Bifocal solid pseudopapillary tumour of the pancreas.

Solid pseudopapillary neoplasm of the pancreas (SPNP) is a rare entity. In this study, we present a woman in her 20's who presented for evaluation of two separate pancreatic masses. On imaging and biopsy, the tail lesion was thought to be a neuroendocrine tumour and the body lesion was thought to be a metastatic lymph node. The patient was brought to the operating room and underwent a distal pancreatectomy and splenectomy. The patient had an uneventful postoperative course and was discharged home on postoperative day 4. Pathology confirmed both masses were consistent with the diagnosis of well-differentiated SPNP with no signs of malignancy including lymphovascular or perineural invasion, or lymph node involvement.

Close relationship between mediators of inflammation and pancreatic cancer: Our experience.

In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance.

We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.

Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production.

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/ß-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.

18 F-FDG Uptake in Pancreatic AL Amyloidosis Associated With Multiple Myeloma.

ABSTRACT: A 60-year-old woman underwent whole-body contrast-enhanced CT because multiple myeloma was suspected. The contrast-enhanced CT showed pancreatic enlargement without main pancreatic duct dilatation and increased peripancreatic fat tissue. 18 F-FDG PET/CT demonstrated diffuse uptake in the enlargement of the pancreas, left and right ventricles, and vertebral column. Biopsy and bone marrow aspiration cytology revealed amyloid light-chain amyloidosis associated with multiple myeloma. Chemotherapy was performed; 18 F-FDG uptake in the pancreas then disappeared, and the pancreatic enlargement decreased. When diffuse 18 F-FDG uptake in pancreatic enlargement is observed in multiple myeloma patients, amyloid light-chain amyloidosis should be considered.

Pinocembrin's protective effect against acute pancreatitis in a rat model: The correlation between TLR4/NF-κB/NLRP3 and miR-34a-5p/SIRT1/Nrf2/HO-1 pathways.

BACKGROUND: Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury. METHODS: Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model. RESULTS: Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio. CONCLUSIONS: Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases.

The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment.

Mesenchymal Stem Cells from Mouse Hair Follicles Inhibit the Development of Type 1 Diabetes.

Mesenchymal stem cells (MSCs) are known for their immunosuppressive properties. Based on the demonstrated anti-inflammatory effect of mouse MSCs from hair follicles (moMSCORS) in a murine wound closure model, this study evaluates their potential for preventing type 1 diabetes (T1D) in C57BL/6 mice. T1D was induced in C57BL/6 mice by repeated low doses of streptozotocin. moMSCORS were injected intravenously on weekly basis. moMSCORS reduced T1D incidence, the insulitis stage, and preserved insulin production in treated animals. moMSCORS primarily exerted immunomodulatory effects by inhibiting CD4+ T cell proliferation and activation. Ex vivo analysis indicated that moMSCORS modified the cellular immune profile within pancreatic lymph nodes and pancreatic infiltrates by reducing the numbers of M1 pro-inflammatory macrophages and T helper 17 cells and upscaling the immunosuppressive T regulatory cells. The proportion of pathogenic insulin-specific CD4+ T cells was down-scaled in the lymph nodes, likely via soluble factors. The moMSCORS detected in the pancreatic infiltrates of treated mice presumably exerted the observed suppressive effect on CD4+ through direct contact. moMSCORS alleviated T1D symptoms in the mouse, qualifying as a candidate for therapeutic products by multiple advantages: non-invasive sampling by epilation, easy access, permanent availability, scalability, and benefits of auto-transplantation.

Hemorrhagic Cysts in the Pancreas: Risk Factors, Treatment, and Outcomes - Insights from a Single-Center Study.

