Pancreatic Inflammation Research Articles

Nanotherapeutics-mediated restoration of pancreatic homeostasis and intestinal barrier for the treatment of severe acute pancreatitis.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas accompanied with intestinal injury, and effective therapeutic modalities are still highly lacking. Herein, a facile and effective nanotherapeutics (pHA@IBNCs) is developed to alleviate pancreatic inflammation and restore intestinal barrier for SAP treatment. Epigallocatechin gallate (EGCG, an anti-oxidant), interleukin-22 (IL-22, an anti-inflammatory and epithelial barrier-protecting cytokine), and bovine serum albumin (a framework protein), are assembled via non-covalent interactions to form nanocomplexes (IBNCs). Then, phenylboronic acid-modified hyaluronic acid (pHA) is synthesized and coated onto IBNCs via formation of the reversible boronate ester bonds to obtain pHA@IBNCs. Upon intravenous injection, pHA@IBNCs could efficiently accumulate at the lesion sites of sodium taurocholate (STC)-induced SAP mice, based on their prolonged blood circulation time and pHA-mediated targeting of activated intestinal epithelial cells and macrophages. Inside the inflammatory microenvironment, over-produced reactive oxygen species (ROS) trigger the shedding of the pHA layer and release of the drug payloads. Thereby, EGCG cooperates with IL-22 to attenuate pancreatitis and restore the intestinal barrier by scavenging ROS, suppressing pro-inflammatory cytokines secretion, and promoting the repair of intestinal epithelia. Such a nano-therapeutic approach targeting multiple pathological events may serve as a promising paradigm for the effective management of SAP.

Endocrine pathology in young rabbits with cystic fibrosis

BackgroundCystic fibrosis (CF) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the CF transmembrane conductance regulator gene. CF-related pancreatic lesions are known to cause exocrine dysfunctions such...

The molecular mechanism of PLD2-mediated regulation of apoptosis and cell edema in pancreatic cells via the Nrf2/NF-κB pathway

This study aimed to elucidate the molecular mechanisms by which PLD2 controls apoptosis and edema in pancreatic cells via the Nrf2/NF-κB pathway. AR42J rat pancreatic cells were treated with 10 nM mitomycin to create an in vitro pancreatitis model (model group), with a control group receiving phosphate-buffered saline. Cells were transfected with a PLD2 overexpression plasmid using Lipofectamine 3000, forming the PLD2 overexpression group. PLD2 protein expression was assessed by Western blotting, and TNF-α, IL-6, and IL-10 levels were measured by RT-qPCR. Nrf2/NF-κB protein expressions were also analyzed. Apoptosis and necrosis were evaluated using Annexin V-FITC/PI staining and the LDH release test. Cell edema was assessed by cell volume, ion content, and membrane damage. Western blotting was used to analyze pan-apoptosis-related proteins. PLD2 expression was lower in the model group compared to controls (P < 0.05) but higher in the PLD2 overexpression group (P < 0.05). TNF-α, IL-6, and IL-10 levels were elevated in the model group (P < 0.05) and reduced in the PLD2 overexpression group (P < 0.05). Nrf2 expression decreased in the model group but increased with PLD2 overexpression (P < 0.05). NF-κB expression increased in the model group but decreased with PLD2 overexpression (P < 0.05). Apoptosis and necrosis rates were higher in the model group (P < 0.05) but lower in the PLD2 overexpression group (P < 0.05). Cell volume, Na + content, and LDH release increased in the model group (P < 0.05) but decreased with PLD2 overexpression (P < 0.05). RIPK1 expression decreased in the model group (P < 0.05) but increased with PLD2 overexpression (P < 0.05). CASP8, FADD, and ZBP1 levels were higher in the model group (P < 0.05) and reduced with PLD2 overexpression (P < 0.05). PLD2 exerts a protective effect in acute pancreatitis by activating Nrf2 and inhibiting NF-κB, reducing apoptosis, cell swelling, and membrane damage. This highlights potential therapeutic targets for pancreatic inflammation.

Interleukin-35: A key player managing pre-diabetes and chronic inflammatory type 1 autoimmune diabetes.

