Pancreatic Development Research Articles

KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.

Oncogenic mutations in KRAS are present in ~95% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) and are considered the initiating event of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. While it is well established that KRAS mutations drive the activation of oncogenic kinase cascades during pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (PP2A) has been implicated in suppressing KRAS-driven cellular transformation and low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of an endogenous inhibitor of PP2A activity, Cancerous Inhibitor of PP2A (CIP2A), and phosphorylation of the PP2A substrate, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56α, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation in vivo, knockout of B56α promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (ADM) and the formation of PanIN lesions. The process of ADM was attenuated ex vivo in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (SMAPs). Together, our results suggest that suppression of PP2A-B56α through KRAS signaling can promote the MYC-driven initiation of pancreatic tumorigenesis.

Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development.

The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic Kras expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell-BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.

Chronic late gestation fetal hyperglucagonaemia results in lower insulin secretion, pancreatic mass, islet area and beta- and α-cell proliferation.

Fetal glucagon concentrations are elevated in the presence of a compromised intrauterine environment, as in cases of placental insufficiency and perinatal acidaemia. Our objective was to investigate the impact of late gestation fetal hyperglucagonaemia on in vivo insulin secretion and pancreatic islet structure. Chronically catheterized late gestation fetal sheep received an intravenous infusion of glucagon at low (5ng/kg/min; GCG-5) or high (50ng/kg/min; GCG-50) concentrations or a vehicle control (CON) for 8-10days.Glucose-stimulated fetal insulin secretion (GSIS) was measured following 3h (acute response) and 8-10days (chronic response) of experimental infusions. Insulin, glucose and amino acid concentrations were measured longitudinally. The pancreas was collected at the study end for histology and gene expression analysis. Acute exposure (3h) to GCG-50 induced a 3-fold increase in basal insulin concentrations with greater GSIS. Meanwhile, chronic exposure to both GCG-5 and GCG-50 decreased basal insulin concentrations 2-fold by day 8-10. Chronic GCG-50 also blunted GSIS at the study end. Fetal amino acid concentrations were decreased within 24h of GCG-5 and GCG-50, while there were no differences in fetal glucose. Histologically, GCG-5 and GCG-50 had lower β- and α-cell proliferation, as well as lower α-cell mass and pancreas weight, while GCG-50 had lower islet area. This study demonstrates that chronic glucagon elevation in late gestation fetuses impairs β-cell proliferation and insulin secretion, which has the potential to contribute to later-life diabetes risk. We speculate that the action of glucagon in lower circulating fetal amino acid concentrations may have a suppressive effect on insulin secretion. KEY POINTS: We have previously demonstrated in a chronically catheterized fetal sheep model that experimentally elevated glucagon in the fetus impairs placental function, reduces fetal protein accretion and lowers fetal weight. In the present study, we further characterized the effects of elevated fetal glucagon on fetal physiology with a focus on pancreatic development and β-cell function. We show that experimentally elevated fetal glucagon results in lower β- and α-cell proliferation, as well as decreased insulin secretion after 8-10days of glucagon infusion. These results have important implications for β-cell reserve and later-life predisposition to diabetes.

Molecular Targets for the Diagnosis and Treatment of Pancreatic Cancer.

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer.

Tankyrase inhibition promotes endocrine commitment of hPSC-derived pancreatic progenitors

Human pluripotent stem cells (hPSCs) have the potential to differentiate into various cell types, including pancreatic insulin-producing β cells, which are crucial for developing therapies for diabetes. However, current methods for directing hPSC differentiation towards pancreatic β-like cells are often inefficient and produce cells that do not fully resemble the native counterparts. Here, we report that highly selective tankyrase inhibitors, such as WIKI4, significantly enhances pancreatic differentiation from hPSCs. Our results show that WIKI4 promotes the formation of pancreatic progenitors that give rise to islet-like cells with improved β-like cell frequencies and glucose responsiveness compared to our standard cultures. These findings not only advance our understanding of pancreatic development, but also provide a promising new tool for generating pancreatic cells for research and potential therapeutic applications.