BACKGROUND Hemorrhagic cysts are rarely discussed subtypes of pancreatic pseudocysts that occur in about 10% of these cases. They are caused by erosion of the walls of neighboring vessels by extravasated proteolytic pancreatic enzymes. A retrospective analysis was performed to clinically characterize risk factors, treatment, and outcome in patients with hemorrhagic cysts of the pancreas. MATERIAL AND METHODS The retrospective study included patients from the Department of Digestive Tract Surgery in Katowice, Poland, who were treated surgically for a pancreatic hemorrhagic cyst from January 2016 to November 2022. We gathered and assessed data on cyst etiology, symptoms, imaging examinations, risk factors, time, type, and complications of surgery. RESULTS The main symptom was abdominal pain, noted in 5 (62.5%) patients. The most common etiology of cyst was acute pancreatitis, which occurred in 5 patients (62.5%). The most common localization was the tail of pancreas, found in 3 patients (36.5%). The largest dimension of the cyst was 98±68 (30-200) mm. Every patient needed surgical intervention. Patients underwent distal pancreatectomy (n=3) or marsupialization (n=5). One (12.5%) postoperative complication was observed, while mortality was 0%. CONCLUSIONS Hemorrhagic cyst is a life-threatening complication of pancreatitis requiring immediate treatment. In most cases, open surgery is the treatment of choice. Despite the continuous development of minimally invasive techniques, surgical treatment remains the only effective treatment method. Depending on the cyst localization and technical possibilities, pancreatectomy or marsupialization can be applied, and both of them have low complication and mortality rates.

A Late Recurrent Metastatic Breast Cancer Mimicking Primary Pancreatic Cancer: Case Report.

Metastasis to the pancreas from malignant tumors is a rare event, representing only 1% to 2% of all pancreatic neoplasms. They occur in 2 different clinicopathological settings: as a manifestation in widespread metastatic disease or as an isolated mass in the pancreas. We report the case of a 41-year-old woman who had a history of invasive lobular breast cancer treated with radical surgery, chemotherapy, and radiotherapy. After 21 years of total remission, she presented for severe lower back pain with jaundice, nausea, and loss of 9 kg in 3 months. Abdominal computed tomography demonstrated a hyper vascularized, irregular solid lesion of 2.6 cm × 2.1 cm in the head of the pancreas with discreet biliary duct dilatation and coelio-mesenteric enlarged lymph nodes measuring 2 cm. The diagnosis of pancreatic metastasis from a lobular breast carcinoma was made by percutaneous biopsy of pancreatic lesion. The multidisciplinary committee decided a palliative treatment. The patient received chemotherapy. The take home message from his case is that we should keep in mind the hypothesis of a solitary metastasis to the pancreas, when the pancreatic lesion develops in a patient who had a clinical history of previous neoplasm especially in those which is known to potentially metastasize to pancreas.

Patients with advanced cancer were treated with immune checkpoint inhibitors and injected with COVID-19 vaccine to improve their prognosis without increasing pancreatic related adverse events.

To investigate immune checkpoint inhibitors (ICIs) induced pancreatic injury (ICIPI), the prognostic effect of COVID-19 vaccine on cancer patients, and whether COVID-19 vaccine increases the incidence of ICIPI. We conducted a retrospective study of 256 stage IV cancer patients treated with ICIs at The First Affiliated Hospital of Anhui Medical University from January 2020 to November 2022. Data collected included pancreatic enzyme levels, treatment outcomes, and vaccination status. Statistical significance was determined using the χ2 test and Kaplan-Meier method (p < .05). Compared to the control group, the vaccinated group (p < .0001) and the group with elevated pancreatic enzyme levels (p = .044) demonstrated higher disease control rates, indicating a direct benefit of vaccination and enzyme monitoring on treatment outcomes. Additionally, vaccinated patients demonstrated longer overall survival versus unvaccinated patients (23.9 months [95% CI, 22.3-25.5] vs 23.6 months [95% CI, 21.1-26.2], HR = 0.45 [95% CI, 0.24-0.86], p = .015) and progression-free survival (17.2 months [95% CI, 14.3-20.1] vs 13.7 months [95% CI, 11.3-16.1], HR = 0.54 [95% CI, 0.36-0.82], p = .004). Importantly, the analysis revealed no significant association between vaccination and pancreatic injury (p = .46). Monitoring pancreatic enzymes can effectively evaluate the therapeutic impact in patients using ICIs. Patients vaccinated against COVID-19 experience better immunotherapy outcomes without an increased risk of ICIPI.

