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.

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.

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.

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.

Genomic signatures of pancreatic adenosquamous carcinoma (PASC).

In pancreatic cancer, pancreatic adenosquamous carcinoma (PASC) containing both ductal adenocarcinoma and squamous carcinoma in the same tumour represents ∼4% of the total incidence. To date, the genomic features of this mixed tumour are still unknown. We analysed the genomes of 17 PASCs and 34 pancreatic ductal adenocarcinomas (PDACs), and showed that PASC carried highly enriched TP53 mutations and 3p loss as compared with PDAC. We also showed that adenomatous and squamous components of PASC harboured comparable genomic alterations, suggesting that the two cellular components develop from the same progenitor cancer cells. Our study has updated genomic knowledge to help with understanding mixed cancers of the pancreas. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Identification of IL-7 as a candidate disease mediator in osteoarthritis in Chinese Han population: a case-control study.

OBJECTIVES: Little is known about the biochemical mediators IL-7 that correlate with the initiation and progression of OA. We performed this study to assess the role of variants of IL-7 in OA susceptibility in the Chinese Han population. METHODS: We performed a retrospective, case-control study in the Chinese Han population from 2013 to 2015. Four single nucleotide polymorphisms were genotyped (using a ligase detection reaction) in 602 patients and 454 controls. Differences between groups were analysed, and association was assessed by the odds ratio (OR) and 95% CI. RESULTS: Among these polymorphisms, rs2583764, rs2583760 and rs6993386 showed no significant association with OA in the Chinese Han population {rs2583764 [P-allele = 0.98651, P-genotype = 0.40392, OR (95% CI): 1.00162 (0.83066, 1.20775)]; rs2583760 [P-allele = 0.384500, P-genotype = 0.58752, OR (95% CI): 0.69859 (0.30996, 1.57449)]; rs6993386 [P-allele = 0.69525, P-genotype = 0.50712, OR (95% CI): 0.96432 (0.80406, 1.15653)]}. However, the results showed that the rs2583759 polymorphism was significantly associated with OA [P-allele = 0.00 P-genotype = 3.86 × 10(-30), OR (95% CI): 0.27794 (0.22407, 0.34476)], even when the 10 000 times permutation was performed (P-allele-permutation < 0.00010, P-genotype-permutation = 0.00010). Haplotype analyses showed A-G-A-C, A-G-A-T and G-G-G-C of rs2583764-rs2583760-rs6993386-rs2583759 were risk factors for OA, both before or after the 10 000 times permutation, indicating IL-7 to be associated with OA. CONCLUSION: There was a significant association between IL-7, especially rs2583759, and OA in the Chinese Han population.

The Interplay Between miR-148a and DNMT1 Might be Exploited for Pancreatic Cancer Therapy.

We discovered the expression level of miR-148a significantly decreased in pancreatic cancer tissues whereas that of DNMT1 increased. In ASPC-1 cancer cells, the overexpression of miR-148a led to a decreased level of DNMT1 and reduced the proliferation and metastasis of ASPC-1 cells. Moreover, the increased expression of miR-148a arrested the UTR methylation of p27, giving rise to an increased level of p27. Interestingly, it was shown that the DNMT1 inhibition enhanced the expression of miR-148a. In vivo studies demonstrated that the tumorigenesis of ASPC-1 was significantly arrested by either the overexpression of miR-148a or the inhibition of DNMT1.

NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn's disease (CD), in Chinese Han population.

