Search

Background: To establish a prognostic score based on clinical routine factors to stratify nasopharyngeal carcinoma patients with bone metastasis into risk groups with different survival rates. Materials and Methods: Total 276 patients from multicenter were retrospectively analyzed. Kaplan-Meier method and Cox regression were used to confirm independent risk factors, which were checked for internal validity by bootstrapping method. The prognostic score, deriving from the corresponding regression coefficients in Cox model, classified patients into low and high risk groups. Finally, two independent cohorts were used for external validation. Results: In development cohort, six risk factors were identified: age>46 year-old (point=1), N>0 stage (point=2), anemia (point=2), bone metastasis free interval≤12 months (point=1), without radiotherapy to primary sites (point=1), and without radiotherapy to first metastasis sites (point=1). The derived prognostic score divided patients into low (score, 0-4) and high (score, 5-8) risk groups, with highly significant differences of 5-year overall survival rates (high vs. low risk: 24.6% vs. 58.2%, HR 3.47, P<0.001). Two external validations presented congruent results. Conclusion: A feasible and applicative prognostic score was successfully established and validated to discriminate bone metastatic nasopharyngeal carcinoma into low/high risk groups, which will be useful for individual treatment., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Purpose: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in Southeast Asia. Because local recurrence and distant metastasis are still the main causes of NPC treatment failure, it is urgent to identify new tumor markers and therapeutic targets for advanced NPC. Experimental Design: RNA sequencing (RNA-seq) was applied to look for interchromosome translocation in NPC. PCR, FISH, and immunoprecipitation were used to examine the fusion gene expression at RNA, DNA, and protein levels in NPC biopsies. MTT assay, colony formation assay, sphere formation assay, co-immunoprecipitation, chromatin immunoprecipitation assay, and in vivo chemoresistance assay were applied to explore the function of RARS-MAD1L1 in NPC. Results: We demonstrated that RARS-MAD1L1 was present in 10.03% (35/349) primary NPC biopsies and 10.7% (9/84) in head and neck cancer (HNC) samples. RARS-MAD1L1 overexpression increased cell proliferation, colony formation, and tumorigenicity in vitro , and the silencing of endogenous RARS-MAD1L1 reduced cancer cell growth and colony formation in vitro In addition, RARS-MAD1L1 increased the side population (SP) ratio and induced chemo- and radioresistance. Furthermore RARS-MAD1L1 interacted with AIMP2, which resulted in activation of FUBP1/c-Myc pathway. The silencing of FUBP1 or the administration of a c-Myc inhibitor abrogated the cancer stem cell (CSC)-like characteristics induced by RARS-MAD1L1. The expression of c-Myc and ABCG2 was higher in RARS-MAD1L1 -positive HNC samples than in negative samples. Conclusions: Our findings indicate that RARS-MAD1L1 might contribute to tumorigenesis, CSC-like properties, and therapeutic resistance, at least in part, through the FUBP1/c-Myc axis, implying that RARS-MAD1L1 might serve as an attractive target for therapeutic intervention for NPC. Clin Cancer Res; 24(3); 659-73. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objective: To explore clinical efficacy of hip replacement for hip-joint diseases with Parkinson disease., Methods: From December 2011 to December 2016, 18 patients with hip-joint diseases with Parkinson disease treated by hip replacement, including 8 males and 10 females aged from 59 to 87 years old with an average of 71 years old. Among them, 3 cases were developmental dysplasia of hip, 3 cases were femoral head necrosis and 12 cases were femoral neck fracture. All patients manifested with obvious pain and limitation of stepping ability. Postoperative complications were observed and Harris score were used to compare hip joint function after operation., Results: The incision were healed well, and pain were alleviated or disappeared, and hip joint function were improved. Eighteen patients were followed up from 1 to 3 years with an average of 2.3 years. At the latest follow up, 14 cases recovered freedom-walk, 2 cases could walk with walking stick, 1 case could walk with walking aid and 1 case was died. Among 18 patients, 2 cases were occurred dislocation, and 1 case were died for cardiac disease at 3 months after operation. Four patients were occurred slight pain. There were significant differences in Harris scores among preoperative (41.7±1.4), 6 months after operation(80.1±5.4) and the final follow-up (83.4±2.1), and 10 cases got excellent result, 4 good, 1 fair and 2 poor., Conclusions: Application of hip replacement for hip-joint diseases with Parkinson disease is a safe and effective clinical therapy, and has advantages of less complications and rapid recovery of hip joint function., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

This study aimed to kinetically discover optimal conditions on characteristics of Reactive Black 5 decolorization/degradation via ferrous (Fe 2+ )-activated potassium persulfate (PS). Monod-like kinetics and interactive model-based response surface methodology (RSM) were applied to fitting and predict optimize treatment. Biodegradability of the intermediates was also tested by shaking culture with two species (Proteus hauseri ZMd44 and Shewanella sp. WLP72). Results showed that the optimal degradation efficiency was predicted (through RSM) as pH 3.72, (PS) = 0.39 mM, and (Fe 2+ ) = 0.29 mM. The transformation products (dl-4-hydroxymandelic acid, benzoic acid, benzene, formic acid, oxalic acid and acetic acid) were less toxic than the original dye solution. According to those results, clean-up of dye pollutants by the Fe 2+ /S 2 O 8 2- process is feasible as a pre-processing for the biodegradation, and the predicted optimal conditions are meaningful for further industry utilization.

