Pancreatic ductal adenocarcinoma (PDAC) presents a unique challenge for researchers due to its late diagnosis caused by vague symptoms and lack of early detection markers. Additionally, PDAC is characterized by an immunosuppressive microenvironment (TME), making it a difficult tumor to treat. While γδ T cells have shown potential for anti-tumor activity, conflicting studies exist regarding their effectiveness in pancreatic cancer. This study aims to explore the hypothesis that the PDAC TME hinders the anti-tumor capabilities of γδ T cells through blockade of cytotoxic functions. For this reason, we chose to enroll PDAC treatment-naive patients to avoid the possibility of therapy modifying the TME. By flow cytometry, our research findings indicate that the presence of γδ T cells among CD45+ cells in tumor tissue is lower compared to CD66+ cells, but higher than in blood. Circulating Vδ1 T cells exhibit a terminal effector memory phenotype (TEMRA) more than Vδ2 T cells. Interestingly, Vδ1 and Vδ2 T cells appear to be more prevalent at different stages of tumor development. In our in vitro culture using conditioned medium derived from Patient-derived organoids ;(PDOs), we observed a shift in expression markers in γδ T cells of healthy individuals toward an activation and exhaustion phenotype, as confirmed by scRNA-seq analysis extracted from a public database. A deeper understanding of γδ T cells in PDAC could be valuable for developing novel therapies aimed at mitigating the impact of the pancreatic tumor microenvironment on this cell population.

Drosophila melanogaster is a highly versatile model organism that has profoundly advanced our understanding of human diseases. With more than 60% of its genes having human homologs, Drosophila provides an invaluable system for modelling a wide range of pathologies, including neurodegenerative disorders, cancer, metabolic diseases, as well as cardiac and muscular conditions. This review highlights key developments in utilizing Drosophila for disease modelling, emphasizing the genetic tools that have transformed research in this field. Technologies such as the GAL4/UAS system, RNA interference (RNAi) and CRISPR-Cas9 have enabled precise genetic manipulation, with CRISPR-Cas9 allowing for the introduction of human disease mutations into orthologous Drosophila genes. These approaches have yielded critical insights into disease mechanisms, identified novel therapeutic targets and facilitated both drug screening and toxicological studies. Articles were selected based on their relevance, impact and contribution to the field, with a particular focus on studies offering innovative perspectives on disease mechanisms or therapeutic strategies. Our findings emphasize the central role of Drosophila in studying complex human diseases, underscoring its genetic similarities to humans and its effectiveness in modelling conditions such as Alzheimer's disease, Parkinson's disease and cancer. This review reaffirms Drosophila's critical role as a model organism, highlighting its potential to drive future research and therapeutic advancements.

The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor SRSF12 as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed Kras mutation and Srsf12 knockout mice (KrasG12DSrsf12 fl/fl) together with Srsf12 fl/flPdx1cre mice and found that depletion of Srsf12 accelerated Kras-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.

We aimed to estimate the incidence and to assess the risk factors associated with pancreatic cancer (PC) in people with HIV (PWH).

We used electronic medical record data from 2009 to 2020 available in the COREVIH Ile-de-France-Est database of PWH treated in Paris public hospitals.

We analyzed data on patient demographics, treatment history, and immunovirologic status. A case-control study was designed; each case (PWH and PC) was matched on age, gender, and duration of HIV infection to 4 controls (PWH without PC).

Twenty-four cases were identified from the database, with an incidence of PC estimated at 28 cases (95% confidence interval: 19 to 43) per 100,000 person-years. The median age was 57 years [interquartile range (IQR) 51-68] at cancer diagnosis. Twenty-one cases (88%) were male. The median CD4 + T-cell count at PC diagnosis was 587/mm 3 (IQR 317-748), and the nadir CD4 + T-cell count was 194 (IQR 98-380). Twenty cases (91%) had a suppressed HIV replication at PC diagnosis. Twelve patients (50%) had metastasis on diagnosis. The median time to death after cancer diagnosis was 11 months (IQR 1-19). Twenty-two cases were matched with 88 controls. There were no statistically significant risk factors of PC identified in our analysis.

PC remains rare in PWH and is associated with a severe prognosis at a relatively young age. Further studies are needed to identify risk factors associated with PC development in PWH.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited early diagnostic methods and therapeutic options, contributing to its poor prognosis. Recent advances in high-throughput sequencing have highlighted the critical roles of noncoding RNAs (ncRNAs), particularly PIWI-interacting RNAs (piRNAs), in cancer biology. In this review, we systematically summarize the emerging roles of piRNAs and their associated PIWI proteins in PDAC pathogenesis, progression, and prognosis. We provide a comprehensive analysis of the molecular mechanisms by which piRNAs/PIWIs regulate gene expression and cellular signaling pathways in PDAC. Furthermore, we discuss their potential as novel biomarkers for early diagnosis and therapeutic targets. Importantly, this review identifies key piRNAs/PIWIs involved in PDAC and proposes innovative strategies for improving diagnosis and treatment outcomes. Our work not only consolidates current knowledge but also offers new perspectives for future research and clinical applications in PDAC management.