OBJECTIVE: This study aimed to investigate whether NLRP3 is associated with IBD in Chinese Han population. METHODS: Three SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients [232 Crohn's disease (CD) patients, 56 ulcerative colitis (UC) patients] and 274 controls. RESULTS: In IBD group, the results showed no significant association. When subdivided to CD and UC, it showed in CD subgroup, there was no significant association. However, in UC subgroup, rs10754558 (P allele=0.015272, P genotype=0.029776, OR [95% CI]=0.604190[0.401200-0.909886]) and rs10925019 (P allele=0.013042, P genotype=0.037045, OR [95% CI]=2.022613[1.149854-3.557812]) have significant associations with UC. The G and T alleles were risk factors of the susceptibility of UC, the GG and TT genotypes may increase risk of this disease. Rs4925648 has no association with UC. The haplotypes analysis results showed as follow: for rs4925648-rs10925019, CC and TT are risk factors for UC (for CC, χ2=3.605, P=0.057613, OR [95% CI]=1.645 [0.980-2.761], for TT, χ2=5.522, P=0.018804, OR [95% CI]=0.426[0.205-0.884]), and for rs10754558-rs10925019, CT and GC haplotypes are risk factors for UC (for CT, χ2=3.545, P=0.059739, OR [95% CI]=0.571[0.317-1.029], for GC, χ2=9.359, P=0.002228, OR [95% CI]=1.904 [1.255-2.887]). CONCLUSIONS: We first demonstrated that rs10754558 and rs10925019 are significantly associated with the susceptibility of UC, but not CD in Chinese Han population, suggesting that NLRP3 may play an important role in the pathogenesis of UC.

Association between miR34b/c polymorphism rs4938723 and cancer risk: a meta-analysis of 11 studies including 6169 cases and 6337 controls.

BACKGROUND: The functional polymorphism rs4938723 in the promoter region of pri-miR-34b/c is potentially associated with susceptibility to several cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Here we conducted a comprehensive meta-analysis to investigate the association between rs4938723 and cancer risk. MATERIAL AND METHODS: Eligible studies extracted from the databases of PubMed, Web of Science, and Cochrane Library were evaluated. Statistical analysis was performed using Revman 5.2 and STATA 12.0 software. RESULTS: By characterizing the extracted data, a total of 11 studies reported in 10 publications including 6169 cases and 6337 controls were selected for further analysis. Our results revealed a significant association between the rs4938723 polymorphism and cancer risk in the codominant model (TC vs. TT: OR=1.10, 95% CI=1.02-1.19, P=0.009) but not in other genetic models. In the stratified analysis of different cancer types, a significant association was found in nasopharyngeal cancer, osteosarcoma, and renal cell cancer. Furthermore, stratified analysis of ethnicity indicated that a highly significant association was shown in the Asian population in a codominant model (TC vs. TT: OR=1.13, 95% CI=1.03-1.24, P=0.007) when compared with African-Americans and Caucasians. CONCLUSIONS: Overall, the current study suggests that the miR-34b/c rs4938723 polymorphism may be associated with the risk of cancers, including nasopharyngeal cancer, osteosarcoma, and renal cell cancer, and to some extent this polymorphism is closely related to cancer susceptibility in Asians.

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.

Downregulation of gas5 increases pancreatic cancer cell proliferation by regulating CDK6.

Recent studies have revealed that long non-coding RNAs (lncRNAs) play important roles in cancer biology and that lncRNA gas5 (growth arrest-specific 5) regulates breast cancer cell growth. However, the role of gas5 in pancreatic cancer progression remains largely unknown. In the current study, we assay the expression level of gas5 in pancreatic cancer tissues and define the role of gas5 in the regulation of pancreatic cancer cell proliferation. We verify that the expression level of gas5 is significantly decreased in pancreatic cancer tissues compared with normal control. Overexpression of gas5 in pancreatic cancer cells inhibits cell proliferation, whereas gas5 inhibition induces a significant decrease in G0/G1 phase and an increase in S phase. We further demonstrate that gas5 negatively regulates CDK6 (cyclin-dependent kinase 6) expression in vitro and in vivo. More importantly, knockdown of CDK6 partially abrogates gas5-siRNA-induced cell proliferation. These data suggest an important role of gas5 in the molecular etiology of pancreatic cancer and implicate the potential application of gas5 in pancreatic cancer therapy.

Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma.

The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P < 0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P > 0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.

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.

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.

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.

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.

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.

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.

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.