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We investigated the prognostic significance of Nudix hydrolase 1 (NUDT1) in hepatocellular carcinoma (HCC). NUDT1 mRNA and protein levels were significantly higher in HCC tissues than normal liver tissues. The level of NUDT1 expression correlated with tumor grade, stage, size, differentiation, degree of vascular invasion, overall survival (OS), and disease-free survival (DFS) in HCC patients. Multivariate analysis showed that NUDT1 expression was an independent prognostic factor for OS and DFS in HCC patients. We constructed a prognostic nomogram with NUDT1 expression, AFP levels, vascular invasion, Child-Pugh classification, age, sex, AJCC staging, and tumor differentiation as variables. This nomogram was highly accurate in predicting the 5-year OS of HCC patients (c-index= 0.709; AUC= 0.740). NUDT1 silencing in HCC cells significantly reduced their survival, colony formation, migration, and invasiveness. Gene set enrichment analysis showed that biological pathways related to cell cycle, fatty acid metabolism, bile acid and bile salt metabolism, and PLK1 signaling were associated with NUDT1, as were the gene ontology terms "DNA binding transcription activator activity," "RNA polymerase II," "nuclear division," and "transmembrane transporter activity." Our study thus demonstrates that NUDT1 is a prognostic biomarker with therapeutic potential in HCC patients.

Backgrounds Endoscopic stricturotomy (ESt) has been shown to be effective in treating inflammatory bowel disease (IBD)-associated anastomotic strictures. However, the outcome of ESt in benign, non-IBD conditions has not been described. The aim of this study was to evaluate the outcome of ESt in the management of IBD and non-IBD-associated strictures. Methods Data of all consecutive IBD and non-IBD patients with benign anastomotic strictures treated with ESt from 2009 to 2016 were extracted. The primary outcomes were surgery-free survival and procedure-related complications. Results A total of 49 IBD and 15 non-IBD patients were included in this study. The IBD group included 25 patients with Crohn’s disease and 24 with ulcerative colitis and ileal pouches. Underlying diseases in the non-IBD group included colorectal cancer (n = 7), diverticulitis (n = 5), large bowel prolapse (n = 2), and constipation (n = 1). Immediate technical success was achieved in all patients in both groups. Bleeding complications occurred on five occasions (4.7% per procedure) in the IBD group, while no complication occurred in the non-IBD group (P = 0.20). Stricture improvement on follow-up endoscopy was found in 10 (20.4%) and 5 (33.3%) patients in the IBD and non-IBD groups, respectively (P = 0.32). Six (12.2%) patients in the IBD group and four (26.7%) patients in the non-IBD group eventually required stricture-related surgery (P = 0.23). IBD patients appeared to have a higher tendency for maintaining surgery-free after the procedure than non-IBD patients (P = 0.08). Conclusions Endoscopic stricturotomy was shown to have comparable outcomes, though non-IBD patients seem to have a higher need for subsequent surgery but a lower complication rate than IBD patients.

Fibroblast growth factor (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/19- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8-12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/19 to hepatic FGFR4 signaling. We used recombinant human FGF19 protein and a small interfering RNA (siRNA) of FGFR4 to regulate expression of the FGF15/19-FGFR4 axis in vitro and in vivo. The proliferation and cell cycle of hepatocytes, the expression levels of FGF15/19-FGFR4 downstream molecules, liver recovery, and lipid metabolism were assessed. We found that both ileal and serum FGF15 expression were upregulated and hepatic FGFR4 was activated after PH in mice. FGF15/19 promoted cell cycle progression, enhanced proliferation, and reduced hepatic lipid accumulation of hepatocytes both in vitro and in vivo. Furthermore, the proliferative effect and lipid regulatory properties of FGF15/19 were dependent on FGFR4 in hepatocytes. In addition, ileal FGF15/19-hepatic FGFR4 transduction during hepatocyte proliferation was regulated by extracellular regulated protein kinase (ERK) 1/2. In conclusion, the ileal FGF15/19 to hepatic FGFR4 axis is activated and promotes LR after PH in mice, supporting the potential of ileal FGF15/19 to hepatic FGFR4 axis-targeted therapy to enhance LR after PH.

