Search

Oxidative stress induced by reactive oxygen species (ROS) is promising treatment approach for pancreatic ductal adenocarcinoma (PDAC), which is typically insensitive to conventional chemotherapy. In this study, BxPC-3 pancreatic cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles (abbreviated as BUC@ZMS) were developed for tumor-targeted cancer therapy via synergistically oxidative stress and overcoming glutathione (GSH) overexpression. Using a combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT), the BUC@ZMS core-shell nanoparticles were able to elicit the death of pancreatic cancer cells through the high production of ROS. Additionally, the BUC@ZMS core-shell nanoparticles could deplete intracellular GSH and increase the sensitivity of tumor cells to oxidative stress. The in vivo results indicated that BUC@ZMS nanoparticles can accumulate specifically in tumor locations and suppress PDAC without generating obvious toxicity. Thus, it was determined that the as-prepared core-shell nanoparticles would be a viable treatment option for solid malignancies.

Objective: To investigate clinical characteristics, radiological features and biomarkers of pancreatic metastases of small cell lung carcinoma (PM-SCLC), and establish a convenient nomogram diagnostic predictive model to differentiate PM-SCLC from pancreatic ductal adenocarcinomas (PDAC) preoperatively. Methods: A total of 299 patients with meeting the criteria (PM-SCLC n=93; PDAC n=206) from January 2016 to March 2022 were retrospectively analyzed, including 249 patients from hospital 1 (training/internal validation cohort) and 50 patients from hospital 2 (external validation cohort). We searched for meaningful clinical characteristics, radiological features and biomarkers and determined the predictors through multivariable logistic regression analysis. Three models: clinical model, CT imaging model, and combined model, were developed for the diagnosis and prediction of PM-SCLC. Nomogram was constructed based on independent predictors. The receiver operating curve was undertaken to estimate the discrimination. Results: Six independent predictors for PM-SCLC diagnosis in multivariate logistic regression analysis, including clinical symptoms, CA199, tumor size, parenchymal atrophy, vascular involvement and enhancement type. The nomogram diagnostic predictive model based on these six independent predictors showed the best performance, achieved the AUCs of the training cohort (n = 174), internal validation cohort (n = 75) and external validation cohort (n = 50) were 0.950 (95%CI, 0.917-0.976), 0.928 (95%CI, 0.873-0.971) and 0.976 (95%CI, 0.944-1.00) respectively. The model achieved 94.50% sensitivity, 83.20% specificity, 86.80% accuracy in the training cohort and 100.00% sensitivity, 80.40% specificity, 86.70% accuracy in the internal validation cohort and 100.00% sensitivity, 88.90% specificity, 87.50% accuracy in the external validation cohort. Conclusion: We proposed a noninvasive and convenient nomogram diagnostic predictive model based on clinical characteristics, radiological features and biomarkers to preoperatively differentiate PM-SCLC from PDAC. [ABSTRACT FROM AUTHOR]

Low migratory dendritic cell (DC) levels pose a challenge in cancer immune surveillance, yet their impact on tumor immune status and immunotherapy responses remains unclear. We present clinical evidence linking reduced migratory DC levels to immune-cold tumor status, resulting in poor patient outcomes. To address this, we develop an autologous DC-based nanovaccination strategy using patient-derived organoid or cancer cell lysate-pulsed cationic nanoparticles (cNPs) to load immunogenic DC-derived microvesicles (cNP cancer cell @MV DC ). This approach transforms immune-cold tumors, increases migratory DCs, activates T cells and natural killer cells, reduces tumor growth, and enhances survival in orthotopic pancreatic and lung cancer models, surpassing conventional methods. In vivo imaging reveals superior cNP cancer cell @MV DC accumulation in tumors and lymph nodes, promoting immune cell infiltration. Mechanistically, cNPs enrich mitochondrial DNA, enhancing cGAS-STING-mediated DC activation and migration. Our strategy shifts cold tumors to a hot state, enhancing antitumor immunity for potential personalized cancer treatments., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gemcitabine is first‐line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif‐containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto‐polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real‐time polymease chain reaction, and immunohistochemical staining. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N‐TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC. [ABSTRACT FROM AUTHOR]