Early detection is crucial for improving survival rates of pancreatic ductal adenocarcinoma (PDA), yet current diagnostic methods can often fail at this stage. Recently, there has been significant interest in improving risk stratification and developing imaging biomarkers, through novel imaging techniques, and most notably, artificial intelligence (AI) technology. This review provides an overview of these advancements, with a focus on deep learning methods for early detection of PDA.

Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN inhibition, paralleled the sensitivity of PDAC cells to the apoptotic effects of TVB FASNis in conventional PDAC cell lines that naturally express varying levels of FASN. FASN inhibition dramatically increased the sensitivity of "FASN-high" expressing PDAC cells to the BCL2/BCL-XL/BCL-W inhibitor ABT-263/navitoclax and the BCL2-selective inhibitor ABT-199/venetoclax, both in vitro and in in vivo xenografted tumors. The ability of TVB FASNis to shift the balance of pro- and anti-apoptotic proteins and thereby push PDAC cells closer to the apoptotic threshold was also observed in cell lines developed from patient-derived xenografts (PDXs) representative of the classical (pancreatic) transcriptomic subtype of PDAC. Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.

Modern pancreatic surgery has gradually changed with the introduction of neoadjuvant therapy. For patients with pancreatic cancer involving peripancreatic visceral arteries who have received neoadjuvant therapy, periarterial divestment has gradually gained popularity, which represents an alternative to arterial resection. There is ongoing debate about whether this approach achieves curative tumor resection comparable to that of arterial resection, and the differences in terms of postoperative complications and oncologic outcomes between the 2 surgical procedures.

We retrospectively analyzed the perioperative and survival outcomes of locally advanced pancreatic cancer patients with celiac axis invasion who underwent distal pancreatectomy in our center from December 2016 to March 2023.

Ninety-five patients underwent neoadjuvant therapy as a priority after diagnosis, among whom 42.1% (n = 40) underwent distal pancreatectomy with celiac axis periarterial divestment, whereas 57.9% (n = 55) underwent distal pancreatectomy with en bloc celiac axis resection. Distal pancreatectomy with celiac axis periarterial divestment showed lower rates of postoperative pancreatic fistula, intraabdominal infection, and postoperative hepatic ischemia compared with distal pancreatectomy with en bloc celiac axis resection, with no significant differences in R0 resection rate, postoperative tumor recurrence, and survival. Furthermore, 46 patients diagnosed with locally advanced pancreatic cancer involving the celiac axis underwent upfront surgery of distal pancreatectomy with en bloc celiac axis resection without neoadjuvant therapy. Neoadjuvant therapy patients exhibited significant advantages in terms of tumor pathologic outcomes and survival compared with those undergoing upfront surgery of distal pancreatectomy with en bloc celiac axis resection.

After neoadjuvant therapy, distal pancreatectomy with celiac axis periarterial divestment in locally advanced pancreatic cancer patients with celiac axis invasion is deemed safe and feasible on the basis of adequate imaging evaluation combined with intraoperative judgment of the surgeons. This technique is recommended to be performed at high-volume pancreatic centers by experienced surgeons.

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable health challenge due to its detection at a late stage and a lack of reliable biomarkers for early detection. Although levels of carbohydrate antigen 19-9 are often used in conjunction with imaging-based tests to aid in the diagnosis of PDAC, there is still a need for more sensitive and specific biomarkers for early detection of PDAC.

We obtained serum samples from 88 subjects (patients with PDAC (n = 58) and controls (n = 30)). We carried out a multi-omics analysis to measure cytokines and related proteins using proximity extension technology and lipidomics and metabolomics using tandem mass spectrometry. Statistical analysis was carried out to find molecular alterations in patients with PDAC and a machine learning model was used to derive a molecular signature of PDAC.

We quantified 1,462 circulatory proteins along with 873 lipids and 1,001 metabolites. A total of 505 proteins, 186 metabolites and 33 lipids including bone marrow stromal antigen 2 (BST2), keratin 18 (KRT18), and cholesteryl ester(20:5) were found to be significantly altered in patients. We identified different levels of sphingosine, sphinganine, urobilinogen and lactose indicating that glycosphingolipid and galactose metabolisms were significantly altered in patients compared to controls. In addition, elevated levels of diacylglycerols and decreased cholesteryl esters were observed in patients. Using a machine learning model, we identified a signature of 38 biomarkers for PDAC, composed of 21 proteins, 4 lipids, and 13 metabolites.

