NUSAP1 promotes pancreatic ductal adenocarcinoma progression by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. METHODS: Differentially expressed genes (DEGs) were screened. A protein‒protein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. RESULTS: Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. CONCLUSIONS: NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

The microbiota and microbiome in pancreatic cancer: more influential than expected.

Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

Identifying the risk factors for pancreatic fistula after laparoscopic pancreaticoduodenectomy in patients with pancreatic cancer.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is a surgical procedure for treating pancreatic cancer; however, the risk of complications remains high owing to the wide range of organs involved during the surgery and the difficulty of anastomosis. Pancreatic fistula (PF) is a major complication that not only increases the risk of postoperative infection and abdominal hemorrhage but may also cause multi-organ failure, which is a serious threat to the patient's life. This study hypothesized the risk factors for PF after LPD. AIM: To identify the risk factors for PF after laparoscopic pancreatoduodenectomy in patients with pancreatic cancer. METHODS: We retrospectively analyzed the data of 201 patients admitted to the Fudan University Shanghai Cancer Center between August 2022 and August 2023 who underwent LPD for pancreatic cancer. On the basis of the PF's incidence (grades B and C), patients were categorized into the PF (n = 15) and non-PF groups (n = 186). Differences in general data, preoperative laboratory indicators, and surgery-related factors between the two groups were compared and analyzed using multifactorial logistic regression and receiver-operating characteristic (ROC) curve analyses. RESULTS: The proportions of males, combined hypertension, soft pancreatic texture, and pancreatic duct diameter ≤ 3 mm; surgery time; body mass index (BMI); and amylase (Am) level in the drainage fluid on the first postoperative day (Am > 1069 U/L) were greater in the PF group than in the non-PF group (P < 0.05), whereas the preoperative monocyte count in the PF group was lower than that in the non-PF group (all P < 0.05). The logistic regression analysis revealed that BMI > 24.91 kg/m² [odds ratio (OR) =13.978, 95% confidence interval (CI): 1.886-103.581], hypertension (OR = 8.484, 95%CI: 1.22-58.994), soft pancreatic texture (OR = 42.015, 95%CI: 5.698-309.782), and operation time > 414 min (OR = 15.41, 95%CI: 1.63-145.674) were risk factors for the development of PF after LPD for pancreatic cancer (all P < 0.05). The areas under the ROC curve for BMI, hypertension, soft pancreatic texture, and time prediction of PF surgery were 0.655, 0.661, 0.873, and 0.758, respectively. CONCLUSION: BMI (> 24.91 kg/m²), hypertension, soft pancreatic texture, and operation time (> 414 min) are considered to be the risk factors for postoperative PF.

A new approach: Evaluation of necroptosis and immune status enables prediction of the tumor microenvironment and treatment targets in pancreatic cancer.

Growing evidence indicates a potential correlation between necroptosis and pancreatic cancer, and the relationship between necroptosis, immune infiltration and the microenvironment in pancreatic cancer has drawn increasing attention. However, two-dimensional phenotype and prognostic assessment systems based on a combination of necroptosis and immunity have not been explored. In our present study, we explored the pancancer genomics signature of necroptosis-related molecules, identifying necroptosis-related molecule mutation profiles, expression profiles, and correlations between expression levels and methylation/CNV levels. We identified distinct necroptotic as well as immune statuses in pancreatic cancer, and a high necroptosis phenotype and high immunity phenotype both indicated better prognosis than a low necroptosis phenotype and low immunity phenotype. The two-dimensional phenotype we constructed has ideal discriminative effects on pancreatic cancer prognosis, inflammation, and the immune microenvironment. The "high-necroptosis and high-immunity (HNHI)" group exhibited the best prognosis and the highest proportion of infiltrating immune cells. The NI score can be used to predict patient prognosis and is correlated with the immune microenvironment score, chemotherapeutic drug IC50, and tumor mutational burden. In addition, it may be useful for predicting the effect of individualized chemotherapy and immunotherapy. Our study also revealed that SLC2A1 is associated with both necroptosis and immunity and acts as a potential oncogene in pancreatic cancer. In conclusion, the two-dimensional phenotype and NI score we developed are promising tools for clinical multiomics applications and prediction of chemotherapy and immunotherapy response and present benefits in terms of precision medicine and individualized treatment decision-making for pancreatic cancer patients.