Our previous findings suggest that sphingosine kinase 2 (SPK2) mediates ischemic tolerance and autophagy in cerebral preconditioning. The aim of this study was to determine by which mechanism SPK2 activates autophagy in neural cells. In both primary murine cortical neurons and HT22 hippocampal neuronal cells, overexpression of SPK2 increased LC3II and enhanced the autophagy flux. SPK2 overexpression protected cortical neurons against oxygen glucose deprivation (OGD) injury, as evidenced by improvement of neuronal morphology, increased cell viability and reduced lactate dehydrogenase release. The inhibition of autophagy effectively suppressed the neuroprotective effect of SPK2. SPK2 overexpression reduced the co-immunoprecipitation of Beclin-1 and Bcl-2, while Beclin-1 knockdown inhibited SPK2-induced autophagy. Both co-immunoprecipitation and GST pull-down analysis suggest that SPK2 directly interacts with Bcl-2. SPK2 might interact to Bcl-2 in the cytoplasm. Notably, an SPK2 mutant with L219A substitution in its putative BH3 domain was not able to activate autophagy. A Tat peptide fused to an 18-amino acid peptide encompassing the native, but not the L219A mutated BH3 domain of SPK2 activated autophagy in neural cells. The Tat-SPK2 peptide also protected neurons against OGD injury through autophagy activation. These results suggest that SPK2 interacts with Bcl-2 via its BH3 domain, thereby dissociating it from Beclin-1 and activating autophagy. The observation that Tat-SPK2 peptide designed from the BH3 domain of SPK2 activates autophagy and protects neural cells against OGD injury suggest that this structure may provide the basis for a novel class of therapeutic agents against ischemic stroke.

Extradomain-B fibronectin (EDB-FN), an oncofetal isoform of FN, is a promising diagnostic and therapeutic target of tumors, including breast cancer. Many EDB-FN-targeted drugs have been developed and have shown therapeutic effects in clinical trials. Molecular imaging to visualize EDB-FN-positive cancers may help select the right patients who will be benefit from EDB-FN-targeted therapy. Although a few EDB-FN-targeted imaging probes have been developed, the complicated manufacturing procedure and expensive material and equipment required limit their application for large-scale screening of EDB-FN-positive cancer patients. Thus, more simple and economic EDB-FN-targeted imaging probes are still urgently needed. Previously, we have identified a breast cancer-targeted peptide, CTVRTSADC. Coincidently, it was later identified as an EDB-FN-targeted peptide and named ZD2. In this study, we found a positive correlation between the binding activity of the ZD2 phage and the expression level of EDB-FN in breast cancer cells. Moreover, we observed the colocalization of the ZD2 peptide with EDB-FN in breast cancer cells. Furthermore, in vivo tumor targeting of the ZD2 phage, near-infrared fluorescence imaging, and flow cytometry showed tumor-specific homing of the ZD2 peptide in mice bearing EDB-FN-positive breast cancers. Importantly, on the basis of this EDB-FN-targeted ZD2 peptide, we developed a kit-formulated probe, 99m Tc-HYNIC-ZD2, for single-photon-emission computed tomography (SPECT) imaging of breast cancer. The high tumor uptake of 99m Tc-HYNIC-ZD2 demonstrated its feasibility for use in visualizing EDB-FN-positive breast cancers in vivo. This kit-formulated EDB-FN-targeted SPECT probe has potential clinical applications for precision screening of EDB-FN-positive cancer patients who may benefit from EDB-FN-targeted therapy., Competing Interests: The authors declare no competing financial interest.

This meta-analysis was performed to evaluate the effect of cognitive behavioural therapy (CBT) in improving the depression symptoms of patients with diabetes. Literature search was conducted in PubMed and Embase up to October 2016 without the initial date. The pooled SMD (standard mean difference) and its 95% confidence interval (CI) were calculated by Revman 5.3. Subgroup analyses were performed by type of diabetes and evaluation criteria of depression. A total of five randomized control trials involving 834 patients with diabetes mellitus (including 417 patients in CBT group and 417 patients in control group) were included in this meta-analysis. The pooled estimates indicated significant improvement of depression by CBT compared with routine approaches in overall outcomes (SMD =-0.33, 95% CI =-0.46 to -0.21, P <0.00001), post-intervention outcomes (SMD =-0.43, 95% CI =-0.73 to -0.12, P =0.006) and outcomes after 12 months intervention (SMD =-0.38, 95% CI = -0.54 to -0.23, P <0.0001). Subgroup analyses showed that the results were not influenced by the type of diabetes. However, the effect of CBT on improving the depression symptoms disappeared when only using CES-D (Centre for Epidemiological Studies scale for Depression) to evaluate depression., (© 2017 The Author(s).)

