Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication.

BACKGROUND: Immunotherapy has emerged as a potent clinical approach for cancer treatment, but only subsets of cancer patients can benefit from it. Targeting lactate metabolism (LM) in tumor cells as a method to potentiate anti-tumor immune responses represents a promising therapeutic strategy. METHODS: Public single-cell RNA-Seq (scRNA-seq) cohorts collected from patients who received immunotherapy were systematically gathered and scrutinized to delineate the association between LM and the immunotherapy response. A novel LM-related signature (LM.SIG) was formulated through an extensive examination of 40 pan-cancer scRNA-seq cohorts. Then, multiple machine learning (ML) algorithms were employed to validate the capacity of LM.SIG for immunotherapy response prediction and survival prognostication based on 8 immunotherapy transcriptomic cohorts and 30 The Cancer Genome Atlas (TCGA) pan-cancer datasets. Moreover, potential targets for immunotherapy were identified based on 17 CRISPR datasets and validated via in vivo and in vitro experiments. RESULTS: The assessment of LM was confirmed to possess a substantial relationship with immunotherapy resistance in 2 immunotherapy scRNA-seq cohorts. Based on large-scale pan-cancer data, there exists a notably adverse correlation between LM.SIG and anti-tumor immunity as well as imbalance infiltration of immune cells, whereas a positive association was observed between LM.SIG and pro-tumorigenic signaling. Utilizing this signature, the ML model predicted immunotherapy response and prognosis with an AUC of 0.73/0.80 in validation sets and 0.70/0.87 in testing sets respectively. Notably, LM.SIG exhibited superior predictive performance across various cancers compared to published signatures. Subsequently, CRISPR screening identified LDHA as a pan-cancer biomarker for estimating immunotherapy response and survival probability which was further validated using immunohistochemistry (IHC) and spatial transcriptomics (ST) datasets. Furthermore, experiments demonstrated that LDHA deficiency in pancreatic cancer elevated the CD8+ T cell antitumor immunity and improved macrophage antitumoral polarization, which in turn enhanced the efficacy of immunotherapy. CONCLUSIONS: We unveiled the tight correlation between LM and resistance to immunotherapy and further established the pan-cancer LM.SIG, holds the potential to emerge as a competitive instrument for the selection of patients suitable for immunotherapy.

Specific human leukocyte antigen class I genotypes predict prognosis in resected pancreatic adenocarcinoma: a retrospective cohort study.

BACKGROUND: Patients with resected pancreatic adenocarcinoma (PAAD) often experience short-term relapse and dismal survival, suggesting an urgent need to develop predictive and/or prognostic biomarkers for these populations. Given the potential associations of the human leukocyte antigen class I ( HLA -I) genotype with oncogenic mutational profile and immunotherapy efficacy, we aimed to assess whether differential HLA -I genotype could predict the postoperative outcomes in resected PAAD patients. MATERIALS AND METHODS: HLA -I ( A , B , and C ) genotyping and somatic variants of 608 Chinese PAAD patients were determined by targeted next-generation sequencing of matched blood cells and tumor tissues. HLA - A / B alleles were classified with the available definition of 12 supertypes. The Kaplan-Meier curves of disease-free survival (DFS) and multivariable Cox proportional-hazards regression analyses were performed to determine the survival difference in 226 selected patients with radical resection. Early-stage (I-II) patients constituted the majority (82%, 185/226) and some stage I-II individuals with high-quality tumor samples were analyzed by RNA-sequencing to examine immunophenotypes. RESULTS: Patients with HLA-A02 + B62 + B44 - had significantly shorter DFS (median, 239 vs. 410 days; hazard ratio=1.65, P =0.0189) than patients without this genotype. Notably, stage I-II patients carrying HLA-A02 + B62 + B44 - had sharply shorter DFS than those without HLA-A02 + B62 + B44 - (median, 237 vs. 427 days; hazard ratio=1.85, P =0.007). Multivariate analysis revealed that HLA-A02 + B62 + B44 - was associated with significantly inferior DFS ( P =0.014) in stage I-II patients but not in stage III patients. Mechanistically, HLA-A02 + B62 + B44 - patients were associated with a high rate of KRAS G12D and TP53 mutations, lower HLA-A expression, and less inflamed T-cell infiltration. CONCLUSION: The current results suggest that a specific combination of germline HLA-A02/B62/B44 supertype, HLA-A02 + B62 + B44 - , was a potential predictor for DFS in early-stage PAAD patients after surgery.