Aberrant glycosylation in pancreatic cancer has been linked to cancer development, progression and chemoresistance. However, the role of glycogene, such as galactosyltransferase, in pancreatic cancer remains unknown. Herein, we establish beta-1.4-galactosyltransferase 1 (B4GALT1) as a clinical marker and regulator of chemoresistance. Clinically, high B4GALT1 expression correlates with poor survival, enhanced tumor size, increased lymph node metastasis, elevated cancer progression and enhanced incidence of relapse in PDAC patients. Expression of B4GALT1 is up-regulated in gemcitabine resistant patient derived organoids as well as chemoresistant cancer cell lines, while genetic perturbation of its expression in PDAC cell lines regulates cancer progression and chemoresistance. Mechanistically, we show that elevated p65 activity transcriptionally up-regulates B4GALT1 expression, which then interacts with and stabilizes cyclin dependent kinase 11 isomer CDK11p110 protein via N-linked glycosylation, in order to promote cancer progression and chemoresistance. Finally, depletion of B4GALT1 rescues the response of chemoresistant cells to gemcitabine in an orthotopic PDAC model. Overall, our data uncovers a mechanism by which p65-B4GALT1-CDK11p110 signalling axis determines cancer progression and chemoresistance, providing a new therapeutic target for an improved pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

ObjectivesTo develop a radiomics signature for predicting surgical portal vein-superior mesenteric vein (PV-SMV) in patients with pancreatic ductal adenocarcinoma (PDAC) and measure the effect of providing the predictions of radiomics signature to radiologists with different diagnostic experiences during imaging interpretation.MethodsBetween February 2008 and June 2020, 146 patients with PDAC in pancreatic head or uncinate process from two institutions were retrospectively included and randomly split into a training (n = 88) and a validation (n =58) cohort. Intraoperative vascular exploration findings were used to identify surgical PV-SMV invasion. Radiomics features were extracted from the portal venous phase CT images. Radiomics signature was built with a linear elastic-net regression model. Area under receiver operating characteristic curve (AUC) of the radiomics signature was calculated. A senior and a junior radiologist independently review CT scans and made the diagnosis for PV-SMV invasion both with and without radiomics score (Radscore) assistance. A 2-sided Pearson’s chi-squared test was conducted to evaluate whether there was a difference in sensitivity, specificity, and accuracy between the radiomics signature and the unassisted radiologists. To assess the incremental value of providing Radscore predictions to the radiologists, we compared the performance between unassisted evaluation and Radscore-assisted evaluation by using the McNemar test.ResultsNumbers of patients identified as presence of surgical PV-SMV invasion were 33 (37.5%) and 19 (32.8%) in the training and validation cohort, respectively. The radiomics signature achieved an AUC of 0.848 (95% confidence interval, 0.724–0.971) in the validation cohort and had a comparable sensitivity, specificity, and accuracy as the senior radiologist in predicting PV-SMV invasion (all p-values > 0.05). Providing predictions of radiomics signature increased both radiologists’ sensitivity in identifying PV-SMV invasion, while only the increase of the junior radiologist was significant (63.2 vs 89.5%, p-value = 0.025) instead of the senior radiologist (73.7 vs 89.5%, p-value = 0.08). Both radiologists’ accuracy had no significant increase when provided radiomics signature assistance (both p-values > 0.05).ConclusionsThe radiomics signature can predict surgical PV-SMV invasion in patients with PDAC and may have incremental value to the diagnostic performance of radiologists during imaging interpretation.

Objectives: To develop a radiomics signature for predicting surgical portal vein-superior mesenteric vein (PV-SMV) in patients with pancreatic ductal adenocarcinoma (PDAC) and measure the effect of providing the predictions of radiomics signature to radiologists with different diagnostic experiences during imaging interpretation. Methods: Between February 2008 and June 2020, 146 patients with PDAC in pancreatic head or uncinate process from two institutions were retrospectively included and randomly split into a training (n = 88) and a validation (n =58) cohort. Intraoperative vascular exploration findings were used to identify surgical PV-SMV invasion. Radiomics features were extracted from the portal venous phase CT images. Radiomics signature was built with a linear elastic-net regression model. Area under receiver operating characteristic curve (AUC) of the radiomics signature was calculated. A senior and a junior radiologist independently review CT scans and made the diagnosis for PV-SMV invasion both with and without radiomics score (Radscore) assistance. A 2-sided Pearson's chi-squared test was conducted to evaluate whether there was a difference in sensitivity, specificity, and accuracy between the radiomics signature and the unassisted radiologists. To assess the incremental value of providing Radscore predictions to the radiologists, we compared the performance between unassisted evaluation and Radscore-assisted evaluation by using the McNemar test. Results: Numbers of patients identified as presence of surgical PV-SMV invasion were 33 (37.5%) and 19 (32.8%) in the training and validation cohort, respectively. The radiomics signature achieved an AUC of 0.848 (95% confidence interval, 0.724–0.971) in the validation cohort and had a comparable sensitivity, specificity, and accuracy as the senior radiologist in predicting PV-SMV invasion (all p -values > 0.05). Providing predictions of radiomics signature increased both radiologists' sensitivity in identifying PV-SMV invasion, while only the increase of the junior radiologist was significant (63.2 vs 89.5%, p -value = 0.025) instead of the senior radiologist (73.7 vs 89.5%, p -value = 0.08). Both radiologists' accuracy had no significant increase when provided radiomics signature assistance (both p -values > 0.05). Conclusions: The radiomics signature can predict surgical PV-SMV invasion in patients with PDAC and may have incremental value to the diagnostic performance of radiologists during imaging interpretation. [ABSTRACT FROM AUTHOR]