Objective : Great heterogeneity exists in clinical behavior and survival outcome in patients with stage IE/IIE extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). In this study, we proposed lymphocyte/monocyte ratio (LMR) as a new prognostic factor for these early stage ENKTL. Methods : We retrospectively examined the LMR as a prognostic variable in a cohort of 379 patients with newly diagnosed stage IE/IIE ENKTL. The relationship between the LMR and clinicopathologic variables were analyzed in Kaplan-Meier log-rank survival analysis, and the Cox proportional hazards model was used to determine the survival significance of the LMR for both progression-free survival (PFS) and overall survival (OS). Results : Patients were categorized into two different groups based on the LMR using cut-off value of 2.0. The 5-year PFS rates in the low and high LMR group were 43.9% and 62.7%, respectively, and the 5-year OS rates in the two groups were 59.1% and 77.7%, respectively. In multivariate analysis, low LMR at diagnosis was associated with worse PFS (hazard ratio 1.611, 95% confidence interval: 1.027-2.525, P =0.038) independent of age (P=0.033) and treatment stratagem (P<0.001), and indicated worse OS (hazard ratio 2.003, 95% confidence interval: 1.124-3.569, P =0.018) independent of age (P=0.007), LDH level (P=0.042), local tumor invasiveness (P=0.008), and treatment stratagem (P<0.001). Conclusion : The LMR is an independent prognostic factor for both DFS and OS in patients with stage IE/IIE ENKTL, and provides additional prognostic value beyond standard clinicopathological parameters., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective The ideal agents for conscious sedation during ambulatory inguinal hernia repair are still unclear. We aimed to compare the analgesic, sedative, haemodynamic, and side effects of dexmedetomidine with those of propofol in combination with fentanyl for conscious sedation in patients undergoing inguinal hernia repair. Methods Eighty patients undergoing unilateral inguinal hernia repair were prospectively randomized to receive either dexmedetomidine (n = 40) or propofol (n = 40). Dexmedetomidine and propofol dosages were adjusted to maintain the targeted level of sedation. Results After administration of sedative drugs, patients who received dexmedetomidine had a significantly lower heart rate. The intraoperative requirement of fentanyl was significantly lower in patients who received dexmedetomidine compared with patients who received propofol. Administration of dexmedetomidine was associated with a reduced postoperative pain score, longer time for onset of sedation, and a slightly longer recovery time. No serious adverse events occurred in either group. The patients' overall satisfaction score was comparable between the two groups. Conclusion Dexmedetomidine is an effective adjuvant when co-administered with fentanyl for conscious sedation in patients who undergo inguinal hernia repair. Administration of dexmedetomidine decreases the requirement of fentanyl and the pain score, but slightly prolongs the time to sedation and recovery.

Background: Weight loss during radiotherapy has been known as a negative prognostic factor for nasopharyngeal carcinoma (NPC) patients, but the factors related to weight loss during radiotherapy were not fully understood. Methods: A total of 322 newly diagnosed NPC patients receiving intensity modulated radiotherapy (IMRT) in Sun Yat-sen University Cancer Center between June 2002 and August 2006 were enrolled. Kaplan-Meier methods and log-rank test were applied for survival analysis; a multiple regression was used to identify the factors related to weight loss during radiotherapy. Results: The mean and median values of weight loss (%) during radiotherapy were 6.85% and 6.70%. NPC patients with critical weight loss (> 5.4%) have poorer overall survival (OS) and distant metastasis-free survival (DMFS) than the patients without critical weight loss ( p = 0.002 and 0.021, respectively). Pre-radiotherapy weight, acute mucosal toxicity, acute pharynx and esophagus toxicity, and acute upper gastrointestinal toxicity were related to the weight loss during radiotherapy independently ( p = 0.01, p < 0.001, p < 0.001, and p = 0.009, respectively). Conclusions : Acute radiation toxicities had significant and independent impact on weight loss during radiotherapy. The vicious circle of acute radiation toxicities and weight loss had bad effect on prognosis of NPC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

This study retrospectively investigated asparaginase-based chemotherapy treatment outcomes with or without radiotherapy in 143 patients with stage IE-IIE extranodal natural killer/T cell lymphoma (ENKTCL). All patients received a median of three cycles of asparaginase-based chemotherapy, while 121 patients received radiotherapy following the chemotherapy. The complete remission (CR) rate for all patients post-chemotherapy was 58.7%, and rose to 73.4% by the end of treatment. Patients who received radiotherapy achieved better survival outcomes than those who did not (89.7% vs. 49.0% for 2-year overall survival (OS), P<0.001; 86.8% vs. 37.4% for 2-year progression-free survival (PFS), P<0.001). Additionally, even patients who achieved CR post-chemotherapy exhibited differential survival rates with or without radiotherapy (90.8% vs. 60% for 2-year OS, P=0.006; 86.1% vs. 60% for 2-year PFS, P=0.044). Multivariate analysis revealed that radiotherapy was an independent factor favoring OS (HR=0.098, 95%CI=0.031-0.314, P=0.001) and PFS (HR=0.156, 95%CI=0.062-0.396, P=0.001). Thus, radiotherapy is recommended for stage IE-IIE ENKTCL patients treated with asparaginase-based chemotherapy, even in cases of CR following chemotherapy.

