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.

Saikosaponin-d increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation.

Objective: The aim of this study was to analyze the effects of saikosaponin-d (SSd) on autophagy activity and radiosensitivity of hepatoma cells, and to elucidate its related molecular mechanisms. Methods: The growth of SMMC-7721 and MHCC97L hepatoma cells were detected by clonal formation and survival fraction. Flow cytometry was used to detect the changes of apoptosis of hepatoma cells. The morphological changes of autophagy of hepatoma cells were observed by transmission electron microscopy and were further quantitatively detected by laser confocal microscopy. The expressions of related proteins were detected by Western blotting. Results: SSd can significantly increase the apoptosis of hepatoma cells induced by radiation and inhibit the proliferation of hepatoma cells. The addition of the autophagy inhibitor chloroquine (CQ) or an mTOR agonist (MHY1485), which could reduce the promoting effect of SSd on radiation-induced apoptosis and inhibitory effect on the proliferation of hepatoma cells. Transmission electron microscopy and confocal microscopy results also showed that the number of autophagosomes was significantly higher in the radiation and SSd co-treatment group than in the radiotherapy or SSd alone group; however, the effect of SSd on autophagy in hepatoma cells was decreased after adding MHY1485, siRNA-P53 or AMPK inhibitor (Compound C). Western blot analysis showed that after the addition of SSd, the phosphorylation of mTOR was significantly decreased by radiation, the expression of the autophagy-related proteins LC3-II and Beclin-1 was increased, p62 was decreased, and the expression of cleaved caspase-3 and cleaved PARP was enhanced; this effect of SSd was partially reversed after the addition of MHY1485, siRNA-P53 or Compound C. Conclusions: SSd increases radiation-induced apoptosis of hepatoma cells by promoting autophagy via inhibiting mTOR phosphorylation and providing a possible potential approach for radiosensitization therapy of liver cancer.

Positive feedback in Cav-1-ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells.

Caveolin-1 (Cav-1) is the principal structural component of caveolae, and its dysregulation occurs in cancer. However, the role of Cav-1 in pancreatic cancer (PDAC) tumorigenesis and metabolism is largely unknown. In this study, we aimed to investigate the effect of pancreatic stellate cell (PSC) Cav-1 on PDAC metabolism and aggression. We found that Cav-1 is expressed at low levels in PDAC stroma and that the loss of stromal Cav-1 is associated with poor survival. In PSCs, knockdown of Cav-1 promoted the production of reactive oxygen species (ROS), while ROS production further reduced the expression of Cav-1. Positive feedback occurs in Cav-1-ROS signalling in PSCs, which promotes PDAC growth and induces stroma-tumour metabolic coupling in PDAC. In PSCs, positive feedback in Cav-1-ROS signalling induced a shift in energy metabolism to glycolysis, with up-regulated expression of glycolytic enzymes (hexokinase 2 (HK-2), 6-phosphofructokinase (PFKP) and pyruvate kinase isozyme type M2 (PKM2)) and transporter (Glut1) expression and down-regulated expression of oxidative phosphorylation (OXPHOS) enzymes (translocase of outer mitochondrial membrane 20 (TOMM20) and NAD(P)H dehydrogenase [quinone] 1 (NQO1)). These events resulted in high levels of glycolysis products such as lactate, which was secreted by up-regulated monocarboxylate transporter 4 (MCT4) in PSCs. Simultaneously, PDAC cells took up these glycolysis products (lactate) through up-regulated MCT1 to undergo OXPHOS, with down-regulated expression of glycolytic enzymes (HK-2, PFKP and PKM2) and up-regulated expression of OXPHOS enzymes (TOMM20 and NQO1). Interrupting the metabolic coupling between the stroma and tumour cells may be an effective method for tumour therapy.

Effect of cumulative fluid balance on acute kidney injury and patient outcomes after orthotopic liver transplantation: A retrospective cohort study.