Diagnostic Assessment of Endoscopic Ultrasonography-Fine Needle Aspiration Cytology in the Pancreas: A Comparison between Liquid-Based Preparation and Conventional Smear.

Background and Objectives: This study aimed to elucidate the cytologic characteristics and diagnostic usefulness of endoscopic ultrasonography-fine needle aspiration cytology (EUS-FNAC) by comparing it with liquid-based preparation (LBP) and conventional smear (CS) in pancreas. Methods: The diagnostic categories (I through VII) were classified according to the World Health Organization Reporting System for Pancreaticobiliary Cytopathology. Ten cytologic features, including nuclear and additional features, were evaluated in 53 cases subjected to EUS-FNAC. Nuclear features comprised irregular nuclear contours, nuclear enlargement, hypochromatic nuclei with parachromatin clearing, and nucleoli. Additional cellular features included isolated atypical cells, mucinous cytoplasm, drunken honeycomb architecture, mitosis, necrotic background, and cellularity. A decision tree analysis was conducted to assess diagnostic efficacy. Results: The diagnostic concordance rate between LBP and CS was 49.1% (26 out of 53 cases). No significant differences in nuclear features were observed between categories III (atypical), VI (suspicious for malignancy), and VII (malignant). The decision tree analysis of LBP indicated that cases with moderate or high cellularity and mitosis could be considered diagnostic for those exhibiting nuclear atypia. Furthermore, in CS, mitosis, isolated atypical cells, and necrotic background exerted a more significant impact on the diagnosis of EUS-FNAC. Conclusions: Significant parameters for interpreting EUS-FNAC may differ between LBP and CS. While nuclear atypia did not influence the diagnosis of categories III, VI, and VII, other cytopathologic features, such as cellularity, mitosis, and necrotic background, may present challenges in diagnosing EUS-FNAC.

Morin inhibits the activity of pancreatic lipase and adipogenesis.

Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.

Ginsenoside Rk1 Ameliorates ER Stress-Induced Apoptosis through Directly Activating IGF-1R in Mouse Pancreatic [Formula: see text]-Cells and Diabetic Pancreas.

Hyperglycemia induces chronic stresses, such as oxidative stress and endoplasmic reticulum (ER) stress, which can result in [Formula: see text]-cell dysfunction and development of Type 2 Diabetes Mellitus (T2DM). Ginsenoside Rk1 is a minor ginsenoside isolated from Ginseng. It has been shown to exert anti-cancer, anti-inflammatory, anti-oxidant, and neuroprotective effects; however, its effects on pancreatic cells in T2DM have never been studied. This study aims to examine the novel effects of Ginsenoside Rk1 on ER stress-induced apoptosis in a pancreatic [Formula: see text]-cell line MIN6 and HFD-induced diabetic pancreas, and their underlying mechanisms. We demonstrated that Ginsenoside Rk1 alleviated ER stress-induced apoptosis in MIN6 cells, which was accomplished by directly targeting and activating insulin-like growth factor 1 receptor (IGF-1R), thus activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Bcl-2-associated agonist of cell death (Bad)-B-cell lymphoma-2 (Bcl-2) pathway. This pathway was also confirmed in an HFD-induced diabetic pancreas. Meanwhile, the use of the IGF-1R inhibitor PQ401 abolished this anti-apoptotic effect, confirming the role of IGF-1R in mediating anti-apoptosis effects exerted by Ginsenoside Rk1. Besides, Ginsenoside Rk1 reduced pancreas weights and increased pancreatic insulin contents, suggesting that it could protect the pancreas from HFD-induced diabetes. Taken together, our study provided novel protective effects of Ginsenoside Rk1 on ER stress-induced [Formula: see text]-cell apoptosis and HFD-induced diabetic pancreases, as well as its direct target with IGF-1R, indicating that Ginsenoside Rk1 could be a potential drug for the treatment of T2DM.