Background: Cervical cancer (CC) is the second most common cancer in females in developing countries. The two viral oncoproteins E6 and E7 mediate the oncogenic activities of high-risk human papillomavirus (HR-HPV), and HR-HPV, especially HPV16 or/and HPV18 (HPV16/18) play critical roles in CC through different pathways. microRNAs (miRNAs) may be associated with CC pathogenesis. Researches have indicated that human papillomavirus (HPV) may regulate cellular miRNA expression through viral E6 and E7. Herein, the purposes of this study were to identify the relationship between HPV infection and aberrantly expressed miRNAs and to investigate their pathogenic roles in CC., Methods: miRNA expression was assessed using a microRNAs microarray in HPV16 E6- and E7-integrated HPV-negative HT-3 cell lines and mock vector-transfected HT-3 cells. The microarray results were validated, and the expression of miR-3156-3p was identified in HPV-positive and -negative CC cell lines as well as primary CC and normal cervical epithelium tissues using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK8), flow cytometry, transwell analysis, tube formation, and Western blotting were used to identify the functional role of miR-3156-3p in CaSki, SiHa, and HeLa cell lines., Results: Six underexpressed microRNAs (miR-3156-3p, 6779-3p, 4779-3p, 6841-3p, 454-5p and 656-5p) were consistently identified in HPV16 E6- and E7-integrated HT-3 cells. Further investigation confirmed a significant decrease of miR-3156-3p in HPV16/18 positive CC lesions. CCK8, flow cytometry, transwell analysis, tube formation assays, and Western blotting of the CC cell lines with miR-3156-3p over/under-expression in vitro showed that miR-3156-3p was involved in cell proliferation, apoptosis, migration, neovascularization, and SLC6A6 regulation., Conclusions: Our findings indicate that miR-3156-3p plays a suppressor-miRNA role in CC and that its expression is associated with HR-HPV infection.

Lindera aggregata (Sims) Kosterm root has been used in traditional Chinese medicine for the treatment of rheumatism palsy, dyspepsia and frequent urination for a long time. Norisoboldine, the main active constituent of this herb drug, possesses outstanding anti-arthritis activity. However, the in vivo disposition of norisoboldine is known to a limited extent, especially under the pathological condition of rheumatoid arthritis (RA). The aim of this study is to investigate whether and how the absorption of norisoboldine is altered in adjuvant-induced arthritis (AIA) rats. Comparative studies of the intestinal absorption of norisoboldine in normal and AIA rats at different pathological stages of the arthritis were performed using in situ single-pass intestinal perfusion, and the effects of an inhibitor of efflux proteins were also investigated. Norisoboldine was shown to be a substrate of P-glycoprotein (P-gp), as P-gp inhibitor verapamil markedly increased the permeability coefficient (P eff ) of norisoboldine by 88% in the intestine of normal rats. Compared with normal rats, AIA rats displayed increased P eff values of norisoboldine by 84% and 86% on day 5 and day 10 after the appearance of the secondary response of arthritis, respectively. Verapamil could eliminate the difference of intestinal absorption of norisoboldine between normal and AIA rats. Further studies showed that impaired expression and activity of P-gp in AIA rats play a decisive role in the absorption enhancement of norisoboldine. Notably, the impairment of P-gp function positively correlated with the severity of arthritis. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

To get inside the properties of N,N-disubstituted Schiff bases, we synthesized three high-yielding benzaldehyde Schiff bases. We used the reaction between salicylaldehyde and different diamine compounds, including diamine, ethanediamine, and o -phenylenediamine, determining the structure of obtained molecules by nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy. We thus evaluated the microbicidal and antitumor activity of these compounds, showing that salicylaldehyde-hydrazine hydrate Schiff base (compound 1a ) significantly inhibited the growth of S. aureus ; salicylaldehyde- o -phenylenediamine Schiff base (compound 1c ) displayed a strong capability to inhibit the proliferation of leukemia cell lines K562 and HEL. Moreover, we observed that the antibacterial action of 1a might be associated with the regulation of the expression of key virulence genes in S. aureus . Compound 1c resulted in a strong apoptotic activity against leukemia cells, also affecting the cell cycle distribution. Overall, our novel N,N-disubstituted Schiff bases possess unique antibacterial or antitumor activities that exhibit the potent application prospect in prophylactic or therapeutic interventions, providing new insights for developing new antibacterial and anticancer chemical agents.