8297 Risk Of Pancreatic Cancer In Patients With Diabetes Mellitus And Pancreatitis: A Nationwide Nested Case-Control Study

Abstract Disclosure: Y. Kim: None. H. Kim: None. M. Yu: None. C. Nam: None. E. Kang: None. Background: Despite diabetes mellitus and pancreatitis being known risk factors for pancreatic cancer, but because of their low incidence, patients with these conditions are not included in pancreatic cancer screening. This study aimed to determine the high-risk subgroup of patients with diabetes and pancreatitis that would benefit from pancreatic cancer screening. Methods: A nested case-control study was conducted using data from the national health information database of the Korean National Health Insurance Service. Patients were categorized into the following groups: type 2 diabetes only (T2D-only), pancreatitis only (PAN-only), type 2 diabetes followed by pancreatitis (T2D-PAN), post-pancreatitis DM (PPDM), and no diabetes and no pancreatitis (NDNP). Conditional logistic regression was used to determine significant associations of each group with pancreatic cancer development risk. Results: The risk of pancreatic cancer was significantly higher in the T2D-PAN (adjusted odds ratio [AOR], 4.96; 95% confidence interval [CI], 4.48-5.49) and PPDM (AOR, 4.71; 95% CI, 4.12-5.37) groups than in the NDNP group. Furthermore, the T2D-PAN and PPDM groups had a significantly higher risk of pancreatic cancer than the T2D-only and PAN-only groups. Compared to patients in the NDNP group, patients with PPDM using insulin had a 9-fold increased risk (AOR, 9.84; 95% CI, 6.77-14.29), and patients with T2D-PAN using insulin had a 6-fold increased risk (AOR, 6.62; 95% CI, 5.33-8.20). Conclusion: Patients with both diabetes and pancreatitis had a higher risk of pancreatic cancer than those with either alone, regardless of the order of occurrence, and insulin use was associated with an additional increase in pancreatic cancer risk. These results suggest that these subgroups of patients could be considered to benefit from pancreatic cancer screening. Presentation: 6/2/2024

Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

S2661 A Case of Pancreatic Neuroendocrine Tumor Recurrence and Development of Type 3c diabetes

S2661 A Case of Pancreatic Neuroendocrine Tumor Recurrence and Development of Type 3c diabetes

OSBPL10-CNBP axis mediates hypoxia-induced pancreatic cancer development.

Pancreatic ductal adenocarcinoma (PDAC) is one of malignancies with worst outcomes among digestive system tumors. Identification of novel biomarkers is of great significance for treatment researchesand prognosis prediction of pancreatic cancer patients. Due to OSBPL10 known involvement in oncogenic activity in other tumors, we elucidated the mechanism underlying its contribution to pancreatic cancer progression. We employed data from the Gene Expression Omnibus database to detect the expression of OSBPL10 in normal and pancreatic cancer tissues. A series of assays were conducted to assess the impact of OSBPL10 on the proliferation and metastatic capacities of pancreatic cancer cells and the influence of OSBPL10 on macrophages were evaluated by Flow cytometry. In addition, Co-immunoprecipitation, mass spectrometry, and western blot assays were utilized to investigate the potential mechanisms of OSBPL10 activity. From our study, OSBPL10 is revealed to be upregulated in pancreatic cancer, with poor prognosis. The overexpression promotes malignant behaviors of pancreatic cancer cells and has an impact on tumor immune microenvironment by stimulating the transformation M1 macrophages into M2 macrophages. Mechanistically, hypoxia induces the expression of OSBPL10 through interaction between hypoxia-inducible factor 1-α and the promoter region of OSBPL10. Additionally, OSBPL10 directly bound to CNBP, mediating CNBP expression and ultimately regulating the proliferation and metastasis capacity of pancreatic cancer cells, as well as influencing macrophage polarization. The research emphasized the oncogenic role of OSBPL10 in pancreatic cancer, uncovering key mechanisms involving hypoxia, HIF-1α, and CNBP. The finding suggests that OSBPL10 is a novel biomarker in pancreatic cancer, making it a potential therapeutic target for intervention in this malignancy.