Association between age at diabetes onset or diabetes duration and subsequent risk of pancreatic cancer: Results from a longitudinal cohort and mendelian randomization study.

Background: The aim of the study is to estimate the incidence of pancreatic cancer among individuals with new-onset type 2 Diabetes (T2DM) and evaluate the relationship of pancreatic cancer risk with age at diabetes onset and diabetes duration. Methods: This longitudinal cohort study included 428,362 new-onset T2DM patients in Shanghai and Mendelian randomization (MR) in the east-Asian population were used to investigate the association. Incidence rates of pancreatic cancer in all patients and by subgroups were calculated and compared to the general population. Findings: A total of 1056 incident pancreatic cancer cases were identified during eight consecutive years of follow-up. The overall pancreatic cancer annual incidence rate was 55·28/100,000 person years in T2DM patients, higher than that in the general population, with a standardized incidence ratio (SIR) of 1·54 (95% confidence interval [CI], 1·45-1·64). The incidence of pancreatic cancer increased with age and a significantly higher incidence was observed in the older groups with T2DM. However, the relative pancreatic cancer risk was inversely related to age of T2DM onset, and a higher SIR of 5·73 (95%CI, 4·49-7·22) was observed in the 20-54 years old group. The risk of pancreatic cancer was elevated at any diabetes duration. Fasting blood glucose ≥10·0 mmol/L was associated with increased risk of pancreatic cancer. MR analysis indicated a positive association between T2DM and pancreatic cancer risk. Interpretation: Efforts toward early and close follow-up programs, especially in individuals with young-onset T2DM, and the improvement of glucose control might represent effective strategies for improving the detection and results of treatment of pancreatic cancer. Funding: Chinese National Natural Science Foundation.

Impact of the transection plan on postoperative pancreatic fistulas occurring after robot-assisted distal pancreatectomy for nonmalignant pancreatic neoplasms.

OBJECTIVES: Postoperative pancreatic fistula (POPF) is the main complication of distal pancreatectomy (DP) and affects the prognosis of patients. The impact of several clinical factors mentioned in recent studies on POPF remains controversial. This study aimed to investigate the impact of a remnant pancreas and other perioperative factors on POPFs occurring after robot-assisted distal pancreatectomy (RDP) for nonmalignant pancreatic neoplasms. METHODS: A total of 197 patients who received robot-assisted distal pancreatectomy (RDP) for nonmalignant pancreatic neoplasms at the Pancreatic Disease Center, Ruijin Hospital Shanghai Jiaotong University School of Medicine from January 2018 to December 2020 were included in this retrospective study. According to the intraoperative transection plan, patients were divided into an RDP body group and an RDP tail group. Clinical and pathological features and perioperative factors affecting POPF were analyzed and compared between the two groups. RESULTS: The results showed that a transection plan involving the tail of the pancreas (OR = 2.133, 95% CI 1.109-4.103, p = 0.023) and spleen preservation (OR = 2.588, 95% CI 1.435-4.665, p = 0.001) independently increased the incidence of POPF in patients with nonmalignant pancreatic neoplasms treated by RDP. A transection plan involving the tail of the pancreas was also an independent risk factor (OR = 3.464, 95% CI 1.270-9.450, p = 0.015) for grade B/C POPF. Length of remnant pancreas > 6.23 cm was an independent risk factor for POPF (OR = 3.116, 95% CI 1.364-7.121, p = 0.007). Length of remnant pancreas > 9.82 cm was an independent risk factor for grade B/C POPF (OR = 3.340, 95% CI 1.386-8.051, p = 0.007). CONCLUSION: This retrospective study suggests that a transection plan involving the tail of the pancreas is an independent risk factor for POPF in patients with nonmalignant neoplasms treated by RDP. We also propose that the postoperative length of the remnant pancreas evaluated by computed tomography scans can be used to identify patients with a high risk of POPF in order to optimize the individualized strategy.