Overall, this study identified several proteins, metabolites and lipids involved in various pathways including cholesterol and lipid metabolism to be changing in patients. In addition, we discovered a multi-analyte signature that could be further tested for detection of PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Mac2-binding protein glycosylated isomer (M2BPGi), a known biomarker for liver fibrosis, is also elevated in other fibrotic tissues. However, its role in PDAC remains unexplored. This study investigates the potential of M2BPGi as a prognostic biomarker for PDAC and elucidates its role in cancer progression.

We analyzed serum M2BPGi levels in 83 PDAC patients and 60 healthy controls, examining the relationship with clinical outcomes. Tissue immunostaining and in vitro experiments were conducted to investigate M2BPGi-secreting cells and its role.

Serum M2BPGi levels were significantly higher in PDAC patients than in controls (0.98 vs. 0.59, p < 0.0001). Notably, elevated serum M2BPGi was associated with worse progression-free survival (144 days vs. 260 days, p = 0.017) and overall survival (OS) (245 days vs. 541 days, p < 0.001) following chemotherapy. Multivariable Cox regression analysis further confirmed that a high serum M2BPGi level is an independent risk factor for OS (HR: 2.44, 95% CI 1.26-4.74, p = 0.008). Immunostaining revealed that M2BPGi is secreted by both cancer cells and cancer-associated fibroblasts (CAFs), with high M2BP expression in CAFs correlating with poor prognosis. Furthermore, M2BPGi-secreting CAFs exhibited characteristics of inflammatory CAFs. M2BPGi directly activated mTOR signaling and epithelial-mesenchymal transition in PDAC cells, enhancing their invasive and migratory capabilities.

Our findings identify M2BPGi as a promising prognostic biomarker for PDAC. Moreover, we demonstrate that inflammatory CAFs promote tumor invasion and contribute to poor outcomes by secreting M2BPGi, revealing a novel mechanism of PDAC progression.

Serine peptidase inhibitor, Kazal type 1 (SPINK1), a 56-amino-acid protein in its mature form, was among the first pancreatic enzymes to be extensively characterized biochemically and functionally. Synthesized primarily in pancreatic acinar cells and traditionally known as pancreatic secretory trypsin inhibitor, SPINK1 protects the pancreas by inhibiting prematurely activated trypsin. Since 2000, interest in SPINK1 has resurged following the discovery of genetic variants linked to chronic pancreatitis (CP). This review provides a historical overview of SPINK1's discovery, function, and gene structure before examining key genetic findings. We highlight three variants with well-characterized pathogenic mechanisms: c.-4141G > T, a causative enhancer variant linked to the extensively studied p.Asn34Ser (c.101A > G), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module; c.194 + 2T > C, a canonical 5' splice site GT > GC variant that retains 10% of wild-type transcript production; and an Alu insertion in the 3'-untranslated region, which causes complete loss of function by forming extended double-stranded RNA structures with pre-existing Alu elements in deep intronic regions. We emphasize the integration of a full-length gene splicing assay (FLGSA) with SpliceAI's predictive capabilities, establishing SPINK1 the first disease gene for which the splicing impact of all possible coding variants was prospectively determined. Findings from both mouse models and genetic association studies support the sentinel acute pancreatitis event (SAPE) model, which explains the progression from acute pancreatitis to CP. Additionally, SPINK1 variants may contribute to an increased risk of pancreatic ductal adenocarcinoma (PDAC). Finally, we discuss the therapeutic potential of SPINK1, particularly through adeno-associated virus type 8 (AAV8)-mediated overexpression of SPINK1 as a strategy for treating and preventing pancreatitis, and highlight key areas for future research.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and highly aggressive, often leading to poor patient prognosis. Existing serum biomarkers like CA19-9 are limited in early diagnosis, failing to meet clinical needs. Machine learning (ML)/deep learning (DL) technologies have shown great potential in biomedicine. This study aims to establish PDAC differential diagnosis and prognosis assessment models using ML combined with serum biomarkers for early diagnosis, risk stratification, and personalized treatment recommendations, improving early diagnosis rates and patient survival.

The study included serum biomarker data and prognosis information from 117 PDAC patients. ML models (Random Forest (RF), Neural Network (NNET), Support Vector Machine (SVM), and Gradient Boosting Machine (GBM)) were used for differential diagnosis, evaluated by accuracy, Kappa test, ROC curve, sensitivity, and specificity. COX proportional hazards model and DeepSurv DL model predicted survival risk, compared by C-index and Log-rank test. Based on DeepSurv's risk predictions, personalized treatment recommendations were made and their effectiveness assessed.

Effective PDAC diagnosis and prognosis models were built using ML. The validation set data shows that the accuracy of the RF, NNET, SVM, and GBM models are 84.21%, 84.21%, 76.97%, and 83.55%; the sensitivity are 91.26%, 90.29%, 89.32%, and 88.35%; and the specificity are 69.39%, 71.43%, 51.02%, and 73.47%. The Kappa values are 0.6266, 0.6307, 0.4336, and 0.6215; and the AUC are 0.889, 0.8488, 0.8488, and 0.8704, respectively. BCAT1, AMY, and CA12-5 were selected as modeling parameters for the prognosis model using COX regression. DeepSurv outperformed the COX model on both training and validation sets, with C-indexes of 0.738 and 0.724, respectively. The Kaplan-Meier survival curves indicate that personalized treatment recommendations based on DeepSurv can help patients achieve survival benefits.