The Clinical Significance of Pancreatic Steatosis in Pancreatic Cancer: A Hospital-Based Study.

Background/Objectives: Pancreatic cancer remains one of the deadliest malignancies worldwide with a pressing need for early detection and intervention strategies. Emerging evidence has suggested a potential link between pancreas steatosis, characterized by excessive pancreatic fat accumulation, and an increased risk of pancreatic cancer development. This retrospective imaging study aims to elucidate the association between pancreatic steatosis and the subsequent development of pancreatic cancer. In the study, we aimed to determine the characteristics of pancreatic cancer with pancreatic steatosis. Methods: During the period of January 2022 to December 2022, we conducted a retrospective study, collecting 101 newly diagnosed pancreas cancer cases from the available image datasets. A comprehensive database of retrospective abdominal imaging studies, comprising computed tomography (CT) and magnetic resonance imaging (MRI), was established from a diverse patient population and subsequently analyzed. Inclusion criteria encompassed patients having available baseline imaging data, allowing for the assessment of pancreatic fat content. Pancreatic fat content was quantified using validated radiological techniques, while demographic, clinical, and histopathological data were all collected. The clinical data and patient characteristics were collected from medical records and analyzed. Results: Preliminary analysis revealed a significant correlation between elevated pancreatic fat content and an increased incidence of subsequent pancreatic cancer. Moreover, subgroup analysis based on age, gender, and comorbidities provided valuable insight into potential risk factors associated with this progression. Additionally, the study identified novel radiological markers that may serve as early indicators of pancreatic cancer development in individuals with pancreatic steatosis. Conclusions: In the imaging study, approximately 30% (30/101) of pancreatic cancer patients presented with pancreatic steatosis. Chronic pancreatitis emerged as the primary factor contributing to pancreatic steatosis in these patients. Importantly, pancreatic steatosis did not significantly impact the prognosis of pancreatic cancer. Follow-up data revealed no significant differences in survival duration between patients with or without pancreatic steatosis. Additionally, no association was found between pancreatic steatosis and hepatic steatosis.

The effect of intrauterine growth restriction on the developing pancreatic immune system.

Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the pancreatic islets and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

Elevated HbA1c Levels Are Associated with a Risk of Pancreatic Cancer: A Case-Control Study.

Background: The early diagnosis of pancreatic cancer (ICD-10 C25) can improve the patient's prognosis. The association between pancreatic cancer and type 2 diabetes (T2D) is known, but not yet fully understood. It is, therefore, necessary to investigate the impact of hemoglobin A1c (HbA1c) serum levels on pancreatic cancer development and the potential intervention options. Methods: In the case-control study, patients from the German IQVIATM Disease Analyzer database aged ≥18 years with a diagnosis of pancreatic cancer (ICD-10 C25) and a diagnosis of T2D (ICD-10: E11) were included. The patients' propensity score matched 1:5 with individuals without pancreatic cancer. Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). Results: An elevated serum HbA1c prior to the index date was found to be significantly associated with an increased risk of a subsequent pancreatic cancer diagnosis for the mean HbA1c values of 6.5-8.4% (OR: 1.38; 95% CI: 1.22-1.57) as well as for mean HbA1c values ≥8.5% (OR: 1.41; 95% CI: 1.16-1.73). The only antihyperglycemic agent negatively associated with the subsequent pancreatic cancer diagnosis was the sodium-glucose cotransporter-2 (SGLT-2) inhibitor, with an odds ratio of 0.80 (95% confidence interval: 0.74-0.87 per year of therapy). This correlation was observed in both age- and sex-stratified subgroups. Conclusions: The data indicate that elevated serum HbA1c levels in patients with T2D are associated with an increased risk of pancreatic cancer development. It is possible that SGLT2 therapy may prove an effective means of reducing the risk of pancreatic cancer, thereby offering a potential avenue for the future reduction in pancreatic cancer incidence in patients with T2D.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p

BackgroundCancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth.Methodstwenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence.ResultsWestern blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics.ConclusionOur results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

Indocyanine green fluorescence in the evaluation of post-resection pancreatic remnant perfusion after a pancreaticoduodenectomy: a clinical study protocol