Silylium ion-mediated cage-opening functionalization of closo-B10H102- salts.

The cage-opening functionalization of stable closo-B10H102- salts is a great way to get various boron clusters. However, the known methods to mediate cage-opening functionalization rely on the use of strong acids, which suffer from low efficiency and narrow substrate scope. Herein, an efficient method to synthesize 6-substituted decaboranyl ethers and sulfides has been developed. The reaction was mediated by trimethylsilyl trifluoromethanesulfonate (TMSOTf) and occurred at room temperature. Six 6-substituted ethers were obtained in 65-92% yields and five 6-substituted sulfides were prepared in 38-58% yields. The reaction had excellent regioselectivity, affording the single B(6) regioisomer in all cases. The interaction between the B-H bonds of the boron cage and the silylium ion was believed to be the key factor in the reaction.

Aberrant human ClpP activation disturbs mitochondrial proteome homeostasis to suppress pancreatic ductal adenocarcinoma.

The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.

Postoperative hyperprogression disease of pancreatic ductal adenocarcinoma after curative resection: a retrospective cohort study.

BACKGROUND: Prognosis for patients recurred rapidly after resection of pancreatic ductal adenocarcinoma (PDAC) was extremely poor. We proposed the concept of postoperative hyper-progression disease (PO-HPD) to define recurrence within 2 months after surgery, explored the role of surgery for postoperative HPD patients and determined the predictive preoperative risk factors and genomic features of PO-HPD. METHODS: 976 patients undergoing curative resection of PDAC were enrolled. Survival data of 1733 stage IV patients from the US Surveillance, Epidemiology and End Results database was also collected. Patients relapsed were grouped into 3 groups regarding of the recurrence time (within 2 months were PO-HPD, within 2 to 12 months were early recurrence (ER) and within > 12 months were late recurrence (LR)). Risk factors for PO-HPD were explored with logistic regression models. Genomic features of 113 patients were investigated using next-generation sequencing-based gene panel testing. RESULTS: 718 of 976 cases relapsed, 101were PO-HPD, 418 were ER and 199 were LR. Total survival of PO-HPD was 12.5 months, shorter than that of ER (16.7 months) and LR (35.1 months), and verged on that of stage IV patients (10.6 months). Preoperative risk factors for PO-HPD included red blood cell count < 3.94*10^12/L, CA19-9 ≥ 288.6 U/mL, CA125 ≥ 22.3 U/mL and tumor size≥3.45 cm. Mutations of CEBPA, ATR and JAK1 were only identified in PO-HPD and they owned lower level of CN gain compared to others. CONCLUSIONS: Prognosis of PO-HPD was extremely poor and the role of surgery for PO-HPD should be prudently assessed.

Machine learning algorithms as early diagnostic tools for pancreatic fistula following pancreaticoduodenectomy and guide drain removal: A retrospective cohort study.

OBJECTIVE: Clinically relevant postoperative pancreatic fistula (CR-POPF) remains the major cause of morbidity following pancreaticoduodenectomy (PD). Several model score systems such as the Fistula Risk Score (FRS) have been developed to predict CR-POPF using preoperative and intraoperative data. Machine learning (ML) algorithms are increasingly applied in the medical field and they could be used to assess the risk of CR-POPF, identify clinically meaningful data and guide drain removal. METHODS: Data from consecutive patients who underwent PD between January 1, 2010 and March 31, 2021 at a single high-volume center was collected retrospectively in this study. Demographics, clinical features, intraoperative parameters, and laboratory values were used to conduct the ML model. Four different ML algorithms (CatBoost, lightGBM, XGBoost and Random Forest) were used to train this model with cross-validation. RESULTS: A total of 2421 patients with 62 clinical parameters were enrolled in this ML model. The majority of patients (76.3%) underwent open PD while others underwent robot-assisted PD. CR-POPF occurred in 424 (17.5%) patients. The CatBoost algorithm outperformed other algorithms with a mean area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval: 0.80-0.82) from the 5-fold cross-validation procedure. In the test dataset, the CatBoost algorithm also achieved the best mean-AUC of 0.83. The most important value was mean drain fluid amylase (DFA) in the first seven postoperative days (POD). The performance of models that used only preoperative data and intraoperative data was marginally lower than that of models that used combined data. CONCLUSION: Our ML algorithms could be applied as early diagnostic tools for CR-POPF in patients who underwent PD. Such real-time clinical decision support tools can identify patients with a high risk of CR-POPF, help in developing the perioperative management plan and guide the optimal timing of drain removal.