Chronic inflammation plays an important role in tumor progression. The aim of this analysis was to evaluate whether inflammatory biomarkers such as the Glasgow prognostic score (GPS), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the lymphocyte-monocyte ratio (LMR) could predict the prognosis of nasopharyngeal carcinoma (NPC). In this analysis, pretreatment GPS, NLR, PLR, LMR of 388 patients who were diagnosed as nonmetastatic NPC and recruited prospectively in the 863 Program No. 2006AA02Z4B4 were assessed. Of those, the 249 cases enrolled between December 27th 2006 and July 31st 2011 were defined as the development set. The rest 139 cases enrolled between August 1st 2011 and July 31st 2013 were defined as the validation set. The variables above were analyzed in the development set, together with age, gender, Karnofsky performance score, T stage, and N stage, with respect to their impact on the disease-specific survival (DSS) through a univariate analysis. The candidate prognostic factors then underwent a multivariate analysis. A nomogram was established to predict the DSS, by involving the independent prognostic factors. Its predction capacity was evaluated through calculating Harrell's concordance index (C-index) in the validation set. After multivariate analysis for the development set, age (≤50 vs. >50 years old), T stage (T1-2 vs. T3-4), N stage (N0-1 vs. N2-3) and pretreatment GPS (0 vs. 1-2), NLR (≤2.5 vs. >2.5), LMR (≤2.35 vs. >2.35) were independent prognostic factors of DSS (P values were 0.002, 0.008, <0.001, 0.004, 0.018, and 0.004, respectively). A nomogram was established by involving all the factors above. Its C-index for predicting the DSS of the validation set was 0.734 (standard error 0.056). Pretreatment GPS, NLR, and LMR were independent prognostic factors of NPC. The nomogram based on them could be used to predict the DSS of NPC patients., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism (rs861539, C > T) has drawn wide attentions as its association with cancer risk and its involvement in DNA repair. Several studies have attempted to link rs861539 to nasopharyngeal cancer (NPC) risk; however, the sample sizes of these studies are small and the results are controversial. To investigate the relationship of rs861539 and NPC susceptibility, we conducted a large-scale case-control study involving 4001 NPC cases and 2967 controls of southern Chinese. Logistic regression analysis revealed significant association for rs861539 and NPC risk under the recessive model (TT vs. CT + CC) with adjustment of age and gender (odds ratio, OR = 2.72; 95 % CI 1.10-6.72; P = 0.03). Further, meta-analysis involving 4457 NPC cases and 4132 controls from four studies showed consistent association of TT carriers and NPC risk (OR = 3.12; 95 % CI 1.58-6.13; P = 0.001). Taken together, our findings based on large-scale sample size suggested rs861539 at XRCC3 to be associated with NPC risk through recessive model.

c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients.

Bergenin, isolated from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao) has hepatoprotective, anti-inflammatory, antitussive, and neuroprotective activities. The aim of the present study was to establish a simple, rapid, and sensitive RP-HPLC method for determination of bergenin in rat plasma and compare its oral pharmacokinetic behaviors in normal and CCl 4 -induced hepatic injury rats. With norisoboldine as an internal standard, chromatographic separation was performed on a C 18 analytical column with acetonitrile and water (11 : 89, V/V) containing 0.1% formic acid as the mobile phase. A good linearity was obtained over the range of 100-10 000 ng·mL -1 . The lower limit of quantification was 50 ng·mL -1 . The developed method was successfully applied to a study of the pharmacokinetic difference of bergenin (100 mg·kg -1 ) between normal and hepatic injury rats after oral administration. Marked alterations of pharmacokinetic parameters in hepatic injury rats were observed. Compared to normal rats, the AUC (0-∞) of bergenin in hepatic injury rats was elevated to 2.11-fold and C max was increased by 130%, whereas CL value was only 55% of the normal rats, suggesting that the systemic exposure of bergenin was significantly increased under hepatic injury status., (Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

As widely used disinfectants, the pollution caused by benzalkonium chloride (BAC) has attracted a lot of attention in recent years. Since it is not suitable for biodegradation, BAC was degraded firstly by Fenton advanced oxidation technologies (AOTs) in this research to enhance the biodegradability of the pollutions. The result revealed that the optimal molar ratio of H2O2/Fe(2+) for BAC degradation was 10:1, and the COD removal rate was 32 %. To clarify the pathway of degradation, the technique of GC-MS was implemented herein to identify intermediates and the toxicity of those BAC intermediates were also novelty tested through microbial fuel cells (MFC). The findings indicated that ten transformation products including benzyl dimethyl amine and dodecane were formed during the H2O2/Fe(2+) processes, which means the degradation pathway of BAC was initiated both on the hydrophobic (alkyl chain) and hydrophilic (benzyl and ammonium moiety) region of the surfactant. The toxicity of BAC before and after treated by Fenton process was monitored through MFC system. The electricity generation was improved 337 % after BAC was treated by H2O2/Fe(2+) oxidation processes which indicated that the toxicity of those intermediates were much lower than BAC. The mechanism and toxicity research in this paper could provide the in-depth understanding to the pathway of BAC degradation and proved the possibility of AOTs for the pretreatment of a biodegradation process.