Interleukin-35 (IL-35) is a novel protein comprising IL-12α and IL-27β chains. The IL12A and EBI3 genes are responsible for its production. The study of IL-35 has experienced a substantial increase in interest in recent years, as demonstrated by many research papers. Recent clinical studies have shown that individuals who do not have a C-peptide have notably reduced amounts of IL-35 in their blood serum. This is accompanied by a drop in the percentage of IL-35+ Treg cells, regulatory B cells, and CD8+ FOXP3+ cells that produce IL-35. This article em-phasizes the potential significance of IL-35 expression in governing the immune response and its involvement in chronic inflammatory autoimmune diabetes in pancreatic inflammation. It demonstrates IL-35's ability to regulate cytokine proportions, modulate B cells, and protect against autoimmune diabetes. However, further investigation is necessary to ascertain the precise mechanism of IL-35, and meticulous planning is essential for clinical studies.

Pancreatic inflammation induced by hypothyroidism in female rabbits is associated with cholesterol accumulation and a reduced expression of CYP51A1, FXRβ, and PPARβ/δ.

In women and animal models, hypothyroidism induces hypercholesterolemia, pancreatitis, and insulitis. We investigated whether lipids are involved in the effects of hypothyroidism in the pancreas. Control (n = 6) and hypothyroid (n = 6) adult female rabbits were used. We quantified serum and pancreatic triacylglycerol and total cholesterol levels, the oxidative and antioxidant status, and the expression of low-density lipoprotein cholesterol receptor (LDLR) in the pancreas. Inflammation of the pancreas was evaluated by infiltration of immune cells positive to CD163 and α-farnesoid receptor (FXRα). Other lipid players involved in both inflammation and insulin secretion of the pancreas, such as lanosterol 14-α-demethylase (CYP51A1), β-farnesoid receptor (FXRβ), 3β-hydroxysteroid dehydrogenase (3β-HSD), and peroxisome proliferator-activated receptor β (PPARβ/δ), were quantified. Groups were compared by t-Student or U-Mann-Whitney tests (p ≤ 0.05). Hypothyroidism induced hypercholesterolemia and a high cholesterol accumulation in the pancreas of female rabbits, without affecting oxidative or antioxidative status nor the expression of LDLR. The pancreas of hypothyroid females showed inflammation identified by a great infiltration of immune cells, macrophages CD163+, and loss of expression of FXRα+ in immune cells. Moreover, a reduced expression of CYP51A1, FXRβ, and PPARβ/δ, but not 3β-HSD, in the hypothyroid pancreas was found. Pancreatitis and insulitis promoted by hypothyroidism may be related to the accumulation of cholesterol, lanosterol actions, and the activation of PPARβ/δ. All inflammatory markers evaluated in this study are related to glucose regulation, suggesting the link between hypothyroidism and diabetes.

Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.

Correlating tissue and plasma‑specific piRNA changes to predict their possible role in pancreatic malignancy and chronic inflammation.

The aggressiveness of pancreatic ductal adenocarcinoma is primarily due to lack of effective early detection biomarkers. Circulating non-coding RNAs serve as diagnostic or prognostic biomarkers in multiple types of cancer. Comparison of their expression between diseased tissue and relevant body fluids such as saliva, urine, bile, pancreatic juice, blood etc. may reveal mechanistic involvement of common non-coding RNAs. piwi-interacting RNAs (piRNAs) are a class of non-coding RNAs. The aim of the present study was to investigate plasma and tumour tissue piRNA changes in patients with pancreatic cancer (PC) and explore the possible role in tumorigenesis and pancreatic inflammation. Sequencing of circulating plasma small RNAs from patients with PC and chronic pancreatitis (CP) was performed and differentially expressed piRNAs were compared with those in tissues. Subsequent search for target genes for those piRNAs was performed followed by pathway and cluster analysis. A total of 36 piRNAs were shown to be deregulated in pancreatic tumour tissue and alteration of 11 piRNAs was detected in plasma of patients with PC. piRNAs hsa-piR-23246, hsa-piR-32858 and hsa-piR-9137 may serve a key role in PC development as their expression was correlated in both plasma and tumour tissue. Key piRNA-target interactions interfering with key biological pathways were also characterized. A total of 19 deregulated piRNAs in plasma samples of patients with CP was identified; these targeted genes responsible for chronic inflammation. Therefore, the present study provides a comprehensive description of piRNA alteration in pancreatic malignancy and inflammation; these may be explored for biomarker potential in future.