[Systematic reviews of mini-invasive surgery versus standard approaches for total knee arthroplasty].

OBJECTIVE: To conduct a systematic review to compare the early efficacies of minimally invasive surgery (MIS) versus conventional approaches in TKA (total knee arthroplasty). METHODS: Randomized controlled trials (RCTs) and clinical controlled trials (CCTs) were retrieved from the databases of MEDLINE (1996.6 - 2010.12), EMBASE (1996.6 - 2010.12), PubMed (1996 - 2010.12) and Cochrane Library (Issue 2, 2012). Journal of Orthopedics (from establishment to December 2010) and Orthopedic Journal of China (from establishment to December 2010) were manually searched. Both RCTs and CCTs were included. The data were extracted by two reviewers with designed extraction form RevMan 4.2.8 software for data analysis. The criteria were as follows: (1) operative duration and reduced blood loss; (2) VAS (visual analog scale) score; (3) faster recovery of ROM (range of movement); (4) quadriceps muscle strength; (5) component positioning malalignment; (6) tibiofemoral angle; (7) rate of complications. RESULTS: A total of 18 RCTs were included. Compared with the standard TKA procedure, the MIS group had a longer operative duration (WMD (weighted mean difference) 14.16, 95%CI (confidence interval) (12.61, 15.71)); reduced blood loss (WMD 8.31, 95%CI (6.16, 10.46)); lower VAS score at Days 3-5 post-operation (WMD 4.99, 95%CI (4.19, 5.78)); better Mean Knee Society scores at Week 6 post-operation (WMD 4.99, 95%CI (4.19, 5.78)), improvement in ROM occurred more rapidly at Month 3 post-TKA (WMD 14.59, 95%CI (8.39, 20.80)). Although the differences were not statistically significant, tibiofemoral angle was more precise in the standard group and the rate of component malalignment occurred more frequently in the MIS group (WMD 0.20, 95%CI (-0.12, 0.52)) (RR 1.57, 95%CI (0.88, 2.83)). CONCLUSION: MIS leads to a faster recovery than conventional surgery with a shorter operative duration, a reduced blood loss, a lower VAS score and a faster recovery of ROM and quadriceps muscle strength. However, the rates of component malalignment and complications occur more frequently in the MIS group. Potential benefits in long-term survival rate and functional improvement require further investigations.

Pyroptosis-related lncRNA pairs to estimate the molecular features and prognostic outcomes of pancreatic ductal adenocarcinoma.

Pyroptosis is a form of programmed cell death associated with inflammatory alterations. However, the intrinsic mechanisms and underlying correlation of pyroptosis-related lncRNAs (PRLs) in pancreatic ductal adenocarcinoma (PDAC) remain unclear. The objective of the current research was to identify pyroptosis-related lncRNAs and a prognostic model to predict the prognosis of patients. We extracted pyroptosis-related lncRNAs to construct a risk model and validated them at Fudan University Shanghai Cancer Center. Crosstalk between lncRNA SNHG10 and GSDMD was found to regulate pyroptosis levels. A new algorithm was used to establish a 0 or 1 PRL pair matrix and prognostic model. Six pyroptosis-related lncRNA pairs were identified and utilized to construct a risk model. The low-risk groups exhibited better prognoses than the high-risk groups. The area under the curve (AUC) indicated extremely high accuracy, reaching 0.810 at 1 year, 0.850 at 2 years, and 0.850 at 3 years in the training set. Patients with different risk scores exhibited distinct metabolic, inflammatory, and immune microenvironments as well as tumor mutation landscapes. Additionally, 9 commonly used chemotherapeutic drugs exhibited different sensitivities between the high- and low-risk groups. To conclude, we propose that pyroptosis exhibits a close correlation with PDAC. Our risk model based on PRL pairs may be beneficial for the accurate estimation of prognostic outcomes, the immune microenvironment, and drug sensitivity, bringing therapeutic hope for patients with PDAC.

Turning up the heat on non-immunoreactive tumors: autophagy influences the immune microenvironment in pancreatic cancer.