This study built efficient PDAC diagnosis and prognosis models using ML, improving early diagnosis rates and prognosis accuracy. The DeepSurv model excelled in prognosis prediction and successfully guided personalized treatment recommendations and supporting PDAC clinical management.

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to its desmoplastic reaction, which impedes therapeutic effectiveness, highlighting the need for advanced vitro models to better mimic the complex tumor environment. The current three-dimensional co-culture models of fibroblasts and endothelial cells are lacking, which presents a challenge for performing more comprehensive in vitro research. Our study developed triple co-culture spheroid models using MiaPaCa-2 and BxPC-3 cancer cell lines, with RLT-PSC and hPSC21 pancreatic stellate cell lines and the endothelial cell line HMEC-1. These models were assessed through growth assays, multicolor flow cytometry to optimize cell ratios, cell viability assays to evaluate drug responses, and a tube formation assay with a spheroid-conditioned medium to examine angiogenesis. Our triple co-culture spheroids effectively replicate the PDAC microenvironment, showing significant variations in drug responses influenced by cellular composition, density, and spatial arrangement. The tube formation assay showcased the potential of our models to quantitatively assess a treatment-induced angiogenic response. These cost-effective triple-co-culture in vitro spheroid models provide vital insights into the PDAC microenvironment, significantly improving the quality of the in vitro evaluation of treatment responses.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

Liver cancer, specifically hepatocellular carcinoma (LIHC), ranks as the second most common cause of cancer-related fatalities globally. Moreover, the occurrence rate of LIHC is steadily increasing. A recently identified gene, SPSB2, has been implicated in cell signaling, impacting the development and progression of non-small cell lung cancer. Nevertheless, studies on the role of SPSB2 in the pathogenesis of LIHC are lacking.

Using the TCGA, GTEx, and GEO databases, we obtained differentially expressed genes that affect the prognosis of patients with LIHC. We utilized the Kruskal-Wallis test, along with univariate and multivariate COX regression analyses, to determine the correlation between SPSB2 and patient clinical indicators. Potential biological functions of SPSB2 in LIHC were explored by enrichment analysis, ssGSEA, and Spearman correlation analysis. Finally, LIHC cell lines Huh7 and SMMC-7721 were used to validate the biological function of SPSB2.

The results showed LIHC patients with higher SPSB2 expression had a poorer prognosis, and SPSB2 expression was significantly correlated with LIHC patients' Histologic grade, Pathologic T stage, Prothrombin time, Pathologic stage, BMI, weight, adjacent hepatic tissue inflammation, AFP level, and OS event (p < 0.05). SPSB2 shows notable enrichment in pathways linked to tumorigenesis and the immune system. Moreover, its expression is strongly connected to immune cells and immune checkpoints. Knockdown of SPSB2 expression in Huh7 cells and SMMC-7721 cells inhibits SPSB2's biological functions, including proliferation, invasion, metastasis, and other phenotypes.

SPSB2 plays a crucial role in the development of LIHC. It is related to the immune response and unfavorable outcomes. SPSB2 may function as a clinical biomarker for prognosis.

S. glabra has been widely used to treat tumors in traditional Chinese medicine (TCM). However, the specific mechanism of action of S. glabra in pancreatic cancer remains unclear. In this study, network pharmacological analysis was used to identify the active components of S. glabra and their corresponding targets for the treatment of pancreatic cancer. Furthermore, molecular docking, molecular dynamic simulations, and in vitro experiments were performed to validate the findings.

The active components of S. glabra and their corresponding targets for the treatment of pancreatic cancer were identified using the TCMSP database and a literature search. Differentially expressed genes were identified using data from the Gene Expression Omnibus (GEO) database, and their protein-protein interaction (PPI) network was constructed using the STRING platform. The target genes of S. glabra were further assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in the R software. Subsequently, a protein-protein interaction (PPI) network and a composite target-pathway network were established. The target genes were subjected to survival and mutation analyses. Molecular docking and molecular dynamic simulations were used to validate the interaction between the hub target genes and S. glabra in vitro. In addition, cell viability and qRT-PCR verification of S. glabra against pancreatic cancer in vitro.

A total of 20 active components and 70 targets were identified. Based on the PPI network, CASP3, MMP9, CCND1, EGF, MMP2, CASP8, ERBB2, STAT1, and PPARG were identified as hub target genes. Enrichment analysis showed that S. glabra may primarily affect pathways such as p53 signaling, transcriptional dysregulation in cancer, proteoglycans in cancer, pancreatic cancer, and cell cycle. Molecular docking and molecular dynamic simulations indicated stable binding between anhydroicaritin-GSK3B and quercetin-PPARG. In vitro experiments demonstrated that treatment with S. glabra significantly inhibited the growth of PANC-1 cells and downregulated expression of GSK3B and PPARG (P < 0.05).