7947 Semaglutide Induced Pancreatitis: A Case Report

Abstract Disclosure: T. Altaweel: None. A. Mathew: None. P. Chalasani: None. L. Lawrence: None. S. Hussain: None. N. Aldaoud: None. Introduction/Background: As semaglutide (GLP1 RA) has become a cornerstone in diabetes and weight management, there have been studies indicating pancreatic inflammation with GLP1 RA use. We report a case of acute necrotizing pancreatitis secondary to semaglutide use.Clinical Case: A 52 year old male with a history of hypertension, morbid obesity with BMI of 40 kg/m2, alcohol induced pancreatitis presented to the hospital complaining of epigastric pain. On presentation, he appeared in distress due to pain but was hemodynamically stable. Physical examination revealed a moderately distended abdomen, tender to palpation over the epigastric area without guarding, and negative Murphy’s sign. The patient reported no alcohol consumption, tobacco usage, or recent abdominal injuries. Laboratory workup revealed elevated WBC 14.6 thous/mcL (4.5-10.5) and lipase 1941 U/L (&amp;lt;60). Abdominal ultrasound showed common bile duct 2 mm without gallstones and CT abdomen revealed acute pancreatitis with suspected necrosis in the pancreatic head and the pancreatic tail. Patient was started on aggressive fluid hydration, pain management and admitted to intensive care. Patient reported that he was started on semaglutide three months ago for weight management by his primary care physician. Patient improved symptomatically with pain control and tolerated oral intake. He was discharged home with recommendations not to resume semaglutide. Conclusion: Semaglutide involves direct stimulation of GLP-1 receptors in pancreatic cells, potentially leading to cell overgrowth, increased pancreatic weight, duct occlusion and inflammation. Despite the SUSTAIN-6 trial indicating no increased risk of acute pancreatitis in diabetic patients using semaglutide, atypical presentations of pancreatitis are noted in patients using the medication for weight management. When all identifiable causes of pancreatitis are eliminated, semaglutide-induced pancreatitis should be a primary consideration in the differential diagnosis. Physicians should exercise caution and give careful consideration when prescribing semaglutide for weight management in patients with conditions that increase risk for pancreatitis. Presentation: 6/2/2024

Pigment Epithelial-Derived Factor in Pancreatic and Liver Cancers-From Inflammation to Cancer.

Gastrointestinal (GI) cancers are among the leading causes of mortality worldwide. Despite the emergence of new possibilities that offer hope regarding the successful treatment of these cancers, they still represent a significant global health burden. These cancers can arise from various cell types within the gastrointestinal tract and may exhibit different characteristics, behaviors, and treatment approaches. Both the prognosis and the outcomes of GI treatment remain problematic because these tumors are primarily diagnosed in advanced clinical stages. Current biomarkers exhibit limited sensitivity and specificity. Therefore, when developing strategies for the diagnosis and treatment of GI cancers, it is of fundamental importance to discover new biomarkers capable of addressing the challenges of early-stage diagnosis and the presence of lymph node metastases. Pigment epithelial-derived factor (PEDF) has garnered interest due to its inhibitory effects on the migration and proliferation of cancer cells. This protein has been suggested to be involved in various inflammation-related diseases, including cancer, through various mechanisms. It was also observed that reducing the level of PEDF is sufficient to trigger an inflammatory response. This suggests that PEDF is an endogenous anti-inflammatory factor. Overall, PEDF is a versatile protein with diverse biological functions that span across different tissues and organ systems. Its multifaceted activities make it an intriguing target for therapeutic interventions in various diseases, including cancer, neurodegeneration, and metabolic disorders. This review, for the first time, summarizes the role of PEDF in the pathogenesis of selected GI cancers and its potential utility in early diagnosis, prognosis, and therapeutic strategies for this malignancy.

Can CONUT and PNI Scores Predict Necrotizing Pancreatitis in Acute Pancreatitis Patients Presenting to the Emergency Department?