BACKGROUND: Autophagy regulators play important roles in the occurrence and development of a variety of tumors and are involved in immune regulation and drug resistance. However, the modulatory roles and prognostic value of autophagy regulators in pancreatic cancer have not been identified. METHODS: Transcriptomic data and survival information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to construct a risk score model. Important clinical features were analyzed to generate a nomogram. In addition, we used various algorithms, including ssGSEA, CIBERSORT, XCELL, EPIC, TIMER, and QUANTISEQ, to evaluate the roles of autophagy regulators in the pancreatic cancer immune microenvironment. Furthermore, the mutation landscape was compared between different risk groups. RESULTS: Pan cancer analysis indicated that most of the autophagy regulators were upregulated in pancreatic cancer and were correlated with methylation and CNV level. MET, TSC1, and ITGA6 were identified as the prognostic autophagy regulators and used to construct a risk score model. Some critical clinical indicators, such as age, American Joint Committee on Cancer (AJCC) T stage, AJCC N stage, alcohol and sex, were combined with the risk model to establish the nomogram, which may offer clinical guidance. In addition, our study demonstrated that the low score groups exhibited high immune activity and high abundances of various immune cells, including T cells, B cells, and NK cells. Patients with high risk scores exhibited lower half inhibitory concentration (IC50) values for paclitaxel and had downregulated expression profiles of PD1, CTLA4, and LAG3. Mutation investigation indicated that the high risk groups exhibited a higher mutation burden and higher mutation number compared to the low risk groups. additionally, we verified our risk stratification method using cytology and histology data from our center, and the results are satisfactory. CONCLUSION: We speculated that autophagy regulators have large effects on the prognosis, immune landscape and drug sensitivity of pancreatic cancer. Our model, which combines critical autophagy regulators and clinical indicators, will provide guidance for clinical treatment.

Construction of a paclitaxel-related competitive endogenous RNA network and identification of a potential regulatory axis in pancreatic cancer.

BACKGROUND: Increasing numbers of studies have elucidated the role of competitive endogenous RNA (ceRNA) networks in carcinogenesis. However, the potential role of the paclitaxel-related ceRNA network in the innate mechanism and prognosis of pancreatic cancer has not been identified. METHODS: Comprehensive bioinformatics analyses were performed to identify drug-related miRNAs (DRmiRNAs), drug-related mRNAs (DRmRNAs) and drug-related lncRNAs (DRlncRNAs) and construct a ceRNA network. The ssGSEA and CIBERSORT algorithms were utilized for immune cell infiltration analysis. Additionally, we validated our paclitaxel-related ceRNA regulatory axis at the gene expression level; functional experiments were conducted to explore the biological functions of the key genes. RESULTS: A total of 182 mRNAs, 13 miRNAs, and 53 lncRNAs were confirmed in the paclitaxel-related ceRNA network. In total, 6 mRNAs, 4 miRNAs, and 6 lncRNAs were identified to establish a risk signature and exhibited optimal prognostic effects. The mRNA signature can predict the abundance of immune cell infiltration and the sensitivity of different chemotherapeutic drugs and may also have a guiding effect in immune checkpoint therapy. A potential PART1/hsa-mir-21/SCRN1 axis was confirmed according to the ceRNA theory and was verified by qPCR. The results indicated that PART1 knockdown markedly increased hsa-mir-21 expression but inhibited SCRN1 expression, weakening the proliferation and migration abilities. CONCLUSIONS: We hypothesized that the paclitaxel-related ceRNA network strongly influences the innate mechanism, prognosis, and immune infiltration of pancreatic cancer. Our risk signatures can accurately predict survival outcomes and provide a clinical basis.

Microorganisms in chemotherapy for pancreatic cancer: An overview of current research and future directions.

Pancreatic cancer is a malignant tumor of the digestive system with a very high mortality rate. While gemcitabine-based chemotherapy is the predominant treatment for terminal pancreatic cancer, its therapeutic effect is not satisfactory. Recently, many studies have found that microorganisms not only play a consequential role in the occurrence and progression of pancreatic cancer but also modulate the effect of chemotherapy to some extent. Moreover, microorganisms may become an important biomarker for predicting pancreatic carcinogenesis and detecting the prognosis of pancreatic cancer. However, the existing experimental literature is not sufficient or convincing. Therefore, further exploration and experiments are imperative to understanding the mechanism underlying the interaction between microorganisms and pancreatic cancer. In this review, we primarily summarize and discuss the influences of oncolytic viruses and bacteria on pancreatic cancer chemotherapy because these are the two types of microorganisms that are most often studied. We focus on some potential methods specific to these two types of microorganisms that can be used to improve the efficacy of chemotherapy in pancreatic cancer therapy.