Background Triple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy. Methods We performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model. Results The abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P

// Jing-Song Chen 1 , Li-Li Liang 2 , Hong-Xu Xu 3 , Fan Chen 4 , Shun-Li Shen 5 , Wei Chen 5 , Lian-Zhou Chen 4 , Qiao Su 6 , Long-Juan Zhang 4 , Jiong Bi 4 , Wen-Tao Zeng 4 , Wen Li 4 , Ning Ma 7 and Xiao-Hui Huang 4 1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China 2 Departments of Pediatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 3 Departments of Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 4 Departments of General Surgical Laboratory, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 5 Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 6 Animal Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 7 Department of Gastrointestinal, Hernia and Abdominal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Correspondence to: Ning Ma, email: maning85322@163.com Xiao-Hui Huang, email: hxiaohui2006@126.com Keywords: miR-338-3p, epithelial-mesenchymal transition, Snail1, N-cadherin, sonic hedgehog Received: November 25, 2015 Accepted: June 04, 2016 Published: June 17, 2016 ABSTRACT Down-regulation of the miRNA miR-338-3p correlates with the invasive ability of hepatocellular carcinoma (HCC) cells. However, it is currently unclear whether down-regulation of miR-338-3p induces epithelial-mesenchymal transition (EMT), which may be the underlying mechanism governing HCC invasion. Here, we demonstrate that restoration of miR-338-3p expression via transfection of a miR-338-3p mimic reversed EMT and inhibited the motility and invasiveness of HCC cells. Conversely, silencing of endogenous miR-338-3p expression with a miR-338-3p-specific inhibitor induced EMT and enhanced HCC cell motility. Additionally, Snail1 (an upstream regulatory protein of EMT) and Gli1 (a key transcription factor in the sonic hedgehog (SHH) signaling pathway) expression was up-regulated in cells treated with the miR-338-3p inhibitor and down-regulated by the miR-338-3p mimic. Further analyses demonstrated that miR-338-3p inhibitor-induced EMT in HCC cells was blocked by treatment with a small interfering RNA (siRNA) targeting Snail1, that the SHH signaling pathway was required for both miR-338-3p inhibitor-induced EMT and up-regulation of Snail1, and that miR-338-3p targeted a sequence within the 3´-untranslated region of N-cadherin mRNA. Notably, miR-338-3p expression was significantly down-regulated in HCC samples from patients with metastases and was associated with poor metastasis-free survival rates. Lastly, correlations between the expression levels of miR-338-3p and E-cadherin, Smoothened (SMO), Gli1, Snail1, N-cadherin, and vimentin were confirmed in HCC xenograft tumors and HCC patient specimens. Our findings suggest that miR-338-3p suppresses EMT and metastasis via both inhibition of the SHH/Gli1 pathway and direct binding of N-cadherin. miR-338-3p is a potential therapeutic target for metastatic HCC.

Background Embryonic Liver Fodrin (ELF) is an adaptor protein of transforming growth factor (TGF-β) signaling cascade. Disruption of ELF results in mislocalization of Smad3 and Smad4, leading to compromised TGF-β signaling. c-Myc is an important oncogenic transcription factor, and the disruption of TGF-β signaling promotes c-Myc-induced hepatocellular carcinoma (HCC) carcinogenesis. However, the prognostic significance of c-Myc in HCC is less understood Methods The expression of c-Myc protein and mRNA were measured by immunohistochemistry (IHC) and qRT- PCR, respectively. IHC was performed to detect TGF-β1 and ELF expression in HCC tissues. Their relationship with clinicopathological factors and overall survival (OS) and disease free survival (DFS) were examined. Results The expression of c-Myc protein and mRNA in HCC tissues were significantly higher in HCC area than those in normal liver tissues. However, the expression were low compared with those adjacent to HCC area. c-Myc protein was independently predictive of DFS and OS, and it was negatively correlated with tumor size (P = 0.031), tumor number (P = 0.038), and recurrence (P = 0.001). Low c-Myc expression was associated with short-term recurrence and poor prognosis. The predictive value of c-Myc combined with TGF-β1 or/and ELF was higher than that of any other single marker. Low c-Myc, high TGF-β1 or/and low ELF expression was associated with the worst DFS and OS. Conclusions Low expression of c-Myc protein predicts poor outcomes in patients with HCC with hepatectomy. The combination of the expression of c-Myc, TGF-β1, and ELF can be used to accurately predict outcomes of patients with HCC.