The p16 gene, which is also known as CDKN2A, INK4A, or CDK4I, and its products that are known to be cell cycle inhibitors and tumor suppressors have been reported to be altered in various human tumor types. Altered p16 has been indicated to be correlated with negative p16 expression using immunohistochemistry (IHC). However, its association with the prognosis remains controversial because the findings of previous studies are inconsistent. The current study evaluated the relationship between the expression levels of p16 and the clinicopathological features associated with prognosis in patients with primary pancreatic ductal adenocarcinomas (PDACs). From January 2013 to December 2017, tissues of 103 PDAC patients who had undergone elective pancreatic resection were obtained and assessed for p16 expression by IHC. No correlation was observed between p16 status and clinicopathological factors (P>0.05). Notably, negative p16 expression on IHC was not significantly associated with poor prognosis using the Kaplan-Meier method. [ABSTRACT FROM AUTHOR]

Background: Significant modifications have been made to the 8th edition of the American Joint Committee on Cancer (AJCC) distant metastases (M) stage classification for metastatic pancreatic neuroendocrine tumors (PanNETs). We aimed to validate this revised classification among metastatic PanNET patients using the Surveillance, Epidemiology, and End Results database. We further sought to evaluate the feasibility of applying this classification to metastatic pancreatic neuroendocrine carcinoma (PanNEC) and pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Stage IV pancreatic neuroendocrine neoplasm (PanNEN, including G1/G2 PanNET and G3 PanNEC classified according to the World Health Organization [WHO] 2010 grading scheme) and PDAC patients with metastatic disease diagnosed between 2010 and 2015 were identified and restaged according to the revised M stage classification for PanNET. Overall survival (OS) was compared using Kaplan-Meier analysis and log-rank test. Uni- and multivariate Cox regression models were utilized to identify prognostic factors. Results: A total of 1,371 stage IV PanNEN and 634 PDAC patients were included. Among PanNEN patients, liver (75.0%) was the most common metastatic site, followed by distant lymph nodes (8.5%), lung (8.4%), bone (7.3%), and brain (1.0%). The 5-year OS for PanNET patients with M1a, M1b, and M1c stage was 44.15, 53.32, and 19.70%, respectively. However, survival comparison showed no significant difference between M1a and M1b stages among PanNET patients. Similar findings were noted after applying this classification to PanNEC patients. Multivariate analysis showed that the age at diagnosis and the number of distant metastatic sites were independent prognostic factors for metastatic PanNEN patients. Interestingly, excellent survival discrimination by M stage among stage IV PDAC patients was noted (M1a vs. M1b vs. M1c, 5-year OS: 5.42, 2.46, and 0%, respectively). Conclusion: Our study is the first large sample-based validation of the AJCC 8th M stage classification for PanNET. The revised classification did not effectively stratify metastatic PanNEN patients. However, further study is warranted to validate this classification for PanNET patients according to the WHO 2017 classification. Interestingly, the revised M stage classification might be feasible for PDAC patients with metastatic disease. [ABSTRACT FROM AUTHOR]