This study demonstrates the potential of S. glabra, a herb in traditional Chinese medicine, for treating pancreatic cancer. The findings provide insights into the mechanism of action of the active ingredients of S. glabra, offering a strong theoretical foundation for its various clinical applications.

Not applicable.

Many elderly patients with pancreatic cancer (PC) often have liver metastasis (LM), and these patients often have poor prognosis and early death (ED). However, few models can accurately predict ED from elderly PC patients with LM. Therefore, we aim to create nomograms to predict ED in elderly PC patients with LM.

All elderly (≥ 60 years old) PC patients with LM from 2010 to 2020 were downloaded from the Surveillance, Epidemiology, and End Result (SEER) database according to the admission criteria. The included data was randomly divided into the training set and the validation set, with a ratio of 7:3. The risk factors for ED in elderly PC patients with LM were determined by univariate and multivariate logistic regression methods, and a nomogram model was established. Lastly, the nomogram is verified by the receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration curve, and decision curve analysis (DCA).

A total of 1,424 elderly PC patients with LM were randomly divided into training set (n = 996) and validation set (n = 428) based on the ratio of 7:3. The independent prognostic factors for ED include T stage, N stage, surgery, chemotherapy, lung metastasis, and other metastases. These variables were used to create nomograms, where the AUC of the training set and the validation set were 0.83 (95% CI 0.80-0.85) and 0.81 (95% CI 0.77-0.85), respectively. Furthermore, the calibration curve shows that the predicted ED is in good agreement with the actual value. DCA also shows good clinical application value.

The developed nomogram can be used to predict the specific probability of ED in elderly PC patients with LM, which is useful in guiding the early prevention and treatment decision-making of this group of people.

Fragmentation of care among patients with pancreatic cancer between specialized tertiary centers and community centers may be associated with increased patient burden and poorer outcomes. However, the impact of distance from a tertiary center on utilization of key ancillary services such as dietician consultation, and palliative or pain medicine consultation is unclear. We sought to examine how this travel distance influences the utilization of key ancillary services.

This retrospective cohort study included 200 consecutive patients who were seen for a diagnosis of pancreatic ductal adenocarcinoma (PDAC) in 2021. Patients were grouped by travel distance: < 12.5, 12.5-49, and > 50 miles. Demographics, disease staging, and use of key ancillary services such as, dietician consultation, palliative, and pain medicine consultation were compared. Multiple logistic regression assessed associations between travel distance and ancillary service utilization.

Of the 200 patients, 14.5% traveled < 12.5 miles, 39.5% traveled 12.5-49 miles, and 46% traveled over 50 miles to our institution. Patients living over 50 miles away were significantly more likely to receive chemotherapy and radiation locally (81.8% vs 44.4%, p < 0.001). Importantly, they were less likely to utilize key ancillary services, including registered dietician consultation (Odds Ratio (OR) 0.34, p = 0.03), pancreatic enzyme prescriptions (OR 0.35, p = 0.03), pain medicine consultation (OR 0.20, p < 0.01), and palliative care consultation (OR 0.24, p < 0.01) compared to those living closer.

Patients living over 50 miles from our institution were significantly less likely to receive key supportive services. Despite similar clinical characteristics, these disparities show how initiatives are necessary to guarantee equitable access to comprehensive cancer care, regardless of geographic location.

Although with a good prognosis of papillary thyroid cancer (PTC), patients with PTC and also experiencing lymph node metastasis (LNM) had higher recurrence and mortality rates. Therefore it was essential to explore novel biomarkers or methods to predict and evaluate the situation in the stages of PTC.

In this study, mRNA sequence datasets from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) were utilized to obtain differentially expressed genes (DEGs) between PTC tumors and normal specimens and DEGs related to lymph node metastasis were identified using weighted gene co-expression network analysis (WGCNA) according to the clinical information. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to query the biological functions and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using a STRING database and a prognosis model was established using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis based on the LNM-related DEGs. Finally, six hub genes were identified and verified in vitro experiments.

A novel six-gene signature model including COL8A2, MET, FN1, MPZL2, PDLIM4 and CLDN10 was established based on a total of 52 DEGs from the intersection of LNM-related modules identified by WGNCA from TCGA, THCA and GSE60542 to predict the situation of lymph node metastasis in PTC. Those six hub genes were all more highly expressed in PTC tumors and played potential biological functions on the development of PTC in in vitro experiments, which had potential values as diagnostic and therapeutic targets.