Discovery of novel KRAS‒PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models.

KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (K D = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.

Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas, and the current histopathological classifications are of limited use in clinical decision-making. There is an unmet need to identify new biomarkers for prognosis-informative molecular subtyping and ultimately for precision medicine. METHODS: We profiled genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNV). Using the CNV information, we performed unsupervised consensus clustering of these patients, differential CNV analysis and functional/pathway enrichment analysis. Cox regression was conducted for progression-free survival analysis, the elastic net algorithm used for prognostic model construction, and rank-based gene set enrichment analysis for exploring tumor microenvironments. FINDINGS: Our data did not support prognostic value of point mutations in either highly mutated genes (such as KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair genes. Instead, associated with worse prognosis were amplified genes involved in DNA repair and receptor tyrosine kinase (RTK) related signalings. Motivated by this observation, we categorized patients into four molecular subtypes (namely repair-deficient, proliferation-active, repair-proficient and repair-enhanced) that differed in prognosis, and also constructed a prognostic model that can stratify patients with low or high risk of relapse. Finally, we analyzed publicly available datasets, not only reinforcing the prognostic value of our identified genes in DNA repair and RTK related signalings, but also identifying tumor microenvironment correlates with prognostic risks. INTERPRETATION: Together with the evidence from genomic footprint analysis, we suggest that repair-deficient and proliferation-active subtypes are better suited for DNA damage therapies, while immunotherapy is highly recommended for repair-proficient and repair-enhanced subtypes. Our results represent a significant step in molecular subtyping, diagnosis and management for PAAD patients. FUNDING: This work was supported by the National Natural Science Foundation of China (grant numbers 81470894, 81502695, 81672325, 81871906, 82073326, 82103482 and 32170663), the Shanghai Sailing Program (grant number 20YF1426900), and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (awarded to H.F.).

Immunity-Related Gene Signature Identifies Subtypes Benefitting From Adjuvant Chemotherapy or Potentially Responding to PD1/PD-L1 Blockage in Pancreatic Cancer.

Tumor microenvironment comprises of a variety of cell types, which is quite complex and involved in chemotherapy and immune checkpoint blockage resistance. In order to explore the mechanisms involved in tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC), we first constructed an immunity-related 18-gene signature using The Cancer Genome Atlas (TCGA) PDAC project data. Then we applied the 18-gene signature to divide PDAC patients into low score and high score groups. Patients in high score group showed inferior prognosis, which was validated in another four independent cohorts, including Ruijin cohort. High score group showed significant enrichment of pathways involved in cell division and cell cycle especially in G1/S phase transition. In high score group, IHC analysis revealed higher levels of the proliferative indexes of Ki67 and PCNA than that in low score group. Prognostic analysis confirmed that patients in high score group could benefit from the gemcitabine-based adjuvant chemotherapy. In low score group, the programmed cell death 1 ligand 1(PD-L1) (+) cases showed worse prognosis but higher T cell infiltration than PD-L1(-) cases. Our immunity-related 18-gene signature could effectively predict PDAC prognosis, and it might be a practical predictive tool to identify PDAC subtype benefitting from gemcitabine-based adjuvant chemotherapy or potentially responding to PD1/PD-L1 blockade therapy.

A novel nomogram for predicting the risk of major complications after pancreaticoduodenectomy in patients with obstructive jaundice.