It has been shown that combined liver-kidney normothermic machine perfusion (NMP) is able to better maintain the circuit's biochemical milieu. Nevertheless, whether the combined perfusion is superior to liver perfusion alone in protecting livers from donation after circulatory death (DCD) is unclear. We aimed to test the hypothesis and explored the mechanisms. Livers from 15 DCD pig donors were subjected to either static cold storage (group A), liver-alone NMP (group B), or combined liver-kidney NMP (group C). Livers were preserved for 6 hours and reperfused ex vivo for 2 hours to simulate transplantation or were transplanted in situ. During perfusion, group C showed an improved acid-base and biochemical environment in the circuit over group B. After reperfusion, the architecture of the liver grafts was best preserved in group C, followed by group B, then group A, as shown by the histology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining of both hepatocytes and biliary epithelium. Ki-67 staining showed substantial hepatocyte proliferation and biliary epithelial regeneration after perfusion in group B and group C. Group C produced more bile in the reperfusion phase than those in group A and group B, with more physiological bile composition and less severe biliary epithelium injury. Von Willebrand factor-positive endothelial cells and E-selectin expression decreased in both group B and group C. Combined liver-kidney NMP not only produced more adenosine triphosphate, protected the nitric oxide signaling pathway, but also diminished oxidative stress (high mobility group box-1 protein and 8-hydroxy-2-deoxy guanosine levels) and inflammatory cytokine (IL6 and IL8) release when compared with liver-alone NMP and CS. In addition, the 7-day survival rate of liver transplant recipients was higher in group C than that in groups A and B. In conclusion, combined liver-kidney NMP can better protect DCD livers from warm ischemia and reperfusion injury probably by maintaining the stability of the internal environment and by abolishing oxidative stress injury. Liver Transplantation 24 67-79 2018 AASLD.

Hypoxia is a key inducer of neovascularization which is essential for tumor growth, invasion and metastasis. It has been proposed that the recruitment of bone-marrow-derived endothelial progenitor cells (BM-EPCs) is pivotal and requires the participation of several tumor-derived cytokines. However, it is not known whether prostate cancer (PCa) cells contribute to the recruitment and vasculogenesis of EPCs in PCa progression. In the present study, we demonstrated that all conditioned medium (CM) of PC-3 PCa cells promoted proliferation and migration, and augmented the vasculogenesis capacity of BM-EPCs, and 24-h hypoxia (24H)-CM presented stronger ability compared to 24-h normoxia (24N)-CM and 48H-CM. Human cytokine antibody array with 174 anti-cytokine antibodies revealed the changes of cytokine in CMs. Twenty-five types of cytokines significantly increased in 24H-CM compared with 24N-CM. Eleven types of cytokines (5 factors increased and 6 decreased) were significantly different between 48H-CM and 48N-CM. Twelve types of cytokines (4 factors increased and 8 decreased) were significantly different between 48H-CM and 24H-CM. Furthermore, according to the gene ontology analysis, all altered cytokines were involved in proliferation, chemotaxis, cell motility, cell migration, vasculogenesis and angiogenesis. Of note, the changed regularity of cytokines in the 24H-CM and 48H-CM of PC-3 cells was in concert with the functional changes of BM-EPCs treated by different CM of PC-3 cells in enhancing the proliferation, migration and vasculogenesis potential of BM-EPCs. These findings suggest that PCa cells may have the potential to modulate their microenvironment and facilitate BM-EPC migration and vasculogenesis by secretion of cytokines in the early stage of hypoxia.

Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme branching from glycolysis in the three-step serine biosynthetic pathway. Recent evidence has shown that PHGDH is amplified in human breast cancer and melanoma and plays a key role in cancer metabolism. However, PHGDH expression in glioma and a potential non-metabolic role in tumorigenesis have not been reported. We analyzed PHGDH levels in specimens from glioma patients and found that PHGDH, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive cancer types. Inhibition of PHGDH expression in glioma cells downregulated the expression of VEGF, MMP-2, CHK2 and cyclin D1 and reduced glioma cell proliferation, invasion and tumorigenicity in vitro and in vivo. Interestingly, we found that the oncogenic transcription factor FOXM1 was also downregulated in PHDGH-silenced glioma cells. Using LC/LC MS analysis, we identified PHGDH as a novel binding partner of FOXM1. PHGDH interacted with and stabilized FOXM1 at the protein level, promoting the proliferation, invasion and tumorigenicity of glioma cells. Our data identified PHGDH as a potential prognostic marker of glial brain tumors and identified a non-metabolic role for PHGDH in glioma tumorigenesis, providing a novel angle of targeting the PHGDH–FOXM1 axis in future brain tumor therapy. Electronic supplementary material The online version of this article (doi:10.1007/s11060-012-1018-x) contains supplementary material, which is available to authorized users.

Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in tumor vasculogenesis because they provide both instructive (release of pro-angiogenic cytokines, such as VEGF) and structural (vessel incorporation and stabilization) functions. Celastrol, derived from Trypterygium wilfordii Hook F., a traditional Chinese medicine plant, has been studied for its antitumorigenic properties, but its mechanism of action is not well understood. The aims of this study are to investigate the effects of Celastrol on VEGF-induced functional activity of BM-EPCs and to identify any mechanisms associated with this process. Here, we show that Celastrol attenuates VEGF secretion in BM-EPCs in vitro. This attenuation, in turn, inhibits the in vitro VEGF-induced cell viability, cell-cell adhesion, cell-ECM adhesion, migration response and vascular tube formation of BM-EPCs. Additionally, Celastrol inhibits the phosphorylation of VEGFR2, endothelial nitric oxide synthase (eNOS), and Akt to attenuate cell functions. Taken together, the present study demonstrates that Celastrol decreases Akt/eNOS signaling in BM-EPCs in vitro. These findings identify novel mechanisms that regulate EPC function and may provide new insights for the medicinal use of Celastrol.

Krüppel-like factor 17 (KLF17), a new member of the Krüppel-like factors (KLFs), has been reported to be a negative regulator of epithelial-mesenchymal transition (EMT) and metastasis in breast cancer. However, the biological role and clinical significance of KLF17 in lung adenocarcinoma has been less clear. In the present study, we showed that KLF17 expression was decreased in lung adenocarcinoma. Reduced expression of KLF17 was correlated significantly with a short survival time in patients with lung adenocarcinoma (P0.0001). Moreover, KLF17 expression was an independent prognostic indicator for patients with lung adenocarcinoma. KLF17 expression level was correlated with the tumor stage (P=0.016) and tumor size (P=0.001) in lung adenocarcinoma. Overexpression of KLF17 inhibited cell growth in A549 and PC-9 cell lines. In conclusion, it is possible that KLF17 inhibits tumor growth in lung adenocarcinoma. The reduced expression of KLF17 is a valuable prognostic indicator for patients with lung adenocarcinoma, and KLF17 could be a novel target for treatment of lung adenocarcinoma.

The objective of this study was to compare the safety and efficacy outcomes of stapled hemorrhoidectomy (PPH) with Milligan–Morgan hemorrhoidectomy (MMH) in the treatment of severe hemorrhoids. A meta-analysis pooled the effects of the safety and efficacy outcomes on PPH, and MMH in ten randomized control trials was presented using a fixed effects model or a random effects model (via RevMan Version 4.2). There was reasonably clear evidence in favor of PPH for operating time, length of hospital stay, pain, anal discharge, and patient satisfaction. However, skin tags and prolapse occurred at higher rates in the PPH group. PPH was not more superior than MMH as to postoperative bleeding, urinary retention, difficulty in defecating, anal fissure and stenosis, sphincter damage, resumption of normal activities, incontinence, pruritus, anal resting and squeeze pressures, and analgesia. PPH may be at least as safe as MMH. However, the efficacy of PPH compared with MMH could not be determined absolutely. More rigorous studies with longer follow-up periods and larger sample sizes need to be conducted.

Background Upregulator of cell proliferation 4 (URG4) has been implicated in the oncogenesis of certain cancers. However, the correlation between URG4 expression and clinicopathological significance in human cancer remains unclear. Therefore, this study investigated its expression and clinicopathological significance in cervical cancer patients. Methods URG4 expression was examined using quantitative PCR (qPCR) and western blotting in normal cervical epithelial cells, cervical cancer cells, and eight matched pairs of cervical cancer tissues and adjacent noncancerous tissues from the same patient. In addition, immunohistochemistry (IHC) was used to examine URG4 expression in paraffin-embedded tissues from 167 cervical cancer patients (FIGO stages Ib1-IIa2). Statistical analyses were performed to evaluate associations between URG4 expression and prognostic and diagnostic factors. Results URG4 was significantly upregulated in the cervical cancer cell lines and tissues compared with the normal cells and adjacent noncancerous cervical tissues. IHC revealed high URG4 expression in 59 out of the 167 (35.13%) cervical cancer specimens. Its expression was significantly correlated with clinical stage (P