Background and Objectives: Acute pancreatitis, characterized by pancreatic inflammation, poses significant morbidity and mortality worldwide, with varied etiologies including gallstones, alcohol, and certain medications. Necrotizing pancreatitis represents a severe form of parenchymal damage with considerable impact on patient quality of life. Early identification of necrotizing pancreatitis is crucial for timely intervention and improved outcomes. The aim of this study was to investigate the usability of CONUT and PNI scores as prognostic indicators. Materials and Methods: We conducted a retrospective observational study involving patients presenting to the emergency department with acute pancreatitis between January 2020 and October 2023. The Controlling Nutritional Status (CONUT) score and Prognostic Nutrition Index (PNI) were calculated from serum biomarkers to assess nutritional status. Patients were categorized into necrotizing and nonnecrotizing pancreatitis groups, and the utility of CONUT and PNI scores in predicting necrotizing pancreatitis was evaluated. Results: A total of 339 patients were included, with 8.26% diagnosed with necrotizing pancreatitis. CONUT and PNI scores significantly differed between necrotizing and nonnecrotizing groups, with higher CONUT scores and lower PNI scores observed in the necrotizing group. Receiver operating characteristic (ROC) curve analysis revealed significant predictive value of CONUT and PNI scores for necrotizing pancreatitis, with cutoff values of >5 and ≤34, respectively. Conclusions: CONUT and PNI scores demonstrate promise in predicting necrotizing pancreatitis in patients admitted to the emergency department with acute pancreatitis. Additionally, these scores may serve as prognostic indicators for mortality in acute pancreatitis patients. Early identification using CONUT and PNI scores could facilitate timely intervention, potentially reducing mortality and morbidity in this patient population.

Extended Review and Updates of Nonalcoholic Fatty Pancreas Disease.

Non-alcoholic fatty pancreatic disease (NAFPD), also known as pancreatic steatosis, is a benign condition characterized by deposition of lipids in the pancreas and is associated with insulin resistance, malnutrition, obesity, metabolic syndrome, aging, and absence of heavy alcohol intake or infection. Similar to nonalcoholic fatty liver disease, NAFPD is a phenotypic entity that includes fat buildup in the pancreas, pancreatic inflammation, and subsequent fibrosis. The extent to which pancreatic fat infiltration is clinically important remains unclear. Despite these clinical associations, most of the clinical effects of NAFPD are not known. NAFPD may be identified by transabdominal and elastography ultrasound, computed tomography scan, or magnetic resonance imaging modalities, but a confirmatory diagnosis can only be made through tissue histology. In addition to complications such as acute and chronic pancreatitis, NAFPD may progress to pancreatic ductal adenocarcinoma. However, further research is required to fully understand the associations, pathophysiology, and effects of NAFPD. This review provides a narrative synthesis of the current literature on the epidemiology, pathophysiology, complications, diagnostic and imaging tools, and management of NAFPD.

Dachaihu Decoction alleviates chronic pancreatitis by regulating MAPK signaling pathway: Insights from network pharmacology and experimental validation