Abnormal interaction between non-coding RNAs has been demonstrated to be a common molecular event in various human cancers, but its significance and underlying mechanisms have not been well documented. RNA-binding proteins (RBPs) are key regulators of RNA transcription and post-transcriptional processing. In this study, we found that RNA-binding protein 24 (RBM24) was frequently downregulated in nasopharyngeal carcinoma (NPC). The restoration of RBM24 expression suppressed NPC cellular proliferation, migration and invasion and impeded metastatic colonization in mouse models. Microarray analyses revealed that miR-25 expression was upregulated by RBM24 expression in NPC cells. Similarly, ectopic miR-25 expression suppressed NPC cellular growth and motility by targeting the pro-oncogenic lncRNA MALAT1, and the knockdown of MALAT1 expression exhibited similar effects as RBM24 restoration in NPC cells. Overall, these findings suggest a novel role of RBM24 as a tumor suppressor. Mechanistically, RBM24 acts at least in part through upregulating the expression of miR-25, which in turn targets MALAT1 for degradation.

To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 controls of southern Chinese. The joint analysis with 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P < 5 × 10 -8 ), including TERT-CLPTM1L at chromosome 5p15 (rs401681; P = 2.65 × 10 -14 ; odds ratio, OR = 0.82) and CIITA at chromosome 16p13 (rs6498114; P = 4.01 × 10 -9 ; OR = 0.87). Conditional analysis revealed that rs401681 accounts for all the tested associations at TERT-CLPTM1L locus, which has been linked with multiple cancers' susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although the prognostic impact of body mass index (BMI) in patients with non-metastatic nasopharyngeal carcinoma (NPC) had been extensively studied, its effect among metastatic NPC patients remains unknown. The purpose of this study was to evaluate the prognostic effect of BMI in patients with metastatic NPC., Methods: We retrospectively studied 819 patients who were diagnosed with distant metastasis from NPC and received treatment between 1998 and 2007. The patients were divided into three subgroups according to the World Health Organization classifications for Asian populations: underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-22.9 kg/m(2)), and overweight/obese (BMI ≥23.0 kg/m(2)). The associations of BMI with overall survival (OS) and progression-free survival (PFS) were determined by Cox regression analysis., Results: Of the 819 patients, 168 (20.5%) were underweight, 431 (52.6%) were normal weight, and 220 (26.9%) were overweight/obese. Multivariate analysis adjusted for covariates showed that overweight/obese patients had a longer OS than underweight patients [hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.49-0.84] and normal weight patients (HR, 0.72; 95% CI, 0.57-0.90); no significant difference in PFS was observed among these three groups (P = 0.407). Moreover, in stratified analysis, no statistically significant differences in the effect of overweight/obese status among different subgroups were observed., Conclusion: For patients with metastatic NPC, overweight/obese status was associated with longer OS but not longer PFS compared with underweight or normal weight status.

Purpose: We aimed to assess the prognostic value of pretreatment high density lipoprotein cholesterol (HDL-C) levels in patients with nasopharyngeal carcinoma (NPC) and investigate the possible biological effects of these lipoproteins on NPC cells in vitro., Experimental Design: We examined the prognostic value of pretreatment HDL-C levels in 2443 patients with non-metastatic NPC from three independent institutions. The Cox proportional hazard model and log-rank test were used to analyze the correlation between HDL-C levels and overall survival (OS). Cell growth, colony formation, and apoptotic assays were used to determine the biological functions of HDL on NPC cells in vitro. All of the statistical tests were two-sided., Results: OS was decreased in patients with high pretreatment HDL-C levels compared with those with low HDL-C levels (P < 0.05). Similarly, a decreased OS was noted in advanced stage (stage III-IV), NPC patients with high pretreatment HDL-C levels (P < 0.01). Multivariate analyses indicated that HDL-C was an independent prognostic factor associated with shorter OS in training cohorts. These findings were confirmed in both independent validation cohorts (P < 0.01). In vitro experiments demonstrated that HDL could increase cell proliferation, invasion, and colony formation, which were largely dependent on the expression of its receptor SR-B1. Finally, HDL could enhance chemoresistance by protecting cancer cells from apoptosis., Conclusions: Pretreatment HDL-C is a poor prognostic factor for patients with NPC. This effect may be associated with the ability of HDL to enhance proliferation, colony formation, migration, and chemoresistance in NPC cells., Competing Interests: We declare that we have no conflicts of interest.