BackgroundPancreaticoduodenectomy is associated with an incidence of postoperative complications of approximately 41%. One of the most severe complications is a postoperative pancreatic fistula. The exact cause of postoperative fistula development is still unknown, but it appears to be multifactorial. Proper perfusion of pancreatic remnant is essential for the healing of pancreaticojejunostomy. To date, there is no method to reliably evaluate the vascular supply of the remnant. One of the methods for the assessment of organ perfusion is the indocyanine green fluorescence. This study aims to determine if indocyanine green fluorescence is a reliable method to measure the perfusion of the post-resection pancreatic remnant. The secondary outcome is to determine if intraoperative evaluation of the vascular supply of the post-resection remnant may predict the increased risk of postoperative pancreatic fistula development.MethodsThis study is designed as a prospective, observational study. All consecutive patients undergoing open or robotic pancreaticoduodenectomies at our department during the 1st May 2024-31st December 2026 period will be enrolled. The exclusion criteria are an allergy to indocyanine green and refusal by the patient. The adequacy of the vascular supply of the post-resection pancreatic remnant will be intraoperatively evaluated using a fluorescence detector. Patients will be divided into two groups: Those with high risk of pancreatic fistula development and those with low risk. The incidence of pancreatic fistulas in both groups is to be compared. Postoperative data including morbidity, mortality, hospital stay, intensive care unit stay and postoperative fistula development will be collected.DiscussionIf an intraoperative assessment of the perfusion of post-resection pancreatic remnant using indocyanine green is proven to be a suitable method to estimate the increased risk of the pancreatic fistula, the list of the existing known risk factors could be expanded. In the most high-risk patients the modification of the surgical procedure could be considered.Trial registrationNumber: NCT06198400 ClinicalTrials.Gov. Date 08.01.2024.

The Impact of Sugar Control on Pancreatic Cancer Progression for the Elderly

Pancreatic cancer is a type of cancer that originates in the pancreas, an organ that aids in digestion and blood sugar regulation. It is characterized as an aggressive type of cancer that presents with symptoms that often go undetected. In 2024, there were an estimated 66,440 new cases of pancreatic cancer and an estimated 51,170 deaths from pancreatic cancer, with a 5-year relative survival rate of 12.8% (SEER, 2023). While traditional medical interventions such as surgery and chemotherapy continue to be the cornerstone of treatment, there is an emerging focus on the potential impact of dietary and nutritional factors in both preventing and managing pancreatic cancer. This approach is particularly relevant for elderly patients due to the heightened risk associated with surgery at their age and their reduced tolerance to chemotherapy regimens. This paper presents a compelling case study of a pancreatic cancer patient who adopted a sugar-restricted diet, resulting in a notable decrease in the tumor marker CA 19-9, which is commonly associated with pancreatic cancer. Building on this individual case study, this paper provides a comprehensive review of current scientific literature to examine the potential relationship between sugar consumption and pancreatic cancer development and progression. By examining this intersection of nutrition and oncology, this study aims to expound upon possible alternative or complementary approaches to pancreatic cancer management, especially for vulnerable populations such as the elderly. This research could lead to new strategies for improving outcomes and quality of life in pancreatic cancer care.

From iPSCs to Pancreatic β Cells: Unveiling Molecular Pathways and Enhancements with Vitamin C and Retinoic Acid in Diabetes Research.

Diabetes mellitus, a chronic and non-transmissible disease, triggers a wide range of micro- and macrovascular complications. The differentiation of pancreatic β-like cells (PβLCs) from induced pluripotent stem cells (iPSCs) offers a promising avenue for regenerative medicine aimed at treating diabetes. Current differentiation protocols strive to emulate pancreatic embryonic development by utilizing cytokines and small molecules at specific doses to activate and inhibit distinct molecular signaling pathways, directing the differentiation of iPSCs into pancreatic β cells. Despite significant progress and improved protocols, the full spectrum of molecular signaling pathways governing pancreatic development and the physiological characteristics of the differentiated cells are not yet fully understood. Here, we report a specific combination of cofactors and small molecules that successfully differentiate iPSCs into PβLCs. Our protocol has shown to be effective, with the resulting cells exhibiting key functional properties of pancreatic β cells, including the expression of crucial molecular markers (pdx1, nkx6.1, ngn3) and the capability to secrete insulin in response to glucose. Furthermore, the addition of vitamin C and retinoic acid in the final stages of differentiation led to the overexpression of specific β cell genes.

