Huaier enhances the tumor-killing effect and reverses gemcitabine-induced stemness by suppressing FoxM1.

BACKGROUND: Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown. PURPOSE: This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer. METHODS: Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression. RESULTS: Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro. CONCLUSION: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.

The mediating role of resilience between emotional intelligence and academic procrastination in nursing undergraduates: A cross-sectional study.

AIM: To investigate the relationship among emotional intelligence (EI), resilience and academic procrastination (AP), and provide suggestions for the development of targeted intervention strategies and lowering of AP level of nursing undergraduates. DESIGN: A cross-sectional study. METHODS: Three provincial universities offering nursing courses in China were investigated in this study. A convenience sample of 256 nursing undergraduates from May 2021 to September 2021 were recruited, with a response rate of 91.4%. Data were collected using face-to-face interviews. The survey tools included the General Information Questionnaire, Academic Procrastination Scale, Emotional Intelligence Scale and Resilience Scale. IBM SPSS v19.0 and Amos 22.0 were used for data analysis. RESULTS: The AP of sampled nursing undergraduates was at the middle level (54.4 ± 21.5). The AP of nursing undergraduates was negatively correlated with EI and resilience. Moreover, the analysis on the mediating role of resilience via structural equation model showed a good fit, with χ2/df = 2.34, RMSEA = 0.07, CFI = 0.99, GFI = 0.95, TLI = 0.98. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Risk factors and prediction score for new-onset diabetes mellitus after liver transplantation.

AIM: New-onset diabetes mellitus is a frequent and severe complication arising after liver transplantation (LT). We aimed to identify the risk factors for new-onset diabetes mellitus after liver transplantation (NODALT) and to develop a risk prediction score system for relevant risks. METHODS: We collected and analyzed data from all recipients who underwent liver transplantation at the First Affiliated Hospital of Xi'an Jiaotong University. The OR derived from a multiple logistic regression predicting the presence of NODALT was used to calculate the risk prediction score. The performance of the risk prediction score was externally validated in patients who were from the CLTR (China Liver Transplant Registry) database. RESULTS: A total of 468 patients met the outlined criteria and finished the follow-up. Overall, NODALT was diagnosed in 115 (24.6%) patients. Age, preoperative impaired fasting glucose (IFG), postoperative fasting plasma glucose (FPG), and the length of hospital stay were significantly associated with the presence of NODALT. The risk prediction score includes age, preoperative IFG, postoperative FPG, and the length of hospital stay. The risk prediction score of the area under the receiver operating curve was 0.785 (95% CI: 0.724-0.846) in the experimental population and 0.782 (95% CI: 0.708-0.856) in the validation population. CONCLUSIONS: Age at the time of transplantation, preoperative IFG, postoperative FPG, and length of hospital stay were independent predictive factors of NODALT. The use of a simple risk prediction score can identify the patients who have the highest risk of NODALT and interventions may start early.

Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas.

Adenosquamous carcinoma of the pancreas (ASCP) is a rare histological subtype of pancreatic cancer with a poor prognosis and a high metastasis rate. However, little is known about its genomic landscape and prognostic biomarkers. A total of 48 ASCP specimens and 98 pancreatic ductal adenocarcinoma (PDAC) tumour specimens were sequenced to explore the genomic landscape and prognostic biomarkers. The homozygous deletion of the 9p21.3 region (including CDKN2A, CDKN2B, and MTAP) (9p21 loss) occurred in both ASCP and PDAC, and a higher frequency of 9p21 loss was observed in ASCP (12.5% vs 2.0%, P = 0.022). Notably, 9p21 loss was significantly associated with poor disease-free survival (DFS) in ASCP patients (mDFS (Median DFS) = 4.17 vs 7.33 months, HR (Hazard Ratio) = 3.70, P = 0.009). The most common gene alterations in patients with ASCP were KRAS (96%), TP53 (81%), CDKN2A (42%), SMAD4 (21%), CDKN2B (13%), and FAT3 (13%). The mutation rates of ACVR2A (6.25% vs 0%), FANCA (6.25% vs 0%), RBM10 (6.25% vs 0%), and SPTA1 (8.33% vs 1.02%) were significantly higher in ASCP than in PDAC. In conclusion, we have comprehensively described the genomic landscape of the largest cohort of ASCP patients to date and highlight that 9p21 loss may be a promising prognostic biomarker for ASCP, which provides a molecular basis for prognosis prediction and new therapeutic strategies for ASCP.