Ethnopharmacological relevanceChronic pancreatitis (CP), a syndrome characterized by inflammatory fibrosis, can impair both the internal and external secretory functions of the pancreas. The global incidence of this disease is gradually increasing. However, the exact pathogenesis remains unclear, resulting in a lack of targeted clinical therapies. According to the principles of traditional Chinese medicine, CP can be attributed to Shaoyang and Yangming syndromes, which manifest as abdominal pain and hypochondriac distension. Dachaihu Decoction (DCHD) is a classic formula from the “Treatise on Febrile and Miscellaneous Disease.” It is frequently prescribed for conditions associated with combined Shaoyang and Yangming syndromes. However, the specific mechanisms by which DCHD prevents and treats CP remain unclear and require further investigation. Aim of the studyUsing a holistic methodology, including network pharmacology, molecular docking, transcriptomic profiling, and animal experimentation, we explored the potential therapeutic mechanisms of DCHD in CP. Materials and methodsIn a mouse model, caerulein was used to induce CP, and DCHD was administered via gastric lavage to assess its therapeutic effect on pancreatic injury caused by caerulein-induced CP. Subsequently, pancreatic tissues were collected for transcriptomic analysis. Screening of DCHD-active ingredient-target pathways for CP treatment was conducted using network pharmacology and further preliminary validation was performed using molecular docking techniques. Additionally, in vivo and in vitro validation was conducted using animal and cells experiments based on the predicted results. ResultsOur findings suggest that DCHD ameliorates pancreatic acinar cell injury, pancreatic inflammation, and fibrosis in mice with CP. Network pharmacology identified 385 potential targets of DCHD associated with CP. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the therapeutic effect of DCHD on CP may be linked to the mitogen-activated protein kinase (MAPK) signaling pathway. Transcriptomic data supported this finding, as it confirmed that DCHD inhibited the pancreatic MAPK signaling pathway in CP. Molecular docking studies further revealed that the top ten active components of DCHD exhibited strong docking activity with key molecules within the MAPK signaling pathway. Finally, animal experiments confirmed that DCHD effectively reduced the phosphorylation of P38, Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in pancreatic tissues. In addition, the expression of p-P38, p-JNK, and p-ERK was reduced in pancreatic stellate cells and macrophages in the DCHD group. We further treated CP mice, human pancreatic stellate cell line (hPSCs), and macrophage cell line RAW264.7 with the active component baicalin from DCHD, and found that baicalin effectively reduced pancreatic damage in CP. Additionally, the expression of key proteins in the MAPK signaling pathway was significantly decreased in both hPSCs and RAW264.7. ConclusionIn summary, DCHD plays an important role in the treatment of chronic pancreatitis, and it may become a promising drug against the progression of CP. The role of DCHD in alleviating pancreatic inflammatory cell infiltration and fibrosis may be related to the regulation of the MAPK signaling pathway.

Abstract B024: Multiplexed 3D atlas of state transitions and potential prognostic role of poly- ADP ribose glycohydrolase (PARG) in chronic pancreatitis and PDAC

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC), a disease predominantly associated with chronic inflammation, ranks as the third-leading cause of cancer-related mortality. The limited efficacy of current PDAC therapies is, in part, attributed to the challenges posed by late- stage diagnosis, highlighting the urgent need for early detection techniques to improve treatment outcomes. Sustained pancreatic inflammation induces the production of reactive oxygen species, leading to the activation of the DNA damage repair network, including enzymes such as poly-ADP ribose glycohydrolase (PARG). PARG is crucial for degrading poly-ADP ribose (PAR) chains catalyzed by PARP and, thus, regulating key cellular responses to DNA damage. However, the role of PARG in the molecular etiology of pancreatic diseases remains unclear. As a first step, we conducted a single-cell spatial analysis on a multiplex immunofluorescence cyclic dataset focusing on pathways involved in: immune and stromal alterations influencing cell-state transitions; differentiation; and critical cellular signaling pathways. Specifically, we evaluated the expression patterns of DNA damage enzymes (i.e., PARG), to elucidate their potential roles in the transformation from chronic inflammation to malignancy. Method: The human pancreatitis tissue microarray (TMA), consisting of 6 normal, 36 pancreatitis, 36 pancreatic intraepithelial neoplasia (PanINs), and 6 PDAC samples in duplicate, obtained from patients with pancreatitis or pancreatic cancer diagnosed at Oregon Health and Science University. We generated a comprehensive 48-plex image dataset that was processed through unsupervised clustering and manual gating to identify common cell types across different stages of pancreatic disease, including epithelial, stromal, immune, and endothelial. Result and conclusion: We observed moderate to strong cytoplasmic PARG expression in pancreatitis samples compared to normal tissue (p &amp;lt; 0.001), which significantly decreased in PanINs (p &amp;lt; 0.001) and PDAC samples (p &amp;lt; 0.001). Notably, the PARG expression was primarily in CK19-positive epithelial cells. Further evaluation showed that DNA damage markers, such as pRPA and γH2AX, increased as the disease progressed from pancreatitis to PanINs to PDAC. Therefore, there was an inverse correlation between PARG expression and DNA damage marker expression in cells exhibiting DNA damage. Additionally, PARG expression was inversely correlated with proliferating cells, marked by Ki67 and PCNA, at the single-cell level. In conclusion, our single-cell spatial analysis supports the notion that PARG expression correlates with resolution of DNA damage and that its reduced expression associates with disease progression and cellular proliferation. Overall, these findings support early phase clinical trials using PARG inhibitors in the oncologic space, and as a potential target for early detection of PDAC and treatment of other pancreatic diseases. Mechanistically, PARG loss may provide a setting for faulty DNA repair and thus, an accumulation of driver mutations. Citation Format: Vidhi M Shah, Jennifer Eng, Koei Chin, Brett C. Sheppard, Jonathan R. Brody, Rosalie C. Sears. Multiplexed 3D atlas of state transitions and potential prognostic role of poly- ADP ribose glycohydrolase (PARG) in chronic pancreatitis and PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B024.

