Identification of Novel Tumor Pyroptosis-Related Antigens and Pyroptosis Subtypes for Developing mRNA Vaccines in Pancreatic Adenocarcinoma.

BACKGROUND: As one of the important components of immunotherapies, mRNA vaccines have displayed promising clinical outcomes in solid tumors. Nonetheless, their efficacy remains unclear in pancreatic adenocarcinoma (PAAD). Given the interaction of pyroptosis with anticancer immunity, our study aims to identify pyroptosis-related antigens for mRNA vaccine development and discern eligible candidates for vaccination. METHODS: Utilizing gene expression data from TCGA and ICGC, we integrated RNA-seq data and compared genetic alterations through cBioPortal. Differential gene expressions were integrated using GEPIA. Relationships between immune cell abundance and tumor antigens were analyzed and visualized via TIMER. WGCNA facilitated the clustering of pyroptosis-related genes, identification of hub genes, and pathway enrichment analyses. Pyroptosis landscape was depicted through graph learning-based dimensional reduction. RESULTS: Four overexpressed and mutant pyroptosis-related genes associated with poor prognosis were identified as potential antigens for mRNA vaccines in PAAD, including ANO6, PAK2, CHMP2B, and RAB5A. These genes displayed positive associations with antigen-presenting cells. PAAD patients were stratified into three pyroptosis subtypes. Notably, the PS3 subtype, characterized by a lower mutation count and TMB, exhibited "cold" immunological traits and superior survival compared to other subtypes. The pyroptosis landscape exhibited considerable heterogeneity among individuals. Furthermore, the turquoise module emerged as an independent prognostic indicator and patients with high expressions of hub genes might not be suitable candidates for mRNA vaccination. CONCLUSIONS: In PAAD, ANO6, PAK2, CHMP2B, and RAB5A are prospective pyroptosis-related antigens for mRNA vaccine development, which holds potential benefits for patients classified as PS3 and those with diminished hub gene expressions, providing insights into personalized mRNA vaccine strategies.

Circulating cell-free DNA methylation-based multi-omics analysis allows early diagnosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC.

Efficacy of nab­paclitaxel vs. Gemcitabine in combination with S­1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

NEDD8-Activating Enzyme Inhibitor MLN4924 Inhibits Both the Tumor Stroma and Angiogenesis in Pancreatic Cancer via Gli1 and REDD1.

PURPOSE: Pancreatic cancer is characterized by a dense desmoplasia stroma, which hinders efficient drug delivery and plays a critical role in tumor progression and metastasis. MLN4924 is a first-in-class NEDD8-activating enzyme inhibitor that exhibits anti-tumor activities toward pancreatic cancer, and given the comprehensive effects that MLN4924 could have, we ask what impact MLN4924 would have on the stroma of pancreatic cancer and its underlying mechanisms. METHODS: Primary pancreatic stellate cells (PSCs) and human HMEC-1 cells were treated with MLN4924 in vitro. The proliferation and extracellular matrix protein levels of PSCs were tested, and their relationship with transcription factor Gli1 in PSCs was investigated. The angiogenic phenotypes of HMEC-1 cells were evaluated using capillary-like tube formation assay, and their relationship with REDD1 in HMEC-1 cells was investigated. RESULTS: In this study, we found that MLN4924 inhibited the proliferation of pancreatic stellate cells and their secretion of collagen and CXCL-1, and the collagen secretion inhibiting effect of MLN4924 was related with transcription factor Gli1. MLN4924 inhibited multiple angiogenic phenotypes of HMEC-1 cells, and mTOR agonist partially relieved the inhibition of MLN4924 on HEMCs. MLN4924 increased the expression of REDD1 and REDD1 knockdown promoted the angiogenic phenotypes of HMEC-1 cells. CONCLUSIONS: Our study suggests that MLN4924 inhibits both the tumor stroma and angiogenesis in pancreatic cancer, and the inhibition effect is related with Gli1 in pancreatic stellate cells and REDD1 in vascular endothelial cells, respectively.