miRs (microRNAs, miRNAs) intricately regulate physiological and pathological processes. Although miR-7a/b protects against cardiomyocyte injury in ischemia/reperfusion injury, the function of miR-7a/b in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Here, we sought to investigate the function of miR-7a/b in post-MI remodeling in a mouse model and to determine the underlying mechanisms involved. miR-7a/b overexpression improved cardiac function, attenuated cardiac remodeling and reduced fibrosis and apoptosis, whereas miR-7a/b silencing caused the opposite effects. Furthermore, miR-7a/b overexpression suppressed specific protein 1 (Sp1) and poly (ADP-ribose) polymerase (PARP-1) expression both in vivo and in vitro, and a luciferase reporter activity assay showed that miR-7a/b could directly bind to Sp1. Mithramycin, an inhibitor of the DNA binding activity of Sp1, effectively repressed PARP-1 and caspase-3, whereas knocking down miR-7a/b partially counteracted these beneficial effects. Additionally, an immunoprecipitation assay indicated that hypoxia triggered activation of the binding activity of Sp1 to the promoters of PARP-1 and caspase-3, which is abrogated by miR-7a/b. In summary, these findings identified miR-7a/b as protectors of cardiac remodeling and hypoxia-induced injury in H9c2 cardiomyoblasts involving Sp1 and PARP-1.

Objective To explore the safety and effectiveness of Shenkang Injection (SI) for con- trast-induced nephropathy (CIN) in elderly patients with chronic kidney disease (CKD). Methods Totally 206 elderly CKD patients who were scheduled to undergo coronary angiography (CAG) were assigned to three groups according to random digit table, i.e., the rehydration therapy group (67 cases) , the SI group (71 cases) , and the control group (68 cases). Patients in the rehydration therapy group received intrave- nous dripping of normal saline 12 h before and after CAG. Patients in the SI group received intravenous drip- ping of SI, while those in the control group received intravenous dripping of 5% glucose injection. SI and 5% glucose injection was respectively used 3 days before CAG and 4 days after CAG, once per day. The inci- dence rate of CIN, and levels of creatinine, blood urea nitrogen (BUN) , serum cystatin C (CysC), kidney injury molecule-1 (KIM-1), and P2-microglobulin (P2-MG) were detected before CAG, 24 h and 96 h after CAG, respectively. Age, sex, SI, contrast dose, pre-CAG indicators of renal function were compared. Their correlations with changed 24-h creatinine value (the difference between the value at post-CAG 24 h and pre-CAG) and CIN incidence rate were analyzed using Sperman correlation and Logistic regression analy- ses. Results Compared with the rehydration therapy group and the control group, the incidence rate of CIN was significantly lower in the SI group (x2 = 5. 32, P <0. 05). Compared with before treatment in the same group, levels of creatinine and CysC were all elevated in the 3 groups after 24-and 96-h treatment (P <0. 05) ; the KIM-1 level increased in rehydration therapy group and the control group (P <0. 05) ; P2-MG level increased in the SI group (P <0.05). Compared with the control group, post-CAG P2-MG level in- creased in the SI group (P <0. 05). There was no statistical difference in other index (P >0. 05). SI was neg- atively with the incidence rate of CIN and changed 24-h creatinine value (r = -0. 612, -0. 517, P <0. 05). The contrast dose was positively with the incidence rate of CIN and changed 24-h creatinine value (r = 0. 644, 0. 562, P <0. 05). Increased contrast dose could elevate the incidence rate of CIN (P <0. 05). SI could obviously lower the incidence rate of CIN (P <0. 05). Conclusion SI could lower the incidence rate of CIN in elder CKD patients by playing certain roles in prevention and treatment.

Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis.

Aim: Paeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-β mediated pulmonary EMT in bleomycin-induced PF mice., Methods: PF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-β1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR., Results: In PF mice, paeoniflorin (50, 100 mg·kg(-1)·d(-1)) or prednisone (6 mg·kg(-1)·d(-1)) significantly decreased the expression of FSP-1 and α-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-β1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and α-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-β1 for 24 h. TGF-β1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1-30 μmol/L) dose-dependently attenuated TGF-β1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-β1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells., Conclusion: Paeoniflorin suppresses the early stages of TGF-β mediated EMT in alveolar epithelial cells, likely by decreasing the expression of the transcription factors Snail via a Smad-dependent pathway involving the up-regulation of Smad7.