AIM: Acute kidney injury (AKI) is a serious complication following orthotopic liver transplantation (OLT) and it affects long-term patient survival. The aims of this study were to identify the effects of cumulative fluid balance (FB) on early post-OLT AKI and adverse outcomes and to construct a model to predict AKI. METHODS: We retrospectively analysed 146 adult patients who underwent OLT. AKI severity was classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Univariate and multivariate logistic regression analyses were used to evaluate the association between cumulative FB and post-OLT AKI. The Kaplan-Meier method was used to estimate the survival rate. RESULTS: Within the perioperative period of 72 hours, 50% (66/132) of patients developed AKI, with 36 (54%), 16 (24%) and 14 (21%) patients having AKI stages 1, 2 and 3, respectively. The cumulative FB was the risk factors for post-OLT AKI (odds ratio [OR], 1.011; 95% confidence interval [CI], 1.156~6.001; P = .021). Preoperative albumin was a protective factor for post-OLT AKI (OR, 0.309; 95% CI, 0.140~0.731; P = .007). The AKI group requires renal replacement therapy (RRT) more (15.2% vs 0%, P = .001) and associated with postoperative complications (56% vs 28.8%, P = .003). The complication-free survival was lower in the AKI group ([11.90 vs 18.74] months, χ2 = 9.60, P = .002). CONCLUSION: Cumulative FB within 72 hours is associated with post-OLT AKI and requires RRT. Cumulative FB impacts the long-term complication-free survival of the recipients.

Paracrine HGF/c-MET enhances the stem cell-like potential and glycolysis of pancreatic cancer cells via activation of YAP/HIF-1α.

Pancreatic stellate cells (PSCs), a pivotal component of the tumor microenvironment, contribute to tumor growth and metastasis. PSC-derived factors are essential for triggering the generation and maintenance of cancer stem cells (CSCs). However, the mechanisms by which paracrine signals regulate CSC-like properties such as glycolytic metabolism have not been fully elucidated. Here, we report that two pancreatic cancer cell lines, Panc-1 and MiaPaCa-2, reacted differently when treated with hepatocyte growth factor (HGF) secreted from PSCs. MiaPaCa-2 cells showed little response with regard to CSC-like properties after HGF treatment. We have shown that in Panc-1 cells by activating its cognate receptor c-MET, paracrine HGF resulted in YAP nuclear translocation and HIF-1α stabilization, thereby promoting the expression of CSC pluripotency markers NANOG, OCT-4 and SOX-2 and tumor sphere formation ability. Furthermore, HGF/c-MET/YAP/HIF-1α signaling enhanced the expression of Hexokinase 2 (HK2) and promoted glycolytic metabolism, which may facilitate CSC-like properties. Collectively, our study demonstrated that HGF/c-MET modulates tumor metabostemness by regulating YAP/HIF-1α and may hold promise as a potential therapeutic target against pancreatic cancer.

Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/ß-catenin pathway in pancreatic cancer cells.

The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/ß-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling.

BACKGROUND/AIMS: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. METHODS: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. RESULTS: SFN can inhibit pancreatic cancer cell growth， promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. CONCLUSION: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer.

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer. METHODS: LSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; Pdx1-Cre (KPC) mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein. RESULTS: Following metformin treatment, pancreatic acinar-to-ductal metaplasia (ADM) and mouse pancreatic intraepithelial neoplasia (mPanIN) were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 (CK19)-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson's trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival. CONCLUSIONS: Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

Diagnostic significance of elevated expression of HBME-1 in papillary thyroid carcinoma.