Introduction: Malignant tumors are associated with a low incidence of postoperative pancreatic fistulas. The presence of peritumoral fibrosis is considered the protective factor for the development of postoperative pancreatic fistulas after pancreatic resections for pancreatic ductal adenocarcinomas. Methods: We analyzed a series of 109 consecutive patients with pancreatic resections for malignant pathology: pancreatic ductal adenocarcinomas and periampullary adenocarcinomas. The incidence of postoperative pancreatic fistulas has been reported in tumor histological type, in the presence of peritumoral fibrosis, and in the association between adenocarcinomas and areas of acute pancreatitis. The data obtained were processed with the statistical analysis program SPSS, and statistically significant p were considered at a value p = 0.002. The presence of peritumoral fibrous tissue was observed in 49.31% of cases without pancreatic fistulas, and in 54.54% of cases that developed this postoperative complication (p = 0.5). Also, the peritumoral fibrous tissue had a uniform distribution depending on the main diagnosis (56.14% in pancreatic ductal adenocarcinoma group vs. 37.04% in periampullary adenocarcinoma group, with a p = 0.08). In the group of patients who associated areas of acute pancreatitis on the resections, the incidence of postoperative pancreatic fistulas was 7.8 times higher (30% vs. 3.8%, p = 0.026). Conclusions: Peritumoral fibrous tissue was not a factor involved in the developing of postoperative pancreatic fistulas. The association of adenocarciomas with areas of acute pancreatitis has led to a significant increase in postoperative pancreatic fistulas, which is a significant and independent risk factor.

Abstract Background: Hepatitis B virus X-interacting protein (HBXIP) is associated with a variety of tumors. The purpose of this study was to investigate the clinicopathological significance of HBXIP expression in pancreatic ductal adenocarcinoma (PDAC) and to explore its potential as a biomarker for PDAC. Methods: Immunohistochemical (IHC) staining was performed on 126 PDAC tissues, 36 paraneoplastic tissues and 22 normal pancreatic tissues. The relationship between high levels of HBXIP expression and pathological features of PDAC patients was evaluated by chi-squared values. Results:The positive rate of HBXIP protein in PDAC tissues was 85.7% (108/126), which was significantly higher than that of adjacent pancreatic tissue (41.7%, 15/36) and normal pancreas (18.2%, 4/22). In addition, strong positive expression of HBXIP was associated with tumor size, positive lymph node metastasis, clinical stage and 80-month overall survival. Patient's age, gender, degree of differentiation, Ki-67 expression index, and calcification were, however, not associated with high levels of HBXIP expression. Conclusions:We present association between HBXIP expression and the pathological features of patients with PDAC. [ABSTRACT FROM AUTHOR]

Avarol is a sesquiterpenoid hydroquinone with potent cytotoxicity. Although resolving endoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Here, we reported that avarol selectively induces cell death in pancreatic ductal adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. Analyses of the molecular mechanisms of avarol-induced apoptosis indicated upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress responses. We also showed that avarol activated the PERK–eIF2α pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK–eIF2α–CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol has potential as a chemotherapeutic agent for PDAC and induces apoptosis by activating the PERK–eIF2α pathway.

The unique tumour microenvironment (TM) of pancreatic ductal adenocarcinoma (PDA) including highly desmoplastic ECM and low tumour perfusion supports a considerable barrier for effective delivery of nanomedicines. Effectively modulating PDA microenvironment to enhance tumour drug delivery represents a pinpoint in the field of PDA treatment. In this study, it was the first time that biomimetic nanoparticles, which were designed in the form of erythrocyte membrane-camouflaged PLGA nanoparticles (MNP), were utilized for PDA microenvironment modulation. Cyclopamine (CYC), an inhibitor of Hedgehog pathway that contributed a lot to desmoplastic ECM of PDA, was selected as the model drug and successfully encapsulated into MNP. Advantages of CYC-loaded MNP (CMNP) included favourable biocompatibility, long circulation time, and powerful TM modulation effect. CMNP could effectively deliver CYC to the tumour site, disrupt tumour ECM, increase functional vessels, and improve tumour perfusion significantly. The combination treatment with CMNP and PTX-loaded MNP (PMNP) successfully improved PTX delivery to tumour, resulting in remarkable tumour growth inhibition in vivo. Therefore, biomimetic nanoparticles provide a new strategy for modulating PDA TM and will have great potential to improve the therapeutic effects of nanomedicines for PDA patients. [ABSTRACT FROM AUTHOR]