BACKGROUND: The aim of this study was to construct and internally validate a nomogram for predicting major complications in obstructive jaundice patients planned to undergo pancreaticoduodenectomy (PD). METHODS: The clinical data of 835 obstructive jaundice patients who underwent PD in a high-volume center were collected and retrospectively analyzed during an 8-year period. Factors affecting the major complication rate were optimized by least absolute shrinkage and selection operator (LASSO) regression analysis and were incorporated in logistic regression analysis. The performance of this nomogram was evaluated by discrimination, calibration, internal validation and clinical utility. RESULTS: Predictors included in the model were sex, American Society of Anesthesiologists (ASA) score, preoperative biliary drainage (PBD), neutrophil-to-lymphocyte ratio (NLR), hemoglobin, prealbumin, total bilirubin, transfusion, and pathology category. The model had good discrimination and calibration with a C-index of 0.700. Internal validation generated an acceptable C-index of 0.701. Decision curve analysis indicated this nomogram was clinically useful for predicting the possibility of major complications at a threshold between 1% and 59%. CONCLUSION: This novel nomogram could be conveniently used and assist in decisions for PBD in clinical practice.

PIWIL1 interacting RNA piR-017061 inhibits pancreatic cancer growth via regulating EFNA5.

PIWI (P element induced wimpy testis) integrating RNAs (piRNAs) are small non-coding RNAs with the length of approximately 30 nucleotides that plays crucial roles in germ cells and adult stem cells. Recently, accumulating data have shown that piRNA and PIWI proteins are involved in tumorigenesis. However, the roles of PIWI proteins and piRNAs in pancreatic cancer are still elusive. Here, we showed that piR-017061 is significantly downregulated in pancreatic cancer patients' samples and pancreatic cancer cell lines. Furthermore, we studied the function of piR-017061 in pancreatic cancer and our data revealed that piR-017061 inhibits pancreatic cancer cell growth in vitro and in vivo. Moreover, we analyzed the genomic loci around piR-017061 and identified EFNA5 as a novel target of piR-017061. Importantly, our data further revealed a direct binding between piR-017061 and EFNA5 mRNA mediated by PIWIL1. Mechanically, piR-017061 cooperates with PIWIL1 to facilitate EFNA5 mRNA degradation and loss of piR-017061 results in accumulation of EFNA5 which facilitates pancreatic cancer development. Hence, our data provided novel insights into PIWI/piRNA-mediated gene regulation and their function in pancreatic cancer. Since PIWI proteins and piRNA predominately express in germline and cancer cells, our study provided novel therapeutic strategy for pancreatic cancer treatment.

Does Pre-operative Biliary Drainage Influence Long-Term Survival in Patients With Obstructive Jaundice With Resectable Pancreatic Head Cancer?

Objectives: Whether pre-operative biliary drainage (PBD) affects long-term survival of patients with obstructive jaundice with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreaticoduodenectomy is still controversial. Most of the previous research did not include the important total serum bilirubin (TB) level before intervention as well as before surgery. The aim of this study is to evaluate the impact of PBD on long-term survival after considering the TB level. Methods: Data were collected retrospectively from patients with obstructive jaundice who underwent resection of pancreatic head cancer in a high-volume center. X-Tile software and Kaplan-Meier survival analysis were applied to determine the optimal cut-off levels for TB and age based on the minimal probability (P)-value and the largest χ2-value. Multivariate Cox regression analyses were performed after univariate analysis to assess independent prognostic factors for overall survival (OS) and disease-free survival (DFS). Results: Of 426 patients with obstructive jaundice who underwent pancreaticoduodenectomy for resectable pancreatic head cancer during a 7 year period, 242 (56.8%) received PBD and 184 (43.2%) underwent surgery directly. The OS of patients who received PBD was significantly worse than that of patients who did not receive PBD by univariate analysis (median of 16.6 vs. 22.2 months, P = 0.048). After including liver function parameters in the multivariate Cox regression, we found that the use of PBD was not associated with OS or DFS, while TB before intervention >150 µmol/L was an independent adverse prognostic factor for both OS [hazard ratio (HR), 1.42; 95% CI, 1.05-1.91] and DFS (HR, 1.38; 95% CI, 1.08-1.77). Conclusions: In patients with obstructive jaundice with resectable pancreatic head cancer, undergoing PBD before pancreaticoduodenectomy did not impair or benefit survival rates compared with surgery alone. However, TB before intervention >150 µmol/L predicted an unfavorable prognosis, irrespective of the PBD procedure.

miR-934 as a Prognostic Marker Facilitates Cell Proliferation and Migration of Pancreatic Tumor by Targeting PROX1.