To enhance immunotherapy efficacy in pancreatic cancer, it is crucial to characterize its immune landscape and identify key factors driving immune alterations. To achieve this, we quantitatively analyzed the immune microenvironment using multiplex immunohistochemistry, assessing the spatial relationships between immune and tumor cells to correlate with patient survival rates and oncological factors. Additionally, through Whole Exome Sequencing analysis based on public data, we explored genetic mutations that could drive these compositions. Finally, we validated T cell (Tc) migration mechanisms using patient-derived tumor organoids with induced KRAS mutation subtypes. Through this approach, we obtained the following meaningful results. First, immune cells in pancreatic cancer are denser in stromal regions than near tumor cells, with higher Tc distribution linked to increased patient survival rates. Second, the distance between tumor and Tc was within 100 μm, with higher Tc density found within 15-30 μm of the tumor cells. Third, while increasing CAF levels correspond to higher Tc density, higher ECM density tends to decrease Tc presence. Fourth, compared to KRAS G12D, KRAS G12V mutation increases various immune cells, notably Tc, which is closely linked to a dramatic rise in vascular cells. Finally, Tc migration was enhanced in tumor organoids with the G12V mutation, attributed to a reduction in the secretion of immunosuppressive cytokines. Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.

Disulfidptosis, a novel form of disulfide stress-induced cell death involved in tumor progression, hasn't be well defined the function in tumor progression. And the clinical impacts of disulfidptosis-related genes (DRGs) in pancreatic adenocarcinoma (PAAD) remain largely unclear. In this study, we identified two distinct disulfidptosis subtypes and found that multilayer DRG alterations were associated with prognosis and TME infiltration characteristics. A three-gene prognostic signature was constructed to predict prognosis, and its clinical significance was characterized in the TCGA-PAAD cohort. The disulfidptosis signature was significantly correlated with prognosis, molecular subtype, CD8 T-cell infiltration, response to immune checkpoint inhibitors and chemotherapeutic drug sensitivity, and its predictive capability in PAAD patients was validated in multiple cohorts. Meanwhile, two anti-PD-L1 immunotherapy cohorts confirmed that low-risk patients exhibited substantially enhanced clinical response and treatment advantages. Furthermore, the expression patterns of DRGs were validated by quantitative real-time PCR. The expression and prognostic predictive capability of GLUT1 were verified by 87 PAAD patients from our cohort. These findings may help us understand the roles of DRGs in PAAD and the molecular characterization of disulfidptosis subtypes. The disulfidptosis signature could be a promising biomarker for prognosis, molecular subtypes, TME infiltration characteristics and immunotherapy efficacy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.

Background: Pancreatic ductal adenocarcinoma is an aggressive neoplasm with a complex carcinogenesis process that must be understood through the interactions between tumor cells and tumor microenvironment cells. Methods: This study was retrospective with a chronological extension period of 16 years and included 56 cases of pancreatic ductal adenocarcinoma. This study identified, quantified, and correlated the cells of the tumor immune microenvironment in pancreatic ductal adenocarcinoma with major prognostic factors as well as overall survival, using an extensive panel of immunohistochemical markers. Results: Three tumor immunotypes were identified: subtype A (hot immunotype), subtype B (intermediate immunotype), and subtype C (cold immunotype). Patients with immunotype C exhibit considerably higher rates of both pancreatic fistulas and acute pancreatitis. Immunotypes B and C significantly increased the risk of this complication by factors of 3.68 (p = 0.002) and 3.94 (p = 0.001), respectively. The estimated probabilities of fistula formation for each immunotype are as follows: 2.5% for immunotype A, 25% for immunotype B, and 28% for immunotype C. There was a statistically significant difference in median survival times according to tumor immunotype (p < 0.001). Specifically, patients with immunotype C tumors had a median survival time of only 120.5 days, compared to 553.5 days for those with immunotype A and 331.5 for immunotype B tumors. Conclusions: The identification of the immunotype of pancreatic ductal adenocarcinoma can be a predictive factor for the occurrence of complications such as pancreatic fistula as well as for overall survival.

Pancreatic cancer is known as one of the poor prognostic cancers, and the most of patients are unable to undergo radical resection due to local progression or distant metastasis at initial diagnosis. In spite of the advancements in surgery and chemotherapy, there are many cases of recurrence after surgery or chemoradiotherapy mainly due to the presence of cancer stem cells (CSCs). CSCs are potential therapeutic target, but current issue is that an identification of CSCs is difficult since they are only present in a small number of tumor cells. Here we demonstrate that hydrogel PCDME can rapidly induce pancreatic cancer cell spheroids with elevated levels of stem cell markers including Sox2, Oct3/4, and Nanog, and the growth rate was reduced. CSCs showed activation of YAP/TAZ signaling, and microarray analysis showed markedly elevated expression of thioredoxin-interacting protein (TXNIP). Primary pancreatic cancer cells also increased TXNIP in addition to stemness markers on gel. In metabolic analysis, CSCs showed a shift of energy production from glycolysis to oxidative phosphorylation (OXPHOS). Furthermore, knockdown of TXNIP on PCDME gel using shRNAs decreased growth speed and in vivo tumorigenicity, suggesting that TXNIP may be involved in CSCs induction.