Background: To explore the application value of computed tomography (CT) texture analysis in differentiating atypical pancreatic neuroendocrine tumors (pNET) from pancreatic ductal adenocarcinomas (PDAC). Materials and methods: This single‐center retrospective study was approved by local institutional review board, and the requirement for informed consent was waived. We retrospectively analyzed 127 patients with 50 PDACs and 77 pNETs in pathology database between January 2012 and May 2017.These patients successfully finished preoperative contrast‐enhanced CT test. Texture parameters (mean, median, 5th, 10th, 25th, 75th, 90th percentiles, skewness, kurtosis and entropy) were extracted from portal images and compared between PDAC and 77 pNET groups using proper statistical method. The optimal parameters for differentiating PDACs and atypical pNETs were gained through receiver operating characteristic (ROC) curves. Results: On the basis of arterial enhancement, 52 pNETs (67%, 52/77) were typical hypervascular and 25 pNETs (32%, 25/77) were atypical hypovascular. Compared with PDACs, atypical pNETs had statistically higher mean, median, 5th, 10th, and 25th percentiles (P = 0.006, 0.024, 0.000, 0.001, 0.021, respectively) and statistically lower skewness (P = 0.017). However, there were no difference for 75th, 90th percentiles, kurtosis and entropy between these two tumors (P = 0.232, 0.415, 0.143, 0.291, respectively). For differentiating PDACs and atypical pNETs, 5th percentile and 5th+skewness were optimal parameters for alone and combined diagnosis, respectively. Conclusion: Volumetric CT texture features, especially combined diagnosis of 5th+skewness can be used as a quantitative tool to distinguish atypical pNETs from PDACs. Differentiating quantitatively atypical pNET from PDAC before treatment is difficult but this study had demonstrated an ability to achieve this by CTTA. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the value of dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity colour mapping (SICM) to differentiate mass-forming focal pancreatitis (MFFP) from pancreatic ductal adenocarcinoma (PDAC).Methods: Forty-one clinicopathologically proven MFFPs and 144 surgically confirmed PDACs were enrolled. Laboratory and MR imaging parameters were used to differentiate MFFP from PDAC. In particular, enhancement patterns on MR images adding SICM were evaluated. By using classification tree analysis (CTA), we determined the predictors for the differentiation of MFFP from PDAC.Results: In the CTA, with all parameters except enhancement pattern on SICM images, ductal obstruction grade and T1 hypointensity grade of the pancreatic lesion were the first and second splitting predictor for differentiation of MFFP from PDAC, in order. By adding an enhancement pattern on the SICM images to CTA, the enhancement pattern was the only splitting predictor to differentiate MFFP from PDAC. The CTA model including enhancement pattern on SICM images has sensitivity of 78.0 %, specificity of 99.3 %, and accuracy of 94.6 % for differentiating MFFP from PDAC.Conclusion: The characterization of enhancement pattern for pancreatic lesions on contrast-enhanced MR images adding SICM would be helpful to differentiate MFFP from PDAC.Key Points: • SICM was useful to characterize enhancement pattern. • Enhancement pattern on SICM was the only splitting predictor on CTA. • This model may be useful for differentiating MFFP from PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is among the most devastating solid malignancies globally owing to the lack of effective therapies, which is characterized by a profuse fibrotic stromal reaction, hypoxia, and an immunosuppressive microenvironment. Although immunotherapy shows tremendous clinical benefits for the management of solid tumors, to date, immunotherapy has largely failed to produce significant improvements in PDAC survival. Thus, the strategy that specifically targets the complicated immunosuppressive tumor microenvironment (TME) and immune-related therapeutic resistance in PDAC is an urgent need. Photothermal immunotherapy, which combines "local tumor hyperthermia" with "immune remodeling", is an effective modality for PDAC treatment. This study develops an injectable peptide-based hydrogel for integration with near-infrared photothermal pigment (biliverdin, (BV)) and a clinically approved immunomodulatory peptide (thymopentin, (TP5)) for local PDAC administration and treatment. The tumors are efficiently ablated using local photothermal therapy. Moreover, the immune response in vivo is correspondingly activated to transform "cold" TME into "hot" TME by improving T-cell infiltration and alleviating tumor hypoxia, thus effectively inhibiting tumor recurrence and metastasis. The strategy developed in this study provides a potent method for the treatment of relapsed and refractory pancreatic malignancies with a poor immune response. [Display omitted] • Biocompatible hydrogels are developed for delivery of immunomodulatory peptides and photothermal agents. • The therapeutics transforms PDAC from immunologically "cold" to "hot" and efficiently inhibits tumor progression. • The therapeutic paradigm provides a promising strategy for treatment of low immunogenic malignancies. [ABSTRACT FROM AUTHOR]