BACKGROUND: Pancreatic cancer is an extremely lethal digestive cancer with late diagnosis and poor prognosis. miR-934 has been reported to serve as an oncogene in multiple cancers, such as ovarian cancer and bladder cancer. However, its role in pancreatic cancer remains undiscovered. MATERIALS AND METHODS: The expression data of miR-934 were obtained from the Gene Expression Omnibus database and from our own patient samples. The clinicopathological data and corresponding follow-up data were retrieved from The Cancer Genome Atlas database. CCK8 and colony formation assays were conducted to measure cell proliferation capacity in vitro. Wound healing and transwell assays were performed to detect the migration ability of pancreatic cancer cell. RESULTS: We found that miR-934 was significantly upregulated in pancreatic tumor samples and cell lines. The expression of miR-934 was related to pathological stages. Upregulated miR-934 was associated with poor prognosis in patients with pancreatic cancer. Mir-934 inhibition reduced, while overexpression promoted, cell proliferation and migration. Mechanically, we found  miR-934 could directly bind to 3'-UTR of PROX1 leading to mRNA derogation. Furthermore, increased cell proliferation and migration caused by miR-934 overexpression could be reversed by forced PROX1 expression. CONCLUSION: miR-934 is an oncogene in pancreatic cancer and could serve as a prognosis indicator for patients with pancreatic cancer, suggesting that miR-934 is a promising therapeutic target for pancreatic cancer.

A Nomogram for Individual Prediction of Poor Prognosis After Radical Surgery in Patients with Primary Pancreatic Duct Adenocarcinoma.

BACKGROUND Pancreatic cancer is a highly malignant tumor characterized by poor prognosis. TNM stage cannot always provide accurate prediction of prognosis, which is vital for individualized treatment. Therefore, a novel way to identify patients with poor prognosis after radical surgery is urgently needed. MATERIAL AND METHODS The nomogram was established based on a discovery cohort that included 554 patients with PDAC who had received radical surgery from 2012 to 2016. The clinicopathological data were collected. Poor prognosis was evaluated using 25 features, in which appropriate features for a prediction model were identified. A prediction model incorporating the selected features was established. The discriminative capacity was assessed by C-index, calibration by calibration plot, and clinical usefulness by decision curve. The bootstrapping approach was used to perform internal validation. RESULTS Characteristics included in the nomogram were coronary artery disease and stroke history, elevated CA125, AJCC stage >II, R0 resection, operating time >6 h, poor differentiation, nerve invasion, length of stay >30 days, and postoperative complications. A C-index of 0.713 indicated good discrimination of the prediction model, and the calibration curve showed acceptable calibration. Survival analysis showed that this model had better discriminative capacity than the AJCC staging system and could distinguish relatively good prognosis from poor prognosis in patients at stage II (especially IIa) and IV. CONCLUSIONS Our study presents a valid and practical model to predict prognosis of pancreatic cancer patients, which contributes to individualized therapy by assisting surgeons to predict poor prognosis in patients who received radical surgery.