Clinical treatment for persistent inflammation, immunosuppression and catabolism syndrome in patients with severe acute pancreatitis (Review).

Severe acute pancreatitis (SAP) is a severe disease with a high prevalence and a 3-15% mortality worldwide, and premature activation of zymogen for any reason is the initial factor for the onset of SAP. Gallstone disease and heavy alcohol consumption are the two most common etiologies of SAP. Persistent inflammation, immunosuppression and catabolism syndrome (PICS) is a life-threatening illness, and there are no effective treatments. The relapse state of PICS mainly leads to high mortality due to septic shock or severe trauma, both of which are dangerous and challenging conditions for clinicians. Thus, it is important for medical staff to identify patients at high risk of PICS and to master the prevention and treatment of PICS in patients with SAP. The present review aims to increase the understanding of the pathogenesis of PICS, produce evidence for PICS diagnosis and highlight clinical treatment for PICS in patients with SAP. With this information, clinical workers could implement standardized and integrated measures at an early stage of SAP to stop its progression to PICS.

[Retracted] Chronic alcohol exposure exacerbates inflammation and triggers pancreatic acinar­to­ductal metaplasia through PI3K/Akt/IKK.

Following the publication of the above article, a concerned reader drew to the Editor's attention that there were a number of apparent anomalies associated with the western blots featured in Figs. 1C and E, 3A, C and E, 4A, C and E, 5B, 8A and C; moreover, the images shown for the immunohistochemical experiments in Fig. 8E contained groupings of cells that were markedly similar in appearance, comparing across the eight separate figure parts. After having conducted an internal investigation of the data in this paper, the Editor of International Journal of Molecular Medicine has judged that the potentially anomalous presentation of the western blotting data and the strikingly similar groupings of cells in Fig. 8E were too extensive that these features could have been attributed to pure coincidence. Therefore, the Editor has decided that this article should be retracted from the publication on the grounds of an overall lack of confidence in the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor sincerely apologizes to the readership for any incovenience caused, and we thank the reader for bringing this matter to our attention. [International Journal of Molecular Medicine 35: 653­663, 2015; DOI: 10.3892/ijmm.2014.2055].

PIK3R3 Missense and NOTCH2 Synonymous Single Nucleotide Polymorphisms Are Associated with Liver Cancer.

BACKGROUND: Single nucleotide polymorphism (SNP) of candidate genes also affects the occurrence and prognosis of liver cancer. We mainly explored the effects of PIK3R3 and NOTCH2 polymorphisms on liver cancer risk among Chinese people. METHODS: Four SNPs (rs785468, rs785467, rs3795666, and rs17024525 in PIK3R3 and NOTCH2) from 709 liver cancer patients and 700 healthy controls were genotyped using the Agena MassARRAY system. The correlation between SNPs and liver cancer risk was evaluated using logistic regression analysis. The SNP-SNP interactions were conducted by the multifactor dimensionality reduction method. RESULTS: The results revealed that PIK3R3-rs785467 reduced the likelihood of liver cancer among Chinese Han people (p < 0.05). In addition, PIK3R3-rs785467 decreased the susceptibility to liver cancer in different populations (females, non-smokers, and age >55 years, p < 0.05). NOTCH2-rs3795666 reduced the susceptibility to liver cancer among males, drinkers, and patients aged >55 years (p < 0.05). CONCLUSIONS: Our results demonstrate that PIK3R3-rs785476 and NOTCH2-rs3795666 polymorphisms are responsible for decreasing the susceptibility of liver cancer development in the Chinese Han population.

Mutant p53 driven-LINC00857, a protein scaffold between FOXM1 and deubiquitinase OTUB1, promotes the metastasis of pancreatic cancer.