Although photothermal therapy (PTT) can induce antitumour immunity, the mechanisms underlying its effects in pancreatic cancer (PC) require further exploration. In this study, the mechanism of action of PTT and its connection to pyroptosis as well as the therapeutic potential of PTT alone and in combination with STING agonists, were investigated. In addition, a biomarker of PC was found to stratify patients who are suitable for PTT.

We explored whether PTT can induce pyroptosis in vitro and evaluated the therapeutic efficacy and antitumour immunity-inducing ability of PTT combined with STING agonist (c-di-GMP) as immune adjuvant in vivo in PC. We also evaluated gasdermin D (GSDMD) expression in tumour tissues and investigated drug sensitivity in patient-derived organoids (PDOs) with differential GSDMD expression.

Our study demonstrated that local PTT induces pyroptosis via the caspase-1/GSDMD pathway and elicits antitumour immunity. PTT combined with a STING agonist exhibits better therapeutic efficacy than PTT alone while limiting distant tumour metastasis, and enhances the immune response by promoting dendritic cell maturation, increasing the frequency of tumour infiltrating T cells, and converting macrophages from the M2 to the M1 phenotype. In addition, we found that GSDMD is highly expressed in tumour tissues and that overexpression of GSDMD in PC might suggest increased resistance to chemotherapy and the potential benefits of local therapy. We further confirmed that PDOs with higher GSDMD expression are less sensitive to a chemotherapeutic agent (5-Fluorouracil) than PDOs with lower GSDMD expression, making GSDMD a new biomarker for identifying patients who may benefit from PTT.

In this work, c-di-GMP was used as an immune adjuvant for PTT to treat PC for the first time, and the results provide clues for the development of novel combination immunotherapies that simultaneously suppress primary tumours and distant metastases. GSDMD has great potential as a new biomarker for the selection of individualized treatment modalities.

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser133 in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

Type 2 diabetes (T2D) is a crucial risk factor for both pancreatic cancer (PC) and kidney cancer (KC). However, effective common drugs for treating PC and/or KC patients who are also suffering from T2D are currently lacking, despite the probability of their co-occurrence. Taking disease-specific multiple drugs during the co-existence of multiple diseases may lead to adverse side effects or toxicity to the patients due to drug-drug interactions. This study aimed to identify T2D-, PC and KC-causing common genomic biomarkers (cGBs) highlighting their pathogenetic mechanisms to explore effective drugs as their common treatment. We analyzed transcriptomic profile datasets, applying weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis approaches to identify T2D-, PC-, and KC-causing cGBs. We then disclosed common pathogenetic mechanisms through gene ontology (GO) terms, KEGG pathways, regulatory networks, and DNA methylation of these cGBs. Initially, we identified 78 common differentially expressed genes (cDEGs) that could distinguish T2D, PC, and KC samples from controls based on their transcriptomic profiles. From these, six top-ranked cDEGs (TOP2A, BIRC5, RRM2, ALB, MUC1, and E2F7) were selected as cGBs and considered targets for exploring common drug molecules for each of three diseases. Functional enrichment analyses, including GO terms, KEGG pathways, and regulatory network analyses involving transcription factors (TFs) and microRNAs, along with DNA methylation and immune infiltration studies, revealed critical common molecular mechanisms linked to PC, KC, and T2D. Finally, we identified six top-ranked drug molecules (NVP.BHG712, Irinotecan, Olaparib, Imatinib, RG-4733, and Linsitinib) as potential common treatments for PC, KC and T2D during their co-existence, supported by the literature reviews. Thus, this bioinformatics study provides valuable insights and resources for developing a genome-guided common treatment strategy for PC and/or KC patients who are also suffering from T2D.

Circulating tumor DNA (ctDNA) is a potential biomarker in pancreatic ductal adenocarcinoma (PDAC). However, studies on residual ctDNA in patients post-chemotherapy are limited. We assessed the prognostic value of residual ctDNA in metastatic PDAC relative to that of carbohydrate antigen 19-9 (CA19-9).

ctDNA analysis using a targeted next-generation sequencing panel was performed at baseline and during chemotherapy response evaluation in 53 patients. Progression-free survival (PFS) and overall survival (OS) were first evaluated based on ctDNA positivity at baseline. For further comparison, patients testing ctDNA-positive at baseline were subdivided based on residual ctDNA into ctDNA responders (no residual ctDNA post-chemotherapy) and ctDNA non-responders (residual ctDNA post-chemotherapy). Additional survival analysis was performed based on CA19-9 levels.

