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Background: Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors. Methods: NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software. Results: Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function. Conclusions: Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors.Methods: NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software.Results: Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function.Conclusions: Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: The occurrence and development of hepatocellular carcinoma (HCC) depends largely on such non-tumor factors as inflammatory condition, immune state, viral infection and liver fibrosis. Various inflammation-based prognostic scores have been associated with survival in patients with HCC, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and the prognostic nutritional index (PNI). The aspartate aminotransferase/platelet count ratio index (APRI) is thought to be a biomarker of liver fibrosis and cirrhosis. This study aims to evaluate the ability of these indices to predict survival in HCC patients after curative hepatectomy, and probe the increased prognostic accuracy of APRI combined with established inflammation-based prognostic scores.Methods: Data were collected retrospectively from 321 patients who underwent curative resection for HCC. Preoperative NLR, PLR, PNI, APRI and clinico-pathological variables were analyzed. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS).Results: Univariate analysis showed that NLR, PLR, PNI and APRI were significantly associated with DFS and OS in HCC patients with curative resection. Multivariate analysis showed that NLR and APRI were superior to PLR and PNI, and both were independently correlated with DFS and OS. Preoperative NLR >2 or APRI >1.68 predicted poor prognosis of patients with HCC after hepatectomy. Furthermore, the predictive range of NLR combined with APRI was more sensitive than that of either measure alone.Conclusions: Preoperative NLR and APRI are independent predictors of DFS and OS in patients with HCC after surgical resection. Higher levels of NLR or APRI predict poorer outcomes in HCC patients. Intriguingly, combining NLR and APRI increases the prognostic accuracy of testing. [ABSTRACT FROM AUTHOR]

Introduction: Central lymph node status in papillary thyroid microcarcinoma (PTMC) plays an important role in treatment decision-making clinically, however, it is not easy to predict central lymph node metastasis (CLNM). The present work focused on finding the more rational alternative for evaluating central lymph node status while identifying influencing factors to construct a model to predict CLNM incidence. Methods: In this study, we retrospectively analyzed the typical sonographic and clinicopathologic features of 546 PTMC patients who underwent surgery, among which, the data of 382 patients were recruited in the training cohort and that of 164 patients in the validation cohort. Based on the outcome of the training cohort, significant influencing factors were further identified through univariate analysis and were considered as independent variables in multivariable logistic regression analysis and incorporated in and presented with a nomogram. Results: In total, six independent predictors, including the age, sex, tumor size, multifocality, capsular invasion, Hashimotos thyroiditis were entered into the nomogram. Both internal validation and external validation revealed the favorable discrimination of our as-constructed nomogram. Calibration curves exhibited high consistency. As suggested by decision-curve analyses, the as-constructed nomogram might be applied in clinic. Besides, the model also distinguished patients according to risk stratification. Conclusions: The novel nomogram containing remarkable influencing factors for CLNM cases was established in the present work. The nomogram can assist clinicians in clinical decision-making. [ABSTRACT FROM AUTHOR]

Introduction: Central lymph node status in papillary thyroid microcarcinoma (PTMC) plays an important role in treatment decision-making clinically, however, it is not easy to predict central lymph node metastasis (CLNM). The present work focused on finding the more rational alternative for evaluating central lymph node status while identifying influencing factors to construct a model to predict CLNM incidence.Methods: In this study, we retrospectively analyzed the typical sonographic and clinicopathologic features of 546 PTMC patients who underwent surgery, among which, the data of 382 patients were recruited in the training cohort and that of 164 patients in the validation cohort. Based on the outcome of the training cohort, significant influencing factors were further identified through univariate analysis and were considered as independent variables in multivariable logistic regression analysis and incorporated in and presented with a nomogram.Results: In total, six independent predictors, including the age, sex, tumor size, multifocality, capsular invasion, Hashimotos thyroiditis were entered into the nomogram. Both internal validation and external validation revealed the favorable discrimination of our as-constructed nomogram. Calibration curves exhibited high consistency. As suggested by decision-curve analyses, the as-constructed nomogram might be applied in clinic. Besides, the model also distinguished patients according to risk stratification.Conclusions: The novel nomogram containing remarkable influencing factors for CLNM cases was established in the present work. The nomogram can assist clinicians in clinical decision-making. [ABSTRACT FROM AUTHOR]

Background: The influence of perioperative blood transfusion (PBT) on postsurgical survival of patients with different stage of hepatocellular carcinoma (HCC) is not well clarified. This study aimed to evaluate the impact of PBT on survival outcomes of different stage of HCC patients.Methods: Consecutive patients who underwent liver resection for HCC between January 2009 and November 2015 were identified from an HCC prospective database in authors' center. The survival outcomes were compared between patients receiving PBT and those without PBT before and after propensity score matching (PSM) in different stage subsets. Cox regression analysis was performed to verify the impact of PBT on outcomes of HCC.Results: Among 1255 patients included, 804 (64.1%) were Barcelona Clinic Liver Cancer (BCLC) stage 0-A, and 347 (27.6%) received PBT. Before PSM, patients with PBT had worse disease free survival (DFS) and overall survival (OS) compared with those without PBT in both BCLC 0-A subset and BCLC B-C subset (all P < 0.05). After PSM, 288 pairs of patients (with and without PBT) were created. In the subset of BCLC 0-A, the median DFS of patients with PBT was shorter than those without PBT (12.0 months vs. 36.0 months, P = 0.001) Similar result was observed for OS (36.0 months vs. 96.0 months, P = 0.001). In the subset of BCLC B-C, both DFS and OS were comparable between patients with PBT and those without PBT. Cox regression analysis showed that PBT involved an increasing risk of DFS (HR = 1.607; P < 0.001) and OS (HR = 1.756; P < 0.001) for this subset. However, PBT had no impact on DFS (P = 0.126) or OS (P = 0.139) for those with stage B-C HCC.Conclusions: PBT negatively influenced oncologic outcomes of patient with BCLC stage 0-A HCC, but not those with stage B-C after curative resection. [ABSTRACT FROM AUTHOR]