Turning to immunosuppressive tumors: Deciphering the immunosenescence-related microenvironment and prognostic characteristics in pancreatic cancer, in which GLUT1 contributes to gemcitabine resistance

Increasing evidence indicates that the remodeling of immune microenvironment heterogeneity influences pancreatic cancer development, as well as sensitivity to chemotherapy and immunotherapy. However, a gap remains in the exploration of the immunosenescence microenvironment in pancreatic cancer. In this study, we identified two immunosenescence-associated isoforms (IMSP1 and IMSP2), with consequential differences in prognosis and immune cell infiltration. We constructed the MLIRS score, a hazard score system with robust prognostic performance (area under the curve, AUC = 0.91), based on multiple machine learning algorithms (101 cross-validation methods). Patients in the high MLIRS score group had worse prognosis (P < 0.0001) and lower abundance of immune cell infiltration. Conversely, the low MLIRS score group showed better sensitivity to chemotherapy and immunotherapy. Additionally, our MLIRS system outperformed 68 other published signatures. We identified the immunosenescence microenvironmental windsock GLUT1 with certain co-expression properties with immunosenescence markers. We further demonstrated its positive modulation ability of proliferation, migration, and gemcitabine resistance in pancreatic cancer cells. To conclude, our study focused on training of composite machine learning algorithms in multiple datasets to develop a robust machine learning modeling system based on immunosenescence and to identify an immunosenescence-related microenvironment windsock, providing direction and guidance for clinical prediction and application.

Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review.

Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.

ПЕРФУЗИОННАЯ КОМПЬЮТЕРНАЯ ТОМОГРАФИЯ – НОВЫЕ ГОРИЗОНТЫ В ДИАГНОСТИКЕ ЗАБОЛЕВАНИЙ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ

Abstract. Introduction. According to the World Health Organization, the most common disease of the pancreas is acute pancreatitis, which can lead to the development of pancreatic necrosis. In this regard, early diagnosis and assessment of the pancreatic necrosis risk development are of paramount importance for choosing adequate treatment approaches and improving outcomes for patients. Radiological research methods have become the “gold” standard in clinical practice for the primary diagnosis of pancreatic diseases. Contrast-enhanced computed tomography has traditionally been used to visualize the pancreas and assess the extent of inflammation and necrotic changes. However, standard computed tomography has limitations in assessing tissue perfusion, which is an important aspect of the pathophysiology of acute pancreatitis. Perfusion computed tomography of the pancreas has become a colossal breakthrough in radiation imaging, has become widespread as a method that allows the quantitative assessment of blood supply to the pancreas, including information about microcirculation, and it can be used for the early detection of ischemic changes that precede tissue necrosis in the pancreas. Aim. To study the capabilities of perfusion computed tomography and computed tomography angiography of the pancreas for evaluating the area of pancreatic necrosis in acute pancreatitis, with the aim of improving diagnosis and planning treatment measures to minimize the consequences and increase patient survival. Materials and Methods. A single-center examination was carried out on 42 patients (18 women, 24 men, mean age 38±2 years) with suspected acute pancreatitis. All patients underwent perfusion computed tomography within the first 3 days; over the next 3-5 days, computed tomography angiography of the pancreas was performed with bolus intravenous contrast to confirm the development of necrotic changes. Results and Discussion. After performing perfusion computed tomography within the first 3 days from the onset of symptoms, areas of ischemic damage to the pancreas tissue were identified in 16 (38.1%) out of 42 patients. After computed tomography angiography, the development of necrotic changes was confirmed in 7 patients (16.7%). The localization of the necrosis zone detected in computed tomography coincided with the ischemic zones on the color hemodynamic maps of perfusion computed tomography.

Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+ progenitors.

Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6. We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs). RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets. These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes. RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 ).