The baseline ctDNA detection rate was 56.6%. Although clinical outcomes tended to be poorer in patients with baseline ctDNA positivity than in those without, the differences were not significant. Residual ctDNA post-chemotherapy was associated with reduced PFS and OS. The prognosis of ctDNA responders was better than that of non-responders but did not significantly differ from that of ctDNA-negative individuals (no ctDNA both at baseline and during post-chemotherapy). Compared with ctDNA responses to chemotherapy, a ≥ 50% decrease in the CA19-9 level had less effect on both PFS and OS based on hazard ratios and significance levels. ctDNA could be monitored in half of the patients whose baseline CA19-9 levels were within the reference range.

Residual ctDNA analysis post-chemotherapy is a promising approach for predicting the clinical outcomes of patients with metastatic PDAC.

Estrogen is thought to be the reason for the higher prevalence of papillary thyroid carcinoma (PTC) in fertile women; however, more study is required to completely comprehend how estrogen affects PTC development at the cellular level. Therefore, we combined Oxford Nanopore Technologies (ONT) sequencing to explore molecular markers of PTC and to investigate the molecular mechanisms by which estrogen promotes PTC development.

The expression levels of ESR1 (ERα) and KRT19 in normal thyroid tissues and cancer tissues as well as in different cancer stages, races, genders, age groups, histological subtypes and nodular metastasis status of the TCGA database were analyzed online by Ualcan; the relationship between ESR1, KRT19 and the survival of THCA patients was analyzed. A PTC xenograft tumor model was established. An ERα specific inhibitor (MPP) was administered and an EDU cell proliferation assay was used to verify the effect of estrogen on PTC proliferation. KRT19 was knocked down in KTC-1 cells, and the proliferation, migration, and invasion abilities of PTC cells were determined using CCK-8, immunofluorescence labeling, Western blot for EMT-related proteins, scratch assay, and Transwell assay. The role of ERα in relation to KRT19 was investigated by Western blot and immunofluorescence. The effects of ERα/KRT19 signaling axis on the proliferation, migration and invasion ability of PTC cells were evaluated using EDU cell proliferation assay and Transwell. Using ONT sequencing, 15 pairs of PTC tissue and paracancer tissue samples were collected. A PPI network was constructed to validate the differential expression of KRT19 in combination with biosignature analysis, and the protein interaction between KRT19 and ESR1 was verified using STRING.

Ualcan showed that the expression of ESR1 and KRT19 was higher in THCA tissues than in normal thyroid tissues. E2 activation of ERα promoted the growth of PTC cells and tissues. si-KRT19 inhibited the proliferation, migration and invasion of PTC cells. KRT19 together with ERα formed the ERα/KRT19 signaling axis. E2 activation of the ERα/KRT19 signaling axis promoted the proliferation, migration, and invasion of PTC cells. ONT sequencing and STRING website verified that KRT19 is significantly differentially expressed in PTC and that ESR1 and KRT19 have protein interactions and are related to the estrogen signaling pathway.

Using public databases, RNA sequencing, and bioinformatics, we discovered that E2 stimulates the ERα/KRT19 signaling axis to stimulate PTC proliferation, migration, and invasion.

Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an "immune hot" tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.

The effectiveness and preferred reconstruction methods of pancreatectomy associated with vein resection (PAVR) for pancreatic cancer, especially for the extensive portal vein/superior mesenteric vein (PV/SMV) resections (more than 4 cm), are still subjects of debate. The aim of this study is to evaluate the safety and feasibility of PAVR by analyzing data from two large institutions from different regions.

From 2008 to 2018, we identified consecutive series of patients with pancreatic cancer who underwent PAVR at Karolinska University Hospital (KUH), Sweden, and Cancer Institute Hospital, Japanese Foundation of Cancer Research (JFCR), Japan. Both institutions adopted the artery-first approach to enhance surgical precision. This study compared the short- and long-term outcomes, vein resection types, and reconstruction methods between the two centers.

A total of 506 patients who underwent PAVR were identified, 211 patients were from KUH and 295 patients were from JFCR. A higher incidence of total pancreatectomy was identified at KUH (24.6 % vs 0.3 %). There were no significant differences in intraoperative estimated blood loss (KUH: 630 ml, JFCR: 600 ml), severe complications rate (8.5 %, 5.1 %), and mortality (2.4 %, 0.7 %). Primary end-to-end anastomosis was primarily performed even if the length of PV/SMV resection was 5 cm or more and achieved successfully with acceptable patency (No thrombus rate: overall cases, 98.0 %; 5 cm or more, 93.5 %).

We report favorable outcomes of PAVR for pancreatic cancer from two high-volume centers in the east and west. Primary end-to-end anastomosis was safe and feasible even if the length of PV/SMV resection was 5 cm or more.

Surgical management of pancreas cancer is complex, including the timing of surgery, surgical approach, intraoperative techniques, and postoperative management, which are reviewed in detail in this manuscript. Ultimately, referral to a high-volume pancreatic surgeon or pancreatic surgery center is critical to ensuring appropriate short-term and long-term outcomes.

Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatmenteffectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT-PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30-41%, whereas activation decreased the response by 11-28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.