Interleukin (IL)-32 is a novel proinflammatory cytokine, which has been shown to play an important role in tumor growth and metastasis. Here, we discovered that IL-32 was aberrantly over-expressed in lung adenocarcinoma tissues and cell lines. Positive expression of IL-32 significantly correlated with the clinical staging, and lymph node and distant metastases. High expression of IL-32 was an independent indicator of poor prognosis in lung adenocarcinoma patients. Moreover, IL-32-facilitated cell migration and invasion in vitro was mediated through transactivation of the nuclear transcription factor (NF)-κB signaling pathway and subsequent upregulation of matrix metalloproteinase (MMP)-2 and MMP9 expression. These studies demonstrate that IL-32 plays a role in the tumor-associated inflammatory microenvironment and that overexpression of IL-32 contributes to invasion and metastasis in primary lung adenocarcinoma, suggesting that it may have clinical utility as a prognostic biomarker and potential target for immunotherapy in lung adenocarcinoma.

The preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen with unknown function, is expressed in many human malignancies and is considered an attractive potential target for tumor immunotherapy. However, studies of its expression and function in osteosarcoma have rarely been reported. In this study, we found that PRAME is expressed in five osteosarcoma cell lines and in more than 70% of osteosarcoma patient specimens. In addition, an immunohistochemical analysis showed that high PRAME expression was associated with poor prognosis and lung metastasis. Furthermore, PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. Our results suggest that PRAME plays an important role in cell proliferation and disease progression in osteosarcoma. However, the detail mechanisms of PRAME function in osteosarcoma require further investigation.

Background Prostate tumor overexpressed 1 (PTOV1) was demonstrated to play an important role in cancer progression and was correlated with unfavorable clinical outcome. However, the clinical role of PTOV1 in cancer remains largely unknown. This study aimed to investigate the expression and clinicopathological significance of PTOV1 in breast cancer. Methods The mRNA and protein expression levels of PTOV1 were analyzed in 12 breast cancer cell lines and eight paired breast cancer tumors by semi-quantitative real time-PCR and western blotting, respectively. Immunohistochemistry was performed to assess PTOV1 protein expression in 169 paraffin-embedded, archived breast cancer samples. Survival analysis and Cox regression analysis were performed to investigate the clinicopathological significance of PTOV1 expression. Results Our data revealed that PTOV1 was frequently overexpressed in breast cancer cell lines compared to normal human breast epithelial cells and in primary breast cancer samples compared to adjacent noncancerous breast tissues, at both the mRNA and protein levels. Moreover, high expression of PTOV1 in breast cancer is strongly associated with clinicopathological characteristics and estrogen receptor expression status (P = 0.003). Breast cancer patients with higher PTOV1 expression had substantially shorter survival times than patients with lower PTOV1 expression (P

Background Tumor suppression of Transforming Growth Factor (TGF-β) signaling pathway requires an adaptor protein, Embryonic Liver Fodrin (ELF). Disruption of ELF expression resulted in miscolocalization of Smad3 and Smad4, then disruption of TGF-β signaling. However, the prognostic significance of ELF for hepatocellular carcinoma (HCC) hasn’t been clarified. This study aimed to investigate whether measuring both TGF-β1 and ELF provides a more powerful predictor for HCC prognosis than either marker alone. Methods TGF-β1 and ELF protein were detected by immunohistochemistry. The relationship between TGF-β1/ELF expression and patients’ clinicopathologic factors was analyzed. The association between TGF-β1/ELF expression and disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the log-rank test, and Multivariate Cox regression analyses. Results The expression of TGF-β1 in HCC tissues was significantly higher than that in normal liver tissues. Conversely, the expression of ELF in HCC tissues declined markedly. ELF protein was correlated with HBsAg, tumor size, tumor number, TNM and recurrence. Data also indicated a significant negative correlation between ELF and TGF-β1. Patients with high TGF-β1 expression or/and low ELF expression appeared to have a poor postoperative disease-free survival and overall survival compared with those with low TGF-β1 expression or/and high ELF expression. Furthermore, the predictive range of ELF combined with TGF-β1 was more sensitive than that of either one alone. Conclusions TGF-β1 and ELF protein are potential and reliable biomarkers for predicting prognosis in HCC patients after hepatic resection. Our current study has demonstrated that the prognostic accuracy of testing can be enhanced by their combination.