Impact of Elevated Serum Triglycerides on Children with Acute Recurrent or Chronic Pancreatitis from INSPPIRE-2

To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP. Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n=559) were analyzed. Subjects were divided into normal triglycerides (<150mg/dL; 1.7mmol/L), any HTG (≥150mg/dL; ≥1.7mmol/L), mild-moderate HTG (150-499mg/dL; 1.7-5.6mmol/L), moderate HTG (500-999mg/dL; 5.6-11.3mmol/L), and severe HTG groups (≥1000mg/dL; ≥11.3mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed. In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days. Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP.

Retrospective Evaluation of Clinical and Biochemical Data in Patients with Pancreatic Conditions

Background: Pancreatic inflammation, also known as pancreatitis, occurs when exocrine pancreatic enzymes infiltrate the pancreas and cause pathological inflammation. Each case of acute pancreatitis is associated with a subset of causes, indicating the presence of known risk factors. Objectives: This paper aims to identify the common causes of pancreatitis and the factors affecting hospitalization and survival at the study site. Methods: Data were collected from the hospital information systems (HIS) using the K85 code from the International Statistical Classification of Diseases 10 (ICD10) at a referral center in Ahvaz, Iran. Demographic information, comorbidities, laboratory parameters, and paraclinical information such as ultrasound documents and reports were gathered. The study focuses on demonstrating the common causes of pancreatitis and factors impacting hospitalization and survival rates from 2017 to 2020. Results: During this period, 84 patients were admitted. The highest number of admissions occurred in 2020, with the majority of patients being 40 - 60 years old, and women constituting a larger proportion. In total, 85.7% of patients were hospitalized for less than 10 days. About 92% were discharged with follow-up advice, while the rest were discharged against medical advice (DAMA). No deaths were recorded during this period due to pancreatitis. Conclusions: The most common comorbidities in this study were gallstones, sludge, and a BMI exceeding 30. Additionally, elevated levels of glucose, creatinine, amylase, and lactate dehydrogenase were associated with prolonged hospitalization.

SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress.

Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90%vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0vs 45.0; p=0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein-stimulated pancreatitis models, Sec16a+/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.

3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered that PanINs are remarkably abundant in the grossly normal pancreas, suggesting that the vast majority will never progress to cancer. Here, through construction of 48 samples of cm3-sized human pancreas tissue, we profiled the immune microenvironment of 1,476 PanINs in 3D and at single-cell resolution to better understand the early evolution of the pancreatic tumor microenvironment and to determine how inflammation may play a role in cancer progression. We found that bulk pancreatic inflammation strongly correlates to PanIN cell fraction. We found that the immune response around PanINs is highly heterogeneous, with distinct immune hotspots and cold spots that appear and disappear in a span of tens of microns. Immune hotspots generally mark locations of higher grade of dysplasia or locations near acinar atrophy. The immune composition at these hotspots is dominated by naïve, cytotoxic, and regulatory T cells, cancer associated fibroblasts, and tumor associated macrophages, with little similarity to the immune composition around less-inflamed PanINs. By mapping FOXP3+ cells in 3D, we found that regulatory T cells are present at higher density in larger PanIN lesions compared to smaller PanINs, suggesting that the early initiation of PanINs may not exhibit an immunosuppressive response. This analysis demonstrates that while PanINs are common in the pancreases of most individuals, inflammation may play a pivotal role, both at the bulk and the microscopic scale, in demarcating regions of significance in cancer progression.

Correlation Between BMI and Severity of Acute Pancreatitis: A Retrospective Study.