PYCR1: A Potential Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor with an extremely poor prognosis in digestive tumors. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays an important role in tumor development. Therefore, we aimed to explore the effect of PYCR1 on the growth of PDAC cells. Methods: Tumor tissues and adjacent normal pancreatic tissues were collected from 89 patients with PDAC. And immunohistochemistry (IHC) was used to analyze the expression level of PYCR1 in both. RNA interference was used to inhibit the expression of PYCR1 in PANC- 1 and AsPC-1 cells. After infection, the expression of PYCR1 protein was detected by Western blot. The proliferation and growth of PDAC cells were detected by Celigo analysis, MTT, and clone formation assay. Cell apoptosis was analyzed by flow cytometry. Furthermore, the effect of PYCR1 interference on tumor growth was evaluated in vivo through injecting tumor cells subcutaneously into nude mice. Results: The expression of PYCR1 in pancreatic cancer tissues was significantly higher than in paired adjacent normal pancreatic tissues (P <0.01). In vitro, the downregulation of PYCR1 expression significantly inhibited the cell proliferation and colony formation, and increased apoptosis in PANC-1 cells and AsPC-1 cells compared with the shCtrl group (P <0.01). And in vivo, PYCR1 interference also significantly inhibited tumor growth both in the tumor volume and weight. Conclusion: PYCR1 interference was able to inhibit cell proliferation and promote cell apoptosis of pancreatic cancer. The PYCR1 may serve as a potential therapeutic and prognostic biomarker for the treatment of pancreatic cancer.

Gene expression profiling reveals the genomic changes caused by MLN4924 and the sensitizing effects of NAPEPLD knockdown in pancreatic cancer.

MLN4924 inhibits the proteolytic degradation of Cullin-Ring E3 ligase (CRL) substrates and exhibits antitumor activity toward various malignancies, including pancreatic cancer. MLN4924 suppresses tumor growth by altering various key regulator proteins; however, its impact on gene expression in tumors remains unknown. In this study, the genomic changes caused by MLN4924 in pancreatic cancer were examined by gene chip analysis and ingenuity pathway analysis. Eleven pathways were significantly altered (5 activated and 6 inhibited), 45 functions were significantly changed (21 activated and 24 inhibited), and the most activated upstream factor was predicted to be TNF. Of 691 differentially expressed genes, NAPEPLD knockdown showed synergism with MLN4924, as determined by real-time quantitative PCR and high content screening. NAPEPLD knockdown enhanced the effect of MLN4924 on inhibiting proliferation and inducing apoptosis in vitro. In a pancreatic cancer nude mouse model, MLN4924 inhibited tumor growth more significantly in the NAPEPLD knockdown group than in the control group. NAPEPLD expression was higher in pancreatic cancer tissues than in the normal pancreas but was not associated with prognosis. These findings indicate that MLN4924 causes extensive genomic changes in pancreatic cancer cells, and targeting NAPEPLD may increase the efficacy of MLN4924.

Upregulated circRNA hsa_circ_0071036 promotes tumourigenesis of pancreatic cancer by sponging miR-489 and predicts unfavorable characteristics and prognosis.

Circular RNAs (circRNAs), the new stars of endogenous non-coding RNAs, are dysregulated in various tumors including pancreatic cancer. Here, we aimed to investigate the biological functions of hsa_circ_0071036 in the tumourigenesis and progression of pancreatic ductal adenocarcinoma (PDAC) and its clinical implications. The differential expression profile of circRNAs in 4 pairs of PDAC tissues was analyzed by microarray assay. Quantitative real-time PCR and fluorescence in situ hybridization (FISH) were utilized to determine the expression patterns and their clinical significance. Functional experiments in vitro and in vivo were performed to explore whether hsa_circ_0071036 functions as an oncogenic circRNA in PDAC. Mechanistically, RT-qPCR, dual luciferase reporter and RNA pull-down assays were conducted to identify the interaction between hsa_circ_0071036 and miR-489 in PDAC. Hsa_circ_0071036 was remarkably overexpressed in PDAC cell lines and tissue samples, which negatively correlated with miR-489 expression. Aberrant expression of hsa_circ_0071036 correlated with poor clinicopathological characteristics and prognoses of PDAC patients. Knockdown of hsa_circ_0071036 suppressed proliferation and invasion and induced apoptosis in vitro. Moreover, the in vivo xenograft model confirmed that silencing of hsa_circ_0071036 attenuated tumor growth. Mechanistic analyses indicated that hsa_circ_0071036 acted as an efficient miRNA sponge for miR-489 in PDAC. In summary, our study revealed that upregulated hsa_circ_0071036 promotes PDAC pathogenesis and progression by directly sponging miR-489, which implies an important role for this circRNA-miRNA functional network.

DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5-year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early-stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage-independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down-regulate cellular ROS level via up-regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Aberration of ARID1A Is Associated With the Tumorigenesis and Prognosis of Sporadic Nonfunctional Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The genetic aberrations that underlie chromatin remodeling in sporadic nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) remain largely unknown. Here, we investigated the dysregulation of the switch/sucrose nonfermentable (SWI/SNF) component ARID1A and its correlation with clinicopathological features and prognosis. METHODS: We sequenced the exomes of sporadic NF-pNETs. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to determine messenger RNA level and protein expression. RESULTS: The sporadic NF-pNETs harbored 264 somatic mutations in 228 different genes, most commonly affecting the SWI/SNF components ARID1B (57.1%) and ARID1A (42.9%). The expression of ARID1A was remarkably downregulated in NF-pNETs and corresponding liver metastases compared with that in normal pancreatic islet tissue. Reduced expression of ARID1A was associated with malignant clinicopathological features (P < 0.05). The loss of ARID1A was related to a high Ki-67 index (P < 0.05). Patients with ARID1A-negative expression had a significantly worse overall survival rate than those with ARID1A-positive expression (P < 0.05). The ARID1A status was an independent predictor of overall survival, and a nomogram integrating ARID1A with clinicopathological features was proposed. CONCLUSIONS: The loss of SWI/SNF components ARID1A may be associated with malignant behaviors and an unfavorable prognosis. Aberrations of ARID1A may contribute to tumorigenesis and metastasis in sporadic NF-pNETs.

Author Correction: piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis.

Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.

Author Correction: PRMT1 promotes pancreatic cancer growth and predicts poor prognosis.

The authors would like to correct the following panels in Figures.

PRMT1 promotes pancreatic cancer growth and predicts poor prognosis.

BACKGROUND: Protein arginine methyltransferase 1 (PRMT1) is the founding member of the PRMT family of proteins, whose members catalyze methylation of arginine residues in various proteins. Although several studies have reported upregulation of PRMT1 in various cancer types, the expression pattern and the underlying mechanism of PRMT1 action in pancreatic ductal adenocarcinoma (PDAC) are still unclear. METHODS: Immunohistochemistry staining as well as RT-PCR was used to determine the expression pattern of PRMT1 in clinical PDAC samples. Lentivirus packaging and transfection were employed to construct cell lines with PRMT1 overexpression or knockdown. MTT and crystal violet assays were used to determine the proliferation rates of PDAC cells. ß-catenin transcription activity was measured using a TOPFlash assay. PRMT1 binding to the promoter region of CTNNB1 was determined by ChIP-qPCR assay. RESULTS: Elevated PRMT1 expression was found in PDAC tissue samples compared to noncancerous normal tissues in 41 patients using a real-time PCR assay and in 90 patients using a tissue microarray (TMA) in conjunction with immunohistochemistry. Analysis of the PRMT1 expression data and PDAC clinical features revealed that PRMT1 expression was significantly correlated with PDAC tumor size and prognosis in postoperative patients. Additional functional experiments revealed that PRMT1 expression promoted the growth of pancreatic cancer-derived cells, both in vitro and in vivo. Mechanistically, we found that PRMT1 increased the cellular ß-catenin level. We also found that PRMT1 and ß-catenin were co-expressed in TCGA and GTEx datasets containing 370 samples. CONCLUSIONS: Collectively, our study provides novel insight into the expression and function of PRMT1 in PDAC and indicates that PRMT1 may serve as a therapeutic target for treating patients with pancreatic ductal adenocarcinoma.

Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer.

Gemcitabine (GEM)-based chemotherapy is commonly used to treat pancreatic cancer. However, acquired resistance to GEM remains a challenge in pancreatic cancer patients. Here we tested whether cancer-associated fibroblasts (CAFs) play vital roles in regulating drug resistance by transferring exosomal miRNA to cancer cells. CAFs were isolated from primary fibroblast of pancreatic cancer patients, and exosomes were collected and identified through transmission electron microscopy and western blotting analysis. The functions of CAFs-derived exosomal miRNA in regulating drug resistance were further investigated. We found that CAFs were innately resistant to GEM. The conditioned medium (CM) and the exosomes derived from CAFs contributed to GEM resistance, and GEM treatment further enhanced the effect of CAFs or CAFs-exosomes on pancreatic cancer cells proliferation. MiR-106b level was upregulated in CAFs and CAFs-exosomes following GEM treatment. MiR-106b was directly transferred from CAFs to pancreatic cancer cells through exosomes. Pretreatment of CAFs with miR-106b inhibitor suppressed miR-106b expression in CAFs-exosomes and resulted in a decreased resistance of cancer cells to GEM. MiR-106b promoted GEM resistance of cancer cells by directly targeting TP53INP1. Summarily, our data demonstrated that CAFs-derived exosomal miR-106b plays a vital role in causing GEM resistance of pancreatic cancer, thus offering a new target for sensitizing pancreatic cancer cells to GEM.

Cell-intrinsic PD-1 promotes proliferation in pancreatic cancer by targeting CYR61/CTGF via the hippo pathway.

Pancreatic ductal adenocarcinoma (PDAC) remains a refractory disease. Programmed cell death protein-1 (PD-1) monotherapy has shown strong performance in targeting several malignancies. However, the effect and mechanism of intrinsic PD-1 in pancreatic cancer cells is still unknown. In this study, associations between clinicopathological characteristics and stained tissue microarrays of PDAC specimens were analyzed along with profiling and functional analyses. The results showed that cell-intrinsic PD-1 was significantly correlated with overall survival (OS). Independently of adaptive immunity, intrinsic PD-1 promoted tumor growth in PDAC. Concomitantly, the overexpression of intrinsic PD-1 enhanced cancer proliferation and inhibited cell apoptosis in vitro and in vivo. Mechanistically, PD-1 binds to the downstream MOB1, thereby inhibiting its phosphorylation. Moreover, greater synergistic tumor suppression in vitro resulted from combining Hippo inhibitors with anti-PD-1 treatment compared with the suppression achieved by either single agent alone. Additionally, Hippo downstream targets, CYR61 (CCN1) and CTGF (CCN2), were directly affected by PD-1 mediated Hippo signaling activation in concert with survival outcomes. Finally, the formulated nomogram showed superior predictive accuracy for OS in comparison with the TNM stage alone. Therefore, PD-1 immunotherapy in combination with Hippo pathway inhibitors may optimize the anti-tumor efficacy in PDAC patients via targeting cell-intrinsic PD-1.

Downregulated expression of RACK1 results in pancreatic cancer growth and metastasis.