Tumour metastasis is the major adverse factor for recurrence and death in pancreatic cancer (PC) patients. P53 mutations are considered to be the second most common type of mutation in PC and significantly promote PC metastasis. However, the molecular mechanisms underlying the effects of p53 mutations, especially the regulatory relationship of the protein with long noncoding RNAs (lncRNAs), remain unclear. In the present study, we demonstrated that the lncRNA LINC00857 exhibits a significantly elevated level in PC and that it is associated with poor prognosis; furthermore, TCGA data showed that LINC00857 expression was significantly upregulated in the mutant p53 group compared with the wild-type p53 group. Gain- and loss-of-function experiments showed that LINC00857 promotes the metastasis of PC cells. We further found that LINC00857 upregulates FOXM1 protein expression and thus accelerates metastasis in vitro and in vivo. Mechanistically, LINC00857 bound simultaneously to FOXM1 and to the deubiquitinase OTUB1, thereby serving as a protein scaffold and enhancing the interaction between FOXM1 and OTUB1, which inhibits FOXM1 degradation through the ubiquitin-proteasome pathway. Interestingly, we found that mutant p53 promotes LINC00857 transcription by binding to its promoter region. Finally, atorvastatin, a commonly prescribe lipid-lowering drug, appeared to inhibit PC metastasis by inhibiting the mutant p53-LINC00857 axis. Taken together, our results provide new insights into the biology driving PC metastasis and indicate that the mutant p53-LINC00857 axis might represent a novel therapeutic target for PC metastasis.

Prognostic nomogram for primary splenic lymphoma: a SEER database-based study.

This study aimed to establish a nomogram model based on the clinicopathological factors affecting the prognosis of patients with primary splenic lymphoma (PSL) to predict the overall survival (OS) and cancer-specific survival (CSS) of patients. A total of 4074 patients diagnosed with PSL were included in this study. Among them, 4052 cases from the SEER (Surveillance, Epidemiology, and End Results) database were randomized into a training set and an internal validation set in a 7:3 ratio. Another 22 patients from the First Affiliated Hospital of Xi'an Jiaotong University were used as an external validation set. The prognostic factors affecting the OS and CSS of patients were analyzed using univariate and multivariate Cox regression models. Survival analysis was performed using Kaplan-Meier (KM) method and compared by Log-rank test. Then, a nomogram model was established to predict OS and CSS. Finally, the model was validated both internally and externally using the concordance index (C-index), receiver operating characteristic curve (ROC), and calibration curve to evaluate its predictive value, and the decision curve analysis (DCA) was conducted to assess its clinical utility. Our results showed that the model displayed a good prediction ability. In the training set, the OS rates at 1, 3, and 5 years were 85.9%, 75.8% and 70.1%, respectively, while the CSS rates at 1, 3, and 5 years were 91.9%, 86.2% and 82.3%, respectively. Predictors in the prediction model of OS included age, sex, marital status, Ann Arbor stage, histology, surgery, chemotherapy and year at diagnosis. On the other hand, predictors in the model of CSS included age, Ann Arbor stage, histology, chemotherapy, and year at diagnosis. Internal and external validation of the nomogram model showed that the C-index for predicting OS was 0.678 (0.662, 0.694) in the training set, 0.672 (0.648, 0.696) in the internal validation set, and 0.704 (0.565, 0.843) in the external validation set; the C-index for predicting CSS was 0.685 (0.661, 0.709) in the training set, 0.683 (0.650, 0.716) in the internal validation set, and 0.676 (0.488, 0.864) in the external validation set. The calibration curves for several groups showed good consistency, and DCA suggested its clinical usability. In conclusion, the nomogram constructed in this study has a good predictive value for the survival of patients with PSL, and can be a clinically applicable and practical prediction tool, facilitating rapid and accurate individualized predictions of the patient survival.

Blood loss during liver transplantation is a predictor of postoperative thrombosis.

Liver transplantation (LT) is an effective way to cure end-stage liver diseases (ESLDs), which have generally been regarded as examples of acquired bleeding disorders. However, postoperative thrombosis after LT is recognised and remains a life-threatening complication. This study aimed to show that blood loss during LT is a predictor of postoperative thrombosis and to establish a predictive model. We analysed the medical records of all patients who underwent LT at the First Affiliated Hospital of Xi'an Jiaotong University from January 2017 to April 2019 to identify the risk factors for post-transplant thrombosis. The predictive nomogram was established based on independent predictors identified by logistic regression analysis. Blood loss during LT of ≥31.25 mL/kg can predict postoperative thrombosis, and the nomogram achieved an accurate prediction.

Huaier suppresses pancreatic cancer progression via activating cell autophagy induced ferroptosis.