Oxidative stress induced by reactive oxygen species (ROS) is promising treatment approach for pancreatic ductal adenocarcinoma (PDAC), which is typically insensitive to conventional chemotherapy. In this study, BxPC-3 pancreatic cancer cell membrane-coated upconversion nanoparticles/Zn x Mn 1-x S core-shell nanoparticles (abbreviated as BUC@ZMS) were developed for tumor-targeted cancer therapy via synergistically oxidative stress and overcoming glutathione (GSH) overexpression. Using a combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT), the BUC@ZMS core-shell nanoparticles were able to elicit the death of pancreatic cancer cells through the high production of ROS. Additionally, the BUC@ZMS core-shell nanoparticles could deplete intracellular GSH and increase the sensitivity of tumor cells to oxidative stress. The in vivo results indicated that BUC@ZMS nanoparticles can accumulate specifically in tumor locations and suppress PDAC without generating obvious toxicity. Thus, it was determined that the as-prepared core-shell nanoparticles would be a viable treatment option for solid malignancies., Competing Interests: We declare that we have no business or personal relationships with other people or organizations to inappropriately influence our research. There is no professional or other personal interest of any nature or type in any product, service and/or company that could be construed to influence the position or scrutiny presented in the manuscript., (© 2023 The Authors. Published by Elsevier Ltd.)

Abstract The rat parvovirus H‐1PV has oncolytic and tumour‐suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co‐treating cancer cells with H‐1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H‐1PV/VPA co‐treatment strongly inhibits tumour growth promoting complete tumour remission in all co‐treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1‐mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H‐1PV/VPA co‐treatment against cervical and pancreatic ductal carcinomas.

Background: Clinical significance of chloride intracellular channel 1 (CLIC1) in pancreatic ductal adenocarcinomas (PDAC) remains largely unknown. This study was performed to assess the expression of CLIC1 in benign and malignant pancreatic lesions, and to assess its clinicopathological significance.Materials and Methods: Tissue samples from resected PDAC (n = 70) and their matched normal pairs were evaluated for CLIC1 expression by immunohistochemical staining. Their expression was correlated with different clinicopathological parameters.Results: CLIC1 expression was significantly higher (67.1%) in PDAC than in adjacent control tissues (25.7%, P < 0.001). High CLIC1 levels were associated with the histological grade (P < 0.001) and tumor size (P < 0.001); but not with sex, age, tumor-node-metastasis (TNM) stage, tumor location, or lymph node metastasis (P < 0.05). Univariate Kaplan-Meier analysis showed that a positive CLIC1 expression was associated with a decreased overall survival (P < 0.01). Multivariate cox regression analysis showed that CLIC1 expression and lymph node metastasis were independent risk factors for disease-free survival.Conclusion: The expression of CLIC1 might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of pancreatic ductal adenocarcinomas. [ABSTRACT FROM AUTHOR]

Objective: To investigate clinical characteristics, radiological features and biomarkers of pancreatic metastases of small cell lung carcinoma (PM-SCLC), and establish a convenient nomogram diagnostic predictive model to differentiate PM-SCLC from pancreatic ductal adenocarcinomas (PDAC) preoperatively., Methods: A total of 299 patients with meeting the criteria (PM-SCLC n=93; PDAC n=206) from January 2016 to March 2022 were retrospectively analyzed, including 249 patients from hospital 1 (training/internal validation cohort) and 50 patients from hospital 2 (external validation cohort). We searched for meaningful clinical characteristics, radiological features and biomarkers and determined the predictors through multivariable logistic regression analysis. Three models: clinical model, CT imaging model, and combined model, were developed for the diagnosis and prediction of PM-SCLC. Nomogram was constructed based on independent predictors. The receiver operating curve was undertaken to estimate the discrimination., Results: Six independent predictors for PM-SCLC diagnosis in multivariate logistic regression analysis, including clinical symptoms, CA199, tumor size, parenchymal atrophy, vascular involvement and enhancement type. The nomogram diagnostic predictive model based on these six independent predictors showed the best performance, achieved the AUCs of the training cohort (n = 174), internal validation cohort (n = 75) and external validation cohort (n = 50) were 0.950 (95%CI, 0.917-0.976), 0.928 (95%CI, 0.873-0.971) and 0.976 (95%CI, 0.944-1.00) respectively. The model achieved 94.50% sensitivity, 83.20% specificity, 86.80% accuracy in the training cohort and 100.00% sensitivity, 80.40% specificity, 86.70% accuracy in the internal validation cohort and 100.00% sensitivity, 88.90% specificity, 87.50% accuracy in the external validation cohort., Conclusion: We proposed a noninvasive and convenient nomogram diagnostic predictive model based on clinical characteristics, radiological features and biomarkers to preoperatively differentiate PM-SCLC from PDAC., Competing Interests: Author Y-GW was employed by General Electric GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Hu, Yang, Feng, Huang, Zheng, Rao, Wei and Yu.)