BACKGROUND: The expression and function of the Receptor for Activated C Kinase 1 (RACK1) in cancer growth and metastasis are confused in different cancers, especially in pancreatic ductal adenocarcinoma (PDAC). METHODS: One-hundred and eighty-two PDAC tissue specimens (95 males and 87 females) including pancreatic cancer tissue and para-carcinoma tissue were collected for analysis between 2005 to 2012. Blood phenotypic parameters using cell count and capillary electrophoresis were investigated. HE staining, real time PCR, Western blot analysis, and soft agar assays were performed to determine the role of RACK1. PURPOSE: In this study, we aim to determine the specific role of RACK1 in the untility of PDAC. RESULTS: We found that RACK1 expression was significantly lower in pancreatic cancer tissue than in para-carcinoma normal pancreatic tissue both in clinic and mice with pancreatic cancer at the early stage. Our results suggested that RACK1 silence could significantly promote cell growth and metastasis of pancreatic cancer cells. But we found that the overexpression of RACK1 has the opposite effect in vitro. In vivo MIAPaca-2 cells overexpressing RACK1, the results demonstrated lower metastatic ability than MIAPaca-2 cells. RACK1 overexpression could decrease the NF-κB transactivation activity of MIAPaca-2 cells, which was consistent with the inhibitory effect of RACK1 overexpression on the pro-migration and pro-invasive target gene of NF-κB, while which could be increased by RACK1 silence. RACK1 silence also enhanced protein expression of pro-migration and pro-invasive NF-κB target genes, which on the contrary, could be reversed by IκBα. Besides, RACK1 expression was significantly associated with lymph node metastasis, vessels metastasis, invasion of nerves as well as TNM staging. The 3-year survival rate of patients with high RACK1 expression was significantly higher than those patients with low RACK1 expression. However, RACK1 expression was not an independent risk factor for of the long-term postoperative survival of patients with pancreatic cancer. CONCLUSION: The obtained results in our study suggested that the low expression of RACK1 was associated with cancer cell growth and metastasis in pancreatic cancer through the activation of the NF-κB pathway. RACK1 could be a potential therapeutic drug target to pancreatic cancer and metastasis.

TRAF6 regulates YAP signaling by promoting the ubiquitination and degradation of MST1 in pancreatic cancer.

TNF receptor-associated factor 6 (TRAF6), a regulator of NF-κB signaling, has been reported to be associated with the oncogenesis of various tumors including pancreatic cancer, but the underlying mechanisms remain unknown. Here, we found that knocking down the expression of TRAF6 impaired YAP signaling. Moreover, TRAF6 promoted the migration and colony formation of pancreatic cancer cells through YAP. Then, we found that TRAF6 interacted with and promoted the ubiquitination and degradation of MST1, and the expression of TRAF6 and MST1 was negatively correlated in primary human pancreatic cancer samples. Our results reveal that TRAF6 regulates YAP signaling by promoting the ubiquitination and degradation of MST1 in pancreatic cancer, suggesting that TRAF6 could be a possible E3 ligase of MST1 and a potential therapeutic target.

Validation of Sendai and Fukuoka consensus guidelines in predicting malignancy in patients with preoperatively diagnosed mucinous pancreatic cystic neoplasms.

BACKGROUND AND OBJECTIVES: The Sendai consensus guidelines (SCG) and Fukuoka consensus guidelines (FCG) have been examined for their roles in predicting advanced neoplasia (AN) in pancreatic cystic neoplasm (PCN) patients with mixed results. We aim to evaluate the utilities of both guidelines in a Chinese cohort with preoperatively diagnosed mucinous PCNs. METHODS: One hundred ninety-seven patients who underwent resections from 2008 to 2015 in Zhong Shan Hospital, Fudan University for suspected PCNs were retrospectively reviewed. Receiver operating characteristic (ROC) curves were calculated and compared to measure diagnostic value. RESULTS: Fifty-five patients were diagnosed with AN pathologically. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the SCG high-risk (SCGHR ) criteria were 87.3%, 28.2%, 32.0%, 85.1%, and 44.7%, respectively, and for the FCG high-risk (FCGHR ) criteria, they were 40.0%, 95.8%, 78.6%, 80.5%, and 80.2%, respectively. ROC curve comparison analyses showed that the FCGHR were superior to the SCGHR (P = 0.02). The performance of the FCGHR was enhanced with CA19-9 incorporated (P = 0.004). CONCLUSIONS: The FCG were superior to the SCG in this retrospective analysis, which could be further improved by the incorporation of CA19-9. However, the practical safety remains uncertain because of missed invasive carcinoma cases.

Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer.

MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication. In vivo study on a xenograft PC mouse model also showed that SCH 900776 increased the efficacy of MLN4924. We also evaluated the level of NEDD8-activating enzyme (NAE), the direct target of MLN4924, and found that NAE level was elevated in PC tissues compared with normal pancreas, but was irrelevant with prognosis. Our findings provide the preclinical evidence and the rationale of the combination therapy of MLN4924 with SCH 900776 or other Chk1 inhibitors to treat PC.