The Incidental Pancreatic Cyst: When to Worry About Cancer.

Incidental pancreatic cystic lesions are a common challenge encountered by diagnostic radiologists. Specifically, given the prevalence of benign pancreatic cystic lesions, determining when to recommend aggressive actions such as surgical resection or endoscopic ultrasound with sampling is difficult. In this article, we review the common types of cystic pancreatic lesions including serous cystadenoma, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm with imaging examples of each. We also discuss high-risk or worrisome imaging features that warrant a referral to a surgeon or endoscopist and provid several examples of these features. These imaging features adhere to the latest guidelines from the International Consensus Guidelines, American Gastroenterological Association (2015), American College of Gastroenterology (2018), American College of Radiology (2010, 2017), and European Guidelines (2013, 2018). Our focused article addresses the imaging dilemma of managing incidental cystic pancreatic lesions, weighing the options between imaging follow-up and aggressive interventions.

Risk assessment for pancreatic fistula by intraoperative image analysis of laparoscopic and robotic gastrectomy.

BACKGROUND: Pancreatic fistula (PF) is one of the most serious postoperative complications of gastrectomy. Misidentification of the boundary between the pancreas and the dissected fat is a primary concern. In this study, we focused on differences in the appearance of the pancreas and the dissected fat in actual surgical images and statistically analyzed the relationship between the pancreas and the dissected fat. METHODS: We analyzed data from 109 gastric cancer patients who underwent curative gastrectomy between November 2018 and March 2023. Intraoperative images were taken from videos of lymph node dissections of Nos.6 and 8a regions, and the mean gray value of the areas was measured using ImageJ software for analysis. The visceral fat area (VFA) was evaluated by preoperative axial CT at the umbilical level using Ziostation software. RESULTS: A significant correlation was observed between the fat/pancreas gray value ratio in the No.8a lymph node region and the drain/serum amylase ratio (P < 0.001). The fat/pancreas gray value ratio in the No.6 lymph node region correlated with VFA (P < 0.001). The VFA and drain/serum amylase ratio were significantly higher in the group with intra-abdominal complications (P = 0.004). CONCLUSIONS: We revealed significant relationships between the fat/pancreas gray value ratio with drain/serum amylase and VFA. Detecting differences in gray values between the pancreas and the dissected fat may lead to a decrease in the drain/serum amylase ratio and PF.

Anti-Hyperglycemic Effect of the Brown Slime Cap Mushroom Chroogomphus rutilus (Agaricomycetes) Crude Polysaccharide In Vitro and In Vivo.

The prevalence of diabetes is increasing worldwide, and it is very important to study new hypoglycemic active substances. In this study, we investigated the hypoglycemic effect of Chroogomphus rutilus crude polysaccharide (CRCP) in HepG2 cells and streptozotocin-induced diabetic mice. A glucose consumption experiment conducted in HepG2 cells demonstrated the in vitro hypoglycemic activity of CRCP. Furthermore, CRCP exhibited significant hypoglycemic effects and effectively ameliorated insulin resistance in insulin resistant HepG2 cells. In high-fat diet and streptozotocin-induced diabetic mice, after 4 weeks of CRCP administration, fasting blood glucose, fasting serum insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glutamate transaminase, alanine transaminase, and insulin resistance index significantly decreased, while high-density lipoprotein cholesterol and insulin sensitivity index (ISI) were markedly increased. Moreover, hematoxylin-eosin (HE) staining and immunofluorescence labeling of tissue sections indicated that CRCP attenuated the pathological damage of liver and pancreas in diabetic mice. These results indicate that CRCP is a potential hypoglycemic agent.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.