This study examined the association between hector battifora mesothelial antigen-1 (HBME-1) expression and papillary thyroid carcinoma (PTC). A total of 206 patients were enrolled in the current study including 96 PTC patients and 110 patients with benign thyroid nodules (BTN). Immunohistochemistry (Envision) were performed to assess the expression of HBME-1. Receiver operating characteristic curve (ROC) curves were applied to evaluate the diagnostic tumor node metastasis (TNM) value of HBME-1. Specimens from 96 patients with PTC and 110 patients with BTC were reviewed. HBME-1 was positively immunostained in PTC tissue, which was significantly higher than that in BTN tissues (77.1 vs. 5.77 %, P < 0.05). Immunohistochemistry also identified that HBME-1 expression did not show any statistically significant differences based on gender, age, tumor size, TNM stage, and lymph node metastasis (P > 0.05). Importantly, HBME-1 expression was correlated with infiltration levels and differential levels in PTC (both P < 0.05). HBME-1 was found to have high sensitivity (94.5 %) and specificity (77.08 %) for PTC diagnosis. Moreover, HBME-1 had a high specificity (83.33 %) at identifying the differential levels of PTC, but a low sensitivity (22.92 %). The sensitivity and specificity of HBME-1 identifying the infiltration levels of PTC were, respectively, 72.70 and 72.00 %. HBME-1 was highly expressed in PTC tissues, and HBME-1 can serve as a potential biomarker in the diagnosis of PTC.

Comparative study of titrated oral misoprostol solution and vaginal dinoprostone for labor induction at term pregnancy.

OBJECTIVE: To evaluate effectiveness and safety of titrated oral misoprostol solution (OMS) in comparison with vaginal dinoprostone for cervix ripening and labor induction in term pregnant women. METHODS: A multicenter randomized controlled trial of women with term singleton pregnancy with indications for labor induction; 481 participants were allocated to receive titrated OMS with different doses by hourly administration according to the procedure or insert vaginal dinoprostone for cervix ripening and labor induction to compare maternal outcomes including indication of labor induction, mode of outcome of delivery, maternal morbidity, and neonatal outcomes between two groups for evaluating the efficacy and safety of titrated oral misoprostol induction. RESULT: Proportion of delivery within 12 h of titrated oral misoprostol is significantly less than vaginal dinoprostone (p = 0.03), but no difference of total vaginal delivery rate (p = 0.93); the mean time of first treatment to vaginal delivery was longer in OMS group (21.3 ± 14.5 h) compared with the vaginal dinoprostone group (15.7 ± 9.6 h). Although the proportion of cesarean section between the two groups showed no statistically significant difference, OMS group showed significantly lower frequency of uterine hyperstimulation, hypertonus, partus precipitatus and non-reassuring fetal heart rate than dinoprostone group. Neonatal outcomes were similar evaluating from Apgar score and NICU admission. Our study also showed that labor induction of women with cervix Bishop score ≤3 needed increased dosage of misoprostol solution. CONCLUSION: Titrated OMS is as effective as vaginal dinoprostone in labor induction for term pregnant women, with safer effect for its lower rate of adverse effect for women.

Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects. METHODS: In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo. RESULTS: Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model. CONCLUSIONS: Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.

The SDF-1/CXCR4 axis induces epithelial­mesenchymal transition in hepatocellular carcinoma.

Hepatic stellate cells play a role in the migration process of hepatocellular carcinoma cells. Here, we address the role of the stromal-derived factor-1/CXC chemokine receptor 4 (SDF-1/CXCR4) axis on hepatocellular carcinoma progression. The expression of the SDF-1 and the CXCR4 was determined through western blotting and real-time PCR analysis using hepatic stellate (LX02) and hepatocellular carcinoma (MHCC97, SMMC7721, Hep3B, and HepG2) cell lines depleted of CXCR4 using shRNA. The migration of hepatocellular carcinoma cells following exogenous treatment with SDF-1 or in co-culture cell systems was measured using the Transwell assay. In parallel, the expression of epithelial­mesenchymal transition (EMT) markers was also determined. We found that SDF-1 is highly expressed in the hepatic stellate cell line LX02 and that the hepatocellular carcinoma cells express high levels of CXCR4. Co-culturing hepatocellular carcinoma cells with LX02 or exogenous treatment with SDF-1 induced an EMT as shown by increased migration. In contrast, ablation of CXCR4 expression in HepG2 cells attenuated the migration of HepG2 cells and suppressed the EMT. Thus, hepatic stellate cells can promote hepatocellular carcinoma cell invasion through the SDF-1/CXCR4 axis.