Background: The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study.Methods: The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored.Results: We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627-2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736-3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC.Conclusions: HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection. Methods: We retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed. Results: On univariate and multivariate analysis, elevated monocyte counts (≥545/mm³), tumor size ≥5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm³, and 36%, 23% and 21% for patients with monocyte counts ≥545/mm³. Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm³, and 64%, 36% and 29% for monocyte counts ≥545/mm³. Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm³, but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm³, whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors. Conclusions: Elevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts. [ABSTRACT FROM AUTHOR]

Background RhoC is a small G protein/GTPase and involved in tumor mobility, invasion and metastasis. Previously, up-regulated RhoC expression is found to play an important role in ovarian carcinogenesis and subsequent progression by modulating proliferation, apoptosis, migration and invasion. Methods We transfected RhoC-expressing plasmid and RhoC siRNA into CAOV3 and OVCAR3 cells respectively. These cells and transfectants were exposed to vascular epithelial growth factor (VEGF), transforming growth factor (TGF)-β1 or their receptor inhibitors with the phenotypes and their related-molecules examined. Results TGF-β1R or VEGFR inhibitor suppressed the proliferation, migration, invasion and lamellipodia formation, the expression of N-cadherin, a-SMA, snail and Notch1 mRNA or protein, and enhanced E-cadherin mRNA and protein expression in CAOV3 and its RhoC- overexpressing transfectants, whereas both growth factors had the opposite effects in OVCAR3 cells and their RhoC-hypoexpressing transfectants. Ectopic RhoC expression enhanced migration, invasion, lamellipodia formation and the alteration in epithelial to mesenchymal transition (EMT) markers of CAOV3 cells regardless of the treatment of VEGFR or TGF-β1R inhibitor, whereas RhoC knockdown resulted in the converse in OVCAR3 cells even with the exposure to VEGF or TGF-β1. Conclusion RhoC expression might be involved in EMT of ovarian epithelial carcinoma cells, stimulated by TGF-β1 and VEGF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood monocyte count is an easily assessable parameter of systemic inflammatory response. The aim of this study was to determine whether monocyte count was prognostic in hepatocellular carcinoma (HCC) following hepatic resection.Methods: We retrospectively reviewed 351 patients with HCC treated with hepatic resection from 2006 to 2009. Preoperative absolute peripheral monocyte count, demographics, and clinical and pathological data were analyzed.Results: On univariate and multivariate analysis, elevated monocyte counts (≥ 545/mm(3)), tumor size ≥ 5 cm, non-capsulation, and multiple tumors were associated with poor disease-free survival (DFS) and overall survival (OS). The 1-, 3- and 5-year DFS rates were 58%, 41% and 35%, respectively, for patients with monocyte counts <545/mm(3), and 36%, 23% and 21% for patients with monocyte counts ≥ 545/mm(3). Correspondingly, the 1-, 3- and 5-year OS rates were 79%, 53% and 46% for monocyte counts <545/mm(3), and 64%, 36% and 29% for monocyte counts ≥ 545/mm(3). Subgroup analysis indicated that DFS after hepatic resection in hepatitis B virus (HBV)-infected patients was significantly better in those with a peripheral blood monocyte counts <545/mm(3), but it did not differ between patients without HBV infection. In addition, DFS was significantly better for patients with a peripheral blood monocyte count <545/mm(3), whether or not cirrhosis was present. Patients with elevated monocyte counts tended to have larger tumors.Conclusions: Elevated preoperative monocyte count is an independent predictor of worse prognosis for patients with HCC after hepatic resection, especially for those with HBV infection. Postoperative adjuvant treatment might be considered for patients with elevated preoperative monocyte counts. [ABSTRACT FROM AUTHOR]

Background: RhoC is a small G protein/GTPase and involved in tumor mobility, invasion and metastasis. Previously, up-regulated RhoC expression is found to play an important role in ovarian carcinogenesis and subsequent progression by modulating proliferation, apoptosis, migration and invasion.Methods: We transfected RhoC-expressing plasmid and RhoC siRNA into CAOV3 and OVCAR3 cells respectively. These cells and transfectants were exposed to vascular epithelial growth factor (VEGF), transforming growth factor (TGF)-β1 or their receptor inhibitors with the phenotypes and their related-molecules examined.Results: TGF-β1R or VEGFR inhibitor suppressed the proliferation, migration, invasion and lamellipodia formation, the expression of N-cadherin, α-SMA, snail and Notch1 mRNA or protein, and enhanced E-cadherin mRNA and protein expression in CAOV3 and its RhoC-overexpressing transfectants, whereas both growth factors had the opposite effects in OVCAR3 cells and their RhoC-hypoexpressing transfectants. Ectopic RhoC expression enhanced migration, invasion, lamellipodia formation and the alteration in epithelial to mesenchymal transition (EMT) markers of CAOV3 cells regardless of the treatment of VEGFR or TGF-β1R inhibitor, whereas RhoC knockdown resulted in the converse in OVCAR3 cells even with the exposure to VEGF or TGF-β1.Conclusion: RhoC expression might be involved in EMT of ovarian epithelial carcinoma cells, stimulated by TGF-β1 and VEGF. [ABSTRACT FROM AUTHOR]