Purpose: The anti-tumour effect of Huaier has been demonstrated in a variety of tumours. Ferroptosis is a newly identified type of programmed cell death accompanied by the accumulation of reactive oxygen species (ROS) and iron in cells and plays a key role in the therapeutic process against malignant tumours. We aimed to explore the potential therapeutic role of Huaier in pancreatic cancer and uncover the relationship between Huaier and ferroptosis. Methods: CCK8 and colony formation assays were used to determine the proliferation of pancreatic cancer cells (PCs). The levels of cellular ROS were analysed by a fluorescence probe, and the accumulation of cellular iron was showed by Prussian blue staining. The autophagosomes and mitochondrial morphology were characterised by transmission electron microscopy (TEM). The levels of intracellular glutathione (GSH) and lipid peroxidation were measured by the corresponding kits. Results: The growth inhibitory effect of Huaier on PCs was concentration- and time-dependent, but this effect was significantly attenuated by ferroptosis inhibitors. In addition, Huaier effectively inhibited the GSH-GPX4 antioxidation system and resulted in the massive accumulation of ROS in PCs As shown by TEM, Huaier-treated PCs exhibited a decrease in mitochondrial cristae and a smaller mitochondrion, accompanied by an increase in autophagosomes. Indeed, we found that autophagy can induce ferroptosis in PCs and that Huaier-induced ferroptosis can be suppressed by the autophagosome inhibitor, Wortmannin. Conclusion: Huaier can activate ferroptosis by inducing autophagy in PCs.

Piezo1 act as a potential oncogene in pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death. A growing number of studies believe that matrix stiffness plays an important role in the development of pancreatic disease. As one of the famous mechanically activated cation channels, Piezo1 has received more attention recently. Here we tried to describe the role of Piezo1 on PDAC progression. It seemed that Piezo1 was a potential tumor-promoting marker of pancreatic cancer. By using Yoda1, we measured the intracellular calcium flux mediated by Piezo1 which confirmed it did act as an intrinsic cation channel in pancreatic cancer cells. Additionally, we also found the inhibition of Piezo1 could inhibit cancer progression in vitro; however, Piezo1 activation (induced by Yoda1) had an oppositive effect. Moreover, Piezo1 activation may also accelerate pancreatic cancer tumor growth/formation via modulating pancreatic cancer cell-tumor microenvironment interactions in vivo. We concluded that Piezo1 acted as an oncogenic gene in pancreatic cancer progression. It might be one of promising targets for pancreatic cancer therapy.

Integrated analysis of necroptosis-related lncRNAs for prognosis and immunotherapy of patients with pancreatic adenocarcinoma.

Accumulating studies have revealed that necroptosis plays a vital role in the occurrence and development of pancreatic adenocarcinoma (PAAD). We aimed to construct a prognostic model for PAAD on the basis of necroptosis-related lncRNAs (NRLs). A coexpression network between necroptosis-related mRNAs and NRLs based on The Cancer Genome Atlas (TCGA) was constructed. Then, differentially expressed necroptosis-related lncRNAs (DENRLs) were screened from TCGA and Genotype-Tissue Expression project (GTEx) datasets. Univariate Cox regression (uni-Cox) analysis was performed on these DENRLs to identify lncRNAs significantly correlated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression was performed for preventing overfitting on these lncRNAs. Multivariate Cox analysis (multi-Cox) was performed to establish a risk model based on lncRNAs that served as an independent prognostic factor. Next, the Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), uni-Cox, multi-Cox regression, nomogram, and calibration curves were constructed to support the accuracy of the model. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were also performed on risk groups, and it was found that the low-risk group was closely correlated with immune infiltration and immunotherapy. To further evaluate the immune differences between different clusters, we divided the patients into two clusters. Cluster 2 was more significantly infiltrated with immune cells and had higher immune scores. These results shed new light on the pathogenesis of PAAD based on NRLs and develop a prognostic model for diagnosing and guiding personalized immunotherapy of PAAD patients.

Mechanically activated ion channel Piezo1 contributes to melanoma malignant progression through AKT/mTOR signaling.