Disrupting the balance between tumor epithelia and stroma is a possible therapeutic approach for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a type of highly lethal malignant tumor. PDAC is locally invasive and is surrounded by a dense desmoplasia or fibrosis, which can involve adjacent vital structures. Previously, the effect of pancreatic stellate cells (PSCs) of stroma in the progression of PDAC has received more attention, and most in vitro and in vivo studies revealed that PSCs appear to confer biological aggressiveness. However, clinical trials targeting desmoplasia or PSCs showed disappointing results. Recent studies found that stromal components, especially activated PSCs, are able to inhibit the occurrence and progression of PDAC. Inhibition of the stroma or desmoplasia through genetic regulations or drugs accelerates the formation and progression of PDAC. Thus, we hypothesized that in various times and spaces, there is a balance between the tumor epithelia and stroma; once the balance is upset, the tumor traits may undergo certain changes. Therefore, finding the key changing points of this relationship to corrupt or influence it, instead of blindly inhibiting the stroma motivation or simply maintaining stroma activation, will destroy the cooperation or promote the competition and antagonism among cells. This approach may render tumors more vulnerable and thus unable to resist anti-cancer therapies.

Endoscopic ultrasonography for tumor node staging and vascular invasion in pancreatic cancer: a meta-analysis.

BACKGROUND/AIMS: The accurate staging of pancreatic cancer (PanCa) is crucial in the development of a stage-specific treatment plan for PanCa patients. We aimed to perform a meta-analysis of endoscopic ultrasonography (EUS) in the tumor node (TN) staging and evaluation of vascular invasion in PanCa. METHODS: A meta-analysis of diagnostic accuracy parameters was performed to evaluate the EUS-based TN staging, and vascular invasion by PanCa was compared to the results of intraoperative staging or to the histopathology of resected specimens. RESULTS: Twenty studies with 726 PanCa cases were identified from 281 articles. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 0.72, 0.90, 6.27, 0.28, and 24.69, respectively, for T1-2 staging and 0.90, 0.72, 3.58, 0.16, and 24.69, respectively, for T3-4 staging. The overall sensitivity, specificity, PLR, NLR, and DOR were 0.62, 0.74, 2.54, 0.51, and 6.67, respectively, for N staging (positive vs. negative) and 0.87, 0.92, 7.16, 0.20, and 56.19, respectively, for vascular invasion. The area under the curve was 0.90, 0.90, 0.79, and 0.94 for T1-2 staging, T3-4 staging, N staging, and vascular invasion, respectively. CONCLUSIONS: EUS is a reliable and accurate diagnostic tool for the TN staging and evaluation of vascular invasion in PanCa. The nodal staging accuracy using EUS is less satisfactory.

Necrolytic migratory erythema as the first manifestation of pancreatic neuroendocrine tumor.

Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient's cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor.

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.

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.

Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer.

Perineural invasion (PNI) is the initial infiltration of tumor cells into the retroperitoneal nerve plexus and along the nerves. It precludes curative resection, is thought to be the major cause of local recurrence following resection, and is a special metastatic route in pancreatic cancer. Glial cell line-derived neurotrophic factor (GDNF) was recently recognized as a key player in the PNI process. This review covers the most recently published studies on the role of GDNF in pancreatic cancer. We introduce the players in PNI, summarize the distribution of GDNF and its receptors in pancreatic cancer, and discuss the effects and underlying mechanism of GDNF in the PNI process. Finally, we also review some potential inhibitors for GDNF-targeted therapy.