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Lymphocytic Esophagitis Is Not Similar to Eosinophilic Esophagitis Except for Seasonal Variation.

OBJECTIVE: Unlike eosinophilic esophagitis (EoE), there is no consensus on the minimum number of intraepithelial lymphocytes (IEL) that is diagnostic of lymphocytic esophagitis (LyE). The aim of this study was to determine whether significant correlations exist between the numbers of intraepithelial lymphocytes (IEL) in esophageal biopsies and clinical and endoscopic manifestations usually associated with EoE. METHODS: H&E slides from esophageal biopsies from 330 patients were reviewed. The number of IEL and intraepithelial eosinophils (IEE) per mm2 was counted in the area with the highest concentration in each biopsy. The numbers were then correlated with clinical and endoscopic findings. RESULTS: As expected, a higher number of IEE was significantly associated with food impaction (p=0.001), dysphagia (p=0.021), esophageal stricture (p=0.017), rings (P<0.0001), and furrows (p<0.0001). By contrast, there was no significant association between increased IEL and any of the aforementioned clinical and endoscopic features in the original 330 patients or in a subset of 233 patients with no IEE. Interestingly, the number of both IEE and IEL varied significantly by the season when the biopsy was obtained, being lowest in the fall and highest in the spring (p=0002 for IEE and p<0.0001 for IEL). CONCLUSION: In esophageal biopsies, increased IEL has no significant correlation with food impaction or dysphagia or with esophageal stricture, rings, or furrows. There is significant variation in the number of IEL depending on the season when the biopsy is obtained, which has not been previously reported.

Distinct Murine Pancreatic Transcriptomic Signatures during Chronic Pancreatitis Recovery.

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.