Melanoma is a highly aggressive cancer that can metastasize at early stage. The aim of this study is to clarify the role of Piezo1 and its potential mechanism in regulating the malignant phenotypes of melanoma. In the present study, we first showed that Piezo1 was abnormally expressed in melanoma, which accelerated the malignant progression by activating AKT/mTOR signaling. Firstly, we found that Piezo1 was upregulated in melanoma and associated with poor survival. Additionally, Piezo1 knockdown significantly weakened intracellular calcium signal and viability of melanoma cells. Furthermore, Piezo1 knockdown inhibited the transendothelial migration and invasion in vitro, as well as metastasis in vivo. Mechanistically, we found that Piezo1 activated AKT/mTOR signaling to maintain malignant phenotypes of melanoma. Therefore, Piezo1 acts as an oncogene in melanoma cells and provides a novel candidate for melanoma diagnosis and treatment.

Incidence and risk factors of suicide among patients with pancreatic cancer: A population-based analysis from 2000 to 2018.

Background: The rate of suicide within one year after diagnosis in pancreatic cancer patients are high, but suicide studies based on the current large-scale data are still a vacancy. Our study aimed to determine, compared to the general population, the standardized mortality ratios (SMRs) of suicide and risk factors associated with pancreatic cancer patients committing suicide to provide clues for prevention. Methods: We collected 199,604 patients diagnosed with pancreatic cancer between 2000 and 2018 from the SEER database. Multivariate logistic regression and multivariate Cox regression were applied to determine the risk factors independently affecting the suicide outcome of pancreatic cancer patients. Results: A total of 180 suicide deaths were observed in the cohort, yielding an overall suicide rate of 88.05 per 100,000 person-years and an SMR of 6.43. In multivariate analyses, males (HR: 12.798, 95% CI: 7.471-21.923), unmarried (HR: 1.826, 95% CI: 1.205-2.767), and divorced, separated or widowed (HR: 1.779, 95% CI: 1.230-2.572) were found associated with a higher risk of suicide. While race black (HR: 0.250, 95% CI: 0.110-0.567), diagnosed with pancreatic neuroendocrine tumor (HR: 0.487, 95% CI: 0.276-0.859), received chemotherapy (HR: 0.456, 95% CI: 0.323-0.646), and received surgical procedures (HR: 0.553, 95% CI: 0.342-0.895) were indicated might protective factors. Conclusions: The 199,604 pancreatic cancer patients diagnosed between 2000 and 2018 had an overall suicide rate of 88.05 per 100,000 person-years and an SMR of 6.43 compared to the U.S. general population. Male, white, unmarried, and diagnosed with pancreatic adenocarcinoma patients were associated with a higher risk of suicide, while cancer-directed surgery and chemotherapy might indicate protective factors. The screening and prevention process should be enhanced for pancreatic cancer patients with adverse risk factors. Moreover, it is reasonable to assume that timely cancer-directed treatment might help reduce the subsequent suicide risk of pancreatic cancer patients.

Development and external validation of a dynamic nomogram to predict the survival for adenosquamous carcinoma of the pancreas.

Objective: We aimed to develop a nomogram to predict the survival and prognosis of adenosquamous carcinoma of the pancreas (ASCP). Background: Adenosquamous carcinoma of the pancreas (ASCP) is a relatively rare histological subtype of pancreatic exocrine neoplasms. It was reported a worse survival in ASCP than in pancreatic adenocarcinoma (PDAC). Prediction of ASCP prognosis is of great importance. Methods: Histologically confirmed ASCP patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database were finally enrolled and divided into development and internal validation cohorts. Moreover, a multi-center cohort of 70 patients from China was registered as the external validation. A nomogram was developed based on independent predictors of ASCP determined in multivariable analysis. Results: A total of 233 patients from SEER were finally included. Univariate and Multivariate analysis showed that tumor size, radiotherapy, chemotherapy, and lymph node ratio (LNR) were considered the independent prognostic indicators. We developed a nomogram according to these four parameters. The C index of the nomogram in the development cohort was 0.696. Through analysis of the area under the curve (AUC) of the different cohorts, we observed that the predictive efficacy of the nomogram for 1-, and 2-year overall survival (OS) were better than those of the American Joint Committee on Cancer (AJCC) TNM (8th) staging system both in the development and validation cohort. External validation confirmed that 1-year survival is 67.2% vs. 29.7%, similar to the internal cohort analysis. Conclusion: The nomogram showed good performance in predicting the survival of ASCP. It could help surgeons to make clinical decisions and develop further plans.