Background Pancreatitis, marked by sterile inflammation of the pancreas, can present as either acute or chronic. It involves the premature activation of proteolytic enzymes, leading to autodigestion, inflammation, and potential systemic effects. This study investigates the impact of obesity on the severity of acute pancreatitis, given its role in systemic inflammation and its association with severe morbidity and mortality. Methods A retrospective analysis was conducted on patients treated for acute pancreatitis over a five-month period at the Royal Albert Edward Infirmary, Wrightington, Wigan and Leigh (WLL) NHS Foundation Trust, Wigan, United Kingdom. Patients were evaluated using diagnostic criteria such as abdominal pain, elevated serum enzyme levels, and imaging results. The study explored correlations between BMI and pancreatitis severity, hospital length of stay, and complications, applying the Atlanta severity classification. Results The analysis revealed a weak, statistically insignificant correlation between BMI and the severity of acute pancreatitis, hospital stay length, and complications. This was consistent across various statistical methods, including Pearson correlation coefficients and multiple linear regression. These findings suggest that, while obesity may influence the inflammatory response in acute pancreatitis, it does not have a significant impact on clinical outcomes within this cohort. Conclusions The study highlights the complex role of obesity in exacerbating pancreatic inflammation but also emphasizes the need for larger, more definitive studies to explore this relationship further. It underscores the importance of early recognition and intervention in managing acute pancreatitis, regardless of BMI status.

Natural history of spontaneous pancreatic portal vein fistulae: A systematic review of the literature

BackgroundSpontaneous pancreatic portal vein fistula (PPVF) - a rare complication of pancreatic inflammation – varies widely in presentation and means of diagnosis but has been previously associated with bleeding complications and mortality. A systematic review of published literature was performed to assess the frequency of outcomes. MethodsA search of electronic databases (PubMed, Ovid MEDLINE, Scopus, EMBASE, gray literature) resulted in 1667 relevant unique manuscripts; 52 met inclusion criteria. ResultsA total of 74 unique (male n = 47, 63.5 %) patients were included. Mean age was 53.5 (±11.9) years. History of alcohol use was reported in 55 (74.3 %). Underlying chronic pancreatitis (CP) was present in 49 (66.2 %). In cases where presenting symptoms were reported (n = 57, 77.4 %), the most frequent were abdominal pain (63.5 %), weight loss (14.9 %), rash (12.2 %), nausea/vomiting (12.2 %), and polyarthritis (9.5 %). Computed tomography was the most common imaging modality used to confirm the diagnosis (n = 20, 27.0 %), followed by magnetic resonance cholangiopancreatography (n = 14, 18.9 %). Portal vein thrombosis was reported in 57 (77.0 %), and bleeding events (luminal, variceal, or intra-pseudocyst) were reported in 13(17.6 %) patients. Younger age was associated with higher risk of bleeding events. Mortality was reported in 12 (16.2 %) patients at any time during follow up. Older age and polyarthritis at presentation were associated with mortality. ConclusionsPPVF is a rare and potentially fatal condition, though rates of bleeding complication and death were relatively low in this population. High-quality observational studies are needed to better understand the pathophysiology and natural history of this diagnosis.

Management of Acute Pancreatitis and Kidney Injury in a Dog

Concurrent acute pancreatitis and acute kidney injury represent significant pathological conditions in dogs, presenting challenges in diagnosis and management. In human medicine this is interconnected and complex co morbid condition. Renal impairment consequently leads to fluid and electrolyte imbalance, in turn causes metabolic disturbances that may predispose to pancreatitis in dogs. Identification of underlying etiology and predisposing factors prevents further recurrence in affected individuals. The critical interplay between AP and AKI needs comprehensive management procedure. This article poses a case study of an eight-year-old Dalmatian cross dog presenting with severe respiratory distress, jaundice and gastrointestinal symptoms. Laboratory findings revealed elevated markers of pancreas, liver and kidney injury. Prompt intervention with fluid therapy, antibiotics and supportive care led to significant clinical improvement. Subsequent re-evaluation demonstrated resolution of pancreatic inflammation and restoration of renal function. This case underscores the importance of early recognition, aggressive intervention and comprehensive management in achieving successful outcomes in dogs with concurrent pancreatitis and acute kidney injury in dogs.