Validation and head-to-head comparison of four models for predicting malignancy of intraductal papillary mucinous neoplasm of the pancreas: A study based on endoscopic ultrasound findings.

BACKGROUND: Several models are currently available for predicting the malignancy of pancreatic intraductal papillary mucinous neoplasm (IPMN), namely, the Pancreatic Surgery Consortium (PSC), the Japan Pancreas Society (JPS), the Johns Hopkins Hospital (JHH), and the Japan-Korea (JPN-KOR) models. However, a head-to-head comparison that shows which model is more accurate for this individualized prediction is lacking. AIM: To perform a head-to-head comparison of the four models for predicting the malignancy of pancreatic IPMN. METHODS: A total of 181 patients with IPMN who had undergone surgical resection were identified from a prospectively maintained database. The characteristics of IPMN in patients were recorded from endoscopic ultrasound imaging data and report archives. The performance of all four models was examined using Harrell's concordance index (C-index), calibration plots, decision curve analyses, and diagnostic tests. RESULTS: Of the 181 included patients, 94 were categorized as having benign disease, and the remaining 87 were categorized as having malignant disease. The C-indexes were 0.842 [95% confidence interval (CI): 0.782-0.901], 0.704 (95%CI: 0.626-0.782), 0.754 (95%CI: 0.684-0.824), and 0.650 (95%CI: 0.483-0.817) for the PSC, JPS, JHH, and JPN-KOR models, respectively. Calibration plots showed that the PSC model had the least pronounced departure from ideal predictions. Of the remaining three models, the JPS and JHH models underestimated the probability of malignancy, while the JPN-KOR model overestimated the malignant potential of branch duct-IPMN. Decision curve analysis revealed that the PSC model resulted in a better clinical net benefit than the three other models. Diagnostic tests also showed a higher accuracy (0.801) for the PSC model. CONCLUSION: The PSC model exhibited the best performance characteristics. Therefore, the PSC model should be considered the best tool for the individualized prediction of malignancy in patients with pancreatic IPMN.

Overexpression of Tbx3 predicts poor prognosis of patients with resectable pancreatic carcinoma.

BACKGROUND: To determine the expressions of Tbx3, a member of subgroup belonging to T-box family, and its prognostic value in pancreatic carcinoma. MATERIALS AND METHODS: We determined the expression levels of Tbx3 on both mRNA and protein levels in 30 pairs of fresh tumor tissues and paratumor tissues by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. In addition, protein level of Tbx3 were identified using immunochemistry in 80 pairs of paraffin-embedded specimen. The correlations between Tbx3 expression and various clinicopathological parameters as well as overall survival were evaluated. RESULTS: Tbx3 mRNA and protein levels in tumor tissues were significantly higher than in the paratumor tissues by qRT-PCR (0.05 ±0.007 vs. 0.087±0.001, p<0.001) and western blotting (1.134±0.043 vs. 0.287±0.017, p<0.001). The statistical analysis based on immunohistochemical evaluation suggested that Tbx3 aberrant expression was significantly associated with several conventional clinicopathological variables, such as gender, age, tumor position, preoperative CA19-9 level, pathological T staging and N staging. Univariate and multivariate analyses revealed that Tbx3 expression was an independent prognostic factor for overall survival (<0.001). CONCLUSIONS: Our results suggest that overexpression of Tbx3 is associated with poor prognosis of pancreatic cancer patients. However, additional clinical trials are needed to accurately validate this observation.

Overexpression of NDC80 is correlated with prognosis of pancreatic cancer and regulates cell proliferation.