Construction and integrated analysis of a lncRNA-associated competing endogenous RNA network reveal functional lncRNAs in pancreatic cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) can serve as a competing endogenous RNA (ceRNA) in regulating gene expression in multiple cancers by sponging miRNA. However, this mechanism is poorly studied in pancreatic cancer. This study aims to identify functional lncRNAs and their potential regulatory mechanisms in pancreatic cancer. METHODS: Differentially expressed lncRNA (DE-lncRNA), miRNA (DE-miRNA) and mRNA (DE-mRNA) were analyzed using data from three datasets (GSE89139, GSE24279 and GSE62452) from the Gene Expression Omnibus (GEO). The lncRNA-miRNA-mRNA interactions were predicted using miRcode and Targetscan. Gene ontology (GO) and pathway analysis of DE-mRNAs were performed using clusterProfiler. Survival analysis was conducted using data from The Cancer Genome Atlas (TCGA) database. RESULTS: Three hundred sixty-six DE-lncRNAs, 28 DE-miRNAs and 330 DE-mRNAs from pancreatic cancer and adjacent tissue were identified. A ceRNA network including 75 DE-lncRNAs, 18 DE-miRNAs and 85 DE-mRNAs was constructed, among which 16 DE-lncRNAs were associated with overall survival and 13 DE-lncRNAs were correlated with tumor progression. Three functional lncRNAs, GABPB1-AS1, ST7-AS1 and PSMG3-AS1, were identified as key functional lncRNAs, and their differential expression and potential ceRNA regulatory mechanism were validated by qPCR using pancreatic cancer cell lines and tissues. CONCLUSIONS: Our study identifies novel lncRNAs associated with progression and prognosis of pancreatic cancer and contributes to better understanding of lncRNA-associated ceRNA regulatory mechanisms in pancreatic cancer.

An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma.

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.

INPP4B As A Prognostic And Diagnostic Marker Regulates Cell Growth Of Pancreatic Cancer Via Activating AKT.

BACKGROUND: Inositol polyphosphate 4-phosphatase type II (INPP4B), a member of the PI3K/Akt signaling pathway, plays a vital role in the initiation and progression of cancers. However, its biological role in pancreatic cancer remains largely undiscovered. Our study aimed to investigate the effects of INPP4B on proliferation in pancreatic cancer and its clinical relevance. MATERIALS AND METHODS: INPP4B expression data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Clinicopathological and survival data were retrieved from the TCGA database. CCK8 and colony formation assays were performed to measure the proliferative capacity of pancreatic cancer. Tumor xenograft models were established to measure cancer proliferative abilities in vivo. RESULTS: INPP4B was upregulated in pancreatic cancer tissue compared with normal tissue. INPP4B knockdown inhibited cell proliferation and promoted apoptosis in pancreatic cancer in vitro and in vivo. INPP4B knockdown also reduced AKT phosphorylation. Moreover, INPP4B was associated with poor overall and disease-free survival, with Cox regression analysis showing that INPP4B could serve as an independent prognostic marker. ROC curve analysis showed that INPP4B possessed moderate diagnostic value. CONCLUSION: Collectively, INPP4B is an oncogenic gene in pancreatic cancer and could serve as a potential diagnostic marker and an independent prognostic marker, suggesting that it could be a novel therapeutic target for pancreatic cancer.

Melittin-induced long non-coding RNA NONHSAT105177 inhibits proliferation and migration of pancreatic ductal adenocarcinoma.

Long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC). Previously, we found that melittin treatment suppressed PDAC tumor growth. However, it is unclear whether lncRNAs have any role in the melittin-induced suppression of PDAC. In this study, we used microarray data to identify 844 lncRNAs that were significantly differentially expressed in response to melittin treatment. Of these lncRNAs, we focused on the lncRNA NONHSAT105177, which had about a 22-fold increase in expression with melittin treatment. We found that melittin treatment increased NONHSAT105177 expression in PDAC cell lines but not in normal pancreatic ductal epithelial cell line. NONHSAT105177 expression was significantly lower in PDAC cancer tissues than in adjacent noncancerous tissues. Additionally, overexpression of NONHSAT105177 inhibited PDAC cell proliferation, migration, and the epithelial-mesenchymal transition (EMT), both in vitro and in vivo. Consistent with the mechanism of action of melittin, NONHSAT105177 significantly downregulated cholesterol pathway genes, including Clusterin (CLU). Moreover, we found that NONHSAT105177 trafficking was mediated by exosomes. The combined findings of our current and previous studies suggest that NONHSAT105177 mediated the melittin-induced inhibition of PDAC cell growth and metastasis, which indicated a potential target for developing new strategies.