The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. [ABSTRACT FROM AUTHOR]

With an estimated 37,000 deaths per year, pancreatic cancer is the fourth leading cause of cancer deaths in the USA. A total of 95% of pancreatic cancers are exocrine neoplasms, known as pancreatic ductal adenocarcinomas (PDACs). The difficulty of early diagnosis and the high prevalence of metastasis associated with PDAC contribute to its dismal prognosis. The past decade has witnessed intensive study and impressive progress in searching for more sensitive, specific and cost-effective biomarkers. This review focuses on the epigenetic biomarkers potentially useful for the management of PDAC. The authors begin with an overview on the available biomarkers, and subsequently discuss the recent development in epigenetic biomarkers, including DNA methylation, miRNA and histone modifications in diversified specimens of cell lines, xenograft, cancer tissues, pancreatic juice and patient blood. These findings raise the possibility for clinical application of epigenetic biomarkers towards screening, early diagnosis, prognosis, chemosensitivity prediction and recurrence surveillance of PDAC patients. [ABSTRACT FROM AUTHOR]

Introduction: Malignant tumors are associated with a low incidence of postoperative pancreatic fistulas. The presence of peritumoral fibrosis is considered the protective factor for the development of postoperative pancreatic fistulas after pancreatic resections for pancreatic ductal adenocarcinomas. Methods: We analyzed a series of 109 consecutive patients with pancreatic resections for malignant pathology: pancreatic ductal adenocarcinomas and periampullary adenocarcinomas. The incidence of postoperative pancreatic fistulas has been reported in tumor histological type, in the presence of peritumoral fibrosis, and in the association between adenocarcinomas and areas of acute pancreatitis. The data obtained were processed with the statistical analysis program SPSS, and statistically significant p were considered at a value <0.05. Results: For the entire study group, the incidence of postoperative pancreatic fistulas was 11.01%. The lowest incidence was observed in the group of patients with pancreatic ductal adenocarcinomas (4.06% vs. 25.72% in the group with periampullary adenocarcinoma), with a p = 0.002. The presence of peritumoral fibrous tissue was observed in 49.31% of cases without pancreatic fistulas, and in 54.54% of cases that developed this postoperative complication (p = 0.5). Also, the peritumoral fibrous tissue had a uniform distribution depending on the main diagnosis (56.14% in pancreatic ductal adenocarcinoma group vs. 37.04% in periampullary adenocarcinoma group, with a p = 0.08). In the group of patients who associated areas of acute pancreatitis on the resections, the incidence of postoperative pancreatic fistulas was 7.8 times higher (30% vs. 3.8%, p = 0.026). Conclusions: Peritumoral fibrous tissue was not a factor involved in the developing of postoperative pancreatic fistulas. The association of adenocarciomas with areas of acute pancreatitis has led to a significant increase in postoperative pancreatic fistulas, which is a significant and independent risk factor. [ABSTRACT FROM AUTHOR]

Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these "inconclusive" specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors ( e.g. , pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors., Competing Interests: Conflict-of-interest statement: Authors have nothing to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aberrant glycosylation in pancreatic cancer has been linked to cancer development, progression and chemoresistance. However, the role of glycogene, such as galactosyltransferase, in pancreatic cancer remains unknown. Herein, we establish beta-1.4-galactosyltransferase 1 (B4GALT1) as a clinical marker and regulator of chemoresistance. Clinically, high B4GALT1 expression correlates with poor survival, enhanced tumor size, increased lymph node metastasis, elevated cancer progression and enhanced incidence of relapse in PDAC patients. Expression of B4GALT1 is up-regulated in gemcitabine resistant patient derived organoids as well as chemoresistant cancer cell lines, while genetic perturbation of its expression in PDAC cell lines regulates cancer progression and chemoresistance. Mechanistically, we show that elevated p65 activity transcriptionally up-regulates B4GALT1 expression, which then interacts with and stabilizes cyclin dependent kinase 11 isomer CDK11 p110 protein via N-linked glycosylation, in order to promote cancer progression and chemoresistance. Finally, depletion of B4GALT1 rescues the response of chemoresistant cells to gemcitabine in an orthotopic PDAC model. Overall, our data uncovers a mechanism by which p65-B4GALT1-CDK11 p110 signalling axis determines cancer progression and chemoresistance, providing a new therapeutic target for an improved pancreatic cancer treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We aimed to explore the effect of long non-coding RNA MVIH (lnc-MVIH) on cell proliferation, migration as well as invasion, and investigate the landscape of its molecular mechanism in pancreatic ductal adenocarcinomas (PDAC). Control overexpression (OE-NC group) and lnc-MVIH overexpression (OE-MVIH group) plasmids were transfected in BxPC-3 cells; control knock-down (KD-NC group) and lnc-MVIH knock-down (KD-MVIH group) plasmids were transfected in PANC-1 cells. Cellular functions were measured and mRNA sequencing was conducted. In 70 PDAC patients, lnc-MVIH expression in tumor and adjacent tissues was detected. Lnc-MVIH expression was higher in human PDAC cell lines than human normal pancreatic ductal epithelial cell line. Cell proliferation, migration and invasion were increased in OE-MVIH group compared to OE-NC group, but decreased in KD-MVIH group compared to KD-NC group. mRNA sequencing showed 145 differentially expressing genes (DEGs) upregulated in OE-MVIH group vs. OE-NC group and downregulated in KD-MVIH group vs. KD-NC group, and 51 DEGs downregulated in OE-MVIH group vs. OE-NC group and upregulated in KD-MVIH group vs. KD-NC group. These DEGs were enriched in several cancer-related pathways (including Hippo signaling pathway, cell cycle, Forkhead box O signaling pathway, apoptosis and advanced glycation end products-RAGE signaling pathway), and the effect of lnc-MVIH on regulating these DEGs was further validated by RT-qPCR. In PDAC patients, lnc-MVIH expression was increased in tumor tissue and correlated with advanced tumor size, lymph node metastasis, TNM stage and poor OS. In conclusion, lnc-MVIH might be a potential therapeutic target which regulated multiple cancer-related pathways in PDAC., Competing Interests: None., (AJTR Copyright © 2020.)

Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.

The complement system is a major pillar of the humoral innate immune system. As a first line of defense against pathogens, it mediates early inflammatory response and links different branches of humoral and cellular immunity. Disorders affecting the exocrine pancreas, such as acute pancreatitis, potentially lead to a life-threatening systemic inflammatory response with aberrant activation of complement and coagulation cascades. Pancreatic proteases can activate key effectors of the complement system, which in turn drive local and systemic inflammation. Beyond that, the extent of pancreas-complement interaction covers complex pro- and anti-inflammatory mechanisms, which to this day remain to be fully elucidated. This review provides a comprehensive overview of the pathophysiological role of complement in diseases of the exocrine pancreas, based on existing experimental and clinical data. Participation of complement in acute and chronic pancreatitis is addressed, as well as its role in tumor immunology. Therapeutic strategies targeting complement in these diseases have long been proposed but have not yet arrived in the clinical setting.

Objectives: Tumor-associated macrophages (TAMs) are thought to be involved in the perineural invasion (PNI) process and to be associated with poor prognoses. The associations between TAMs, PNI, and clinicopathological features in pancreatic ductal adenocarcinomas (PDAs) remain to be elucidated., Methods: Fifty-nine PDA patients who had undergone pancreaticoduodenectomy were retrospectively examined. The PNI statuses and TAMs were reviewed following H&E staining and S-100, CD68, and CD163 immunohistochemical staining. The relationships between PNI, TAMs, and overall survival and various clinical and histopathologic factors were investigated., Results: PNI was identified in 83% (49/59) of the cases, the TAM density of the PNI(+) group was greater than that of the PNI(-) group, and the infiltrating TAMs around the nerves that were invaded by cancer were much more numerous than those around the nerves without cancer cell invasion. The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs. In the PNI(+) group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses., Conclusions: TAMs might enhance PNI, and the incidence of PNI was associated with poor prognosis. PNI(+) status and high levels of TAM infiltration further worsen the prognosis. Therapies targeting TAMs might represent auxiliary and preventive treatment for PNI in PDA patients.