AIMS: NDC80/Hec1, one of four proteins of the outer kinetochore NDC80 complex, is involved in the tumorigenesis of a variety of cancers. In this study, we focused on that NDC80 is overexpressed in human pancreatic cancer and investigates the role of NDC80-knockdown in pancreatic cancer cells proliferation. MATERIALS AND METHODS: We determined the expression levels of NDC80 on both mRNA and protein levels in fresh pancreatic cancer tissues and cells by quantitative real-time polymerase chain reaction and immunoblotting, respectively. Furthermore, protein level of NDC80 was identified using immunochemistry in paraffin-embedded tumor specimen, with correlation between NDC80 expression and various clinicopathological parameters evaluated. The role of NDC80 in pancreatic cancer cells (Panc-1) growth was investigated by lentivirus-mediated silencing of NDC80. The effect of NDC80 deletion on cell proliferation was analyzed by MTT assay and clone formation assay, while cell cycle distributions and apoptosis were analyzed by flow cytometry. RESULTS: The mRNA and protein of NDC80 were overexpressed in pancreatic cancer tissues and cells. The statistical analysis based on immunohistochemical evaluation suggested that NDC80 overexpression was signifi cantly associated with clinicopathological parameters including pathological T staging and N staging, which may be served as an predictor for poor outcomes. The silencing of NDC80 in Panc-1 cells could suppress cell proliferation and colony formation. Furthermore, the NDC80-siRNA infected Panc-1 cells lead to cell cycle arrest at G2/M phase and induction of apoptosis. CONCLUSION: These results demonstrated that NDC80 plays an essential role in the tumorigenesis of pancreatic cancer, and might serve as potential prognostic and therapeutic target for treatment of pancreatic cancer.

Novel blood-based microRNA biomarkers for diagnosis of pancreatic cancer: a meta-analysis.

BACKGROUND: Recently, several studies have shown that blood-based microRNAs in patients with pancreatic cancer (PC) could be aberrantly expressed. The purpose of this meta-analysis was to evaluate blood-based microRNAs as novel biomarkers for diagnosis of PC. METHODS: Eligible studies which had evaluated the diagnostic performance of blood-based microRNAs and had been published from February 2004 to February 2014 were retrieved. The quality of the studies was evaluated with the QUADAS-2 tool. The performance characteristics were pooled using random-effects models. Statistical analysis was performed with STATA and Meta-Disc1.4 software. RESULTS: The global meta-analysis included 12 studies from 8 articles, which contained 1,060 blood-based samples of PC patients and 935 blood-based samples of non-PC patients. Summary results suggested pooled sensitivity of 0.87 (95% confidence interval [95% CI], 0.85-0.89), specificity 0.92 (95% CI, 0.90-0.94), positive likelihood ratio 11.18 (95% CI, 5.57-22.46), negative likelihood ratio 0.16 (95% CI, 0.11-0.23), diagnostic odds ratio 88.98 (95% CI, 39.85-198.69) and the area under the summary receiver operating characteristic (SROC) curve 0.96. CONCLUSIONS: This meta-analysis demonstrated blood-based microRNA expression profiles with the potential to discriminate PC patients from non-PC patients, which have moderate diagnostic accuracy. However, further validation studies are needed for their clinical significance in the diagnosis of PC to be established.

Overexpression of Tbx3 is correlated with Epithelial-Mesenchymal Transition phenotype and predicts poor prognosis of colorectal cancer.

AIMS: To investigate the clinical significance of Tbx3 in colorectal cancer (CRC) and the possible association between Tbx3 expression and Epithelial- Transition Mesenchymal (EMT) phenotype. METHODS: Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were employed to evaluate the expression of Tbx3 in 30 fresh CRC and matched normal tissues. Using immunochemistry, protein level of Tbx3 and EMT markers (E-cadherin and N-cadherin) were identified in 150 pairs of paraffin-embedded specimen. RESULTS: The results of qRT-PCR and western blotting showed that Tbx3 expression was higher in CRC tissues than in corresponding normal tissues. The statistical analysis based on immunohistochemical evaluation suggested that Tbx3 aberrant expression was significantly associated with tumor size (P=0.049), differentiation (P=0.032), invasion (P=0.019), lymph node metastasis (P=0.049) and TNM stage (P=0.018). Patients who displayed high expression of Tbx3 may achieve a poorer overall survival (OS) and disease-free survival (DFS), compared to those with low expression of Tbx3. This tendency was also observed in patients with intermediate levels of disease (II and III stage). The multivariate analysis indicated Tbx3 expression could independently predict the outcome of CRC patients. Interestingly, correlation analysis suggested Tbx3 expression was negatively correlated with E-cadherin expression, but positively correlated with N-cadherin expression. CONCLUSION: Tbx3 may promote CRC progression by involving EMT program and has the potential to be an effective prognostic predictor for CRC patients.