Background: With the improved overall survival (OS) of nasopharyngeal carcinoma (NPC) patients, the importance of quality of life (QoL) is increasingly being recognized. For some radiosensitive NPC patients, whether low-dose radiotherapy can improve the QoL without affecting clinical efficacy is unknown. This study aimed to assess the survival rates and QoL of NPC patients treated with 50 Gy radiotherapy plus hematoporphyrin derivative (HPD)., Methods: Forty-six newly diagnosed NPC patients treated with 50 Gy radiotherapy plus HPD between June 1988 and July 1992 were analyzed. All patients were restaged according to the 7th edition of the American Joint Committee on Cancer staging system. The radiotherapy plan was designed on the basis of pretreatment computed tomography. The OS, local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. QoL was assessed using the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group., Results: The 5-year OS, LRFS, DMFS, and DFS rates were 74.3%, 72.6%, 82.1%, and 61.2%, respectively. The corresponding 10-year rates were 38.4%, 62.9%, 78.5%, and 49.8%, respectively, and the 20-year rates were 27.7%, 51.4%, 78.5%, and 40.7%, respectively. None of the patients developed severe radiation-related complications, such as radiation-induced temporal lobe necrosis, hearing loss, trismus, and dysphagia., Conclusion: Some NPC patients were sensitive to 50 Gy radiotherapy plus HPD, and this sensitivity was characterized by long-term survival without significant late treatment morbidities.

Background: Nasal-type extranodal natural killer/T-cell lymphoma (ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract. However, it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement. The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL., Methods: To develop a nomogram, we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011. The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index (C-index) and calibration curve., Results: The 5-year overall survival (OS) and progression-free survival (PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL (OS: 68.2% vs. 46.0%, P = 0.030; PFS: 53.4% vs. 26.6%, P = 0.010). The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage IIE ENKTCL (OS: 66.3% vs. 59.2%, P = 0.003; PFS: 51.4% vs. 40.3%, P = 0.009). Multivariate analysis showed that age >60 years, ECOG performance status score ≥2, elevated lactate dehydrogenase (LDH) level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year OS rate; age >60 years, elevated LDH level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year PFS rate. The nomogram included the primary site and regional lymph node involvement based on multivariate analysis. The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates, and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634, respectively., Conclusions: The primary site and regional lymph node involvement are independent prognostic factors for early-stage ENKTCL treated with chemotherapy followed by definitive radiotherapy.

Background and Purpose: Madecassoside has potent anti-pulmonary fibrosis (PF) effects when administered p.o., despite having extremely low oral bioavailability. Herein, we explored the mechanism of this anti-PF effect with regard to gut hormones., Experimental Approach: A PF model was established in mice by intratracheal instillation of bleomycin. Haematoxylin and eosin stain and Masson's trichrome stain were used to assess histological changes in the lung. Quantitative-PCR and Western blot detected mRNA and protein levels, respectively, and cytokines were measured by ELISA. Small interfering RNA was used for gene-silencing. EMSA was applied to detect DNA-binding activity., Key Results: Administration of madecassoside, p.o., but not its main metabolite madecassic acid, exhibited a direct anti-PF effect in mice. However, i.p. madecassoside had no anti-PF effect. Madecassoside increased the expression of hepatocyte growth factor (HGF) in colon tissues, and HGF receptor antagonists attenuated its anti-PF effect. Madecassoside facilitated the secretion of HGF from colonic epithelial cells by activating the PPAR-γ pathway, as shown by an up-regulation of PPAR-γ mRNA expression, nuclear translocation and DNA-binding activity both in vitro and in vivo. Also GW9662, a selective PPAR-γ antagonist, almost completely prevented the madecassoside-induced increased expression of HGF and amelioration of PF., Conclusions and Implications: The potent anti-PF effects induced by p.o. madecassoside in mice are not mediated by its metabolites or itself after absorption into blood. Instead, madecassoside increases the activity of PPAR-γ, which subsequently increases HGF expression in colonic epithelial cells. HGF then enters into the circulation and lung tissue to exert an anti-PF effect., (© 2016 The British Pharmacological Society.)

Serum amyloid A (SAA), a major acute-phase reactant, modulates angiogenesis in many diseases. Vascular endothelial growth factor receptor 2 (VEGFR2) is the primary angiogenic receptor for vascular endothelial growth factor (VEGF), but the possibility of an interaction between SAA and VEGFR2 has not yet been resolved. Here, we investigated if SAA stimulates the expression of VEGFR2 and promotes angiogenesis in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant SAA (rSAA), and the messenger RNA (mRNA) and protein expression of VEGFR2 was detected by Western blot analysis and quantitative real-time PCR. Formyl peptide receptor-like 1 (FPRL1) agonist (WKYMVm) and antagonist (WRW(4)) and inhibitors of mitogen-activated protein kinases (MAPKs) were used to investigate the mechanism of regulation of VEGFR2.We show that SAA induces VEGFR2 expression in a time- and dose-dependent manner in HUVECs. In addition, SAA promotes tube formation in HUVECs. The effect of SAA on tube formation was shown to be the result of an increase in VEGFR2 expression, which was blocked by the multi-angiokinase receptor inhibitor BIBF1120. These activities of SAA appear to be mediated by FPRL1/MAPK signaling pathways, as they were mimicked by WKYMVm and abrogated by WRW(4) and inhibitors of MAPKs. These observations indicate that SAA induces VEGFR2 expression and promotes tube formation in HUVECs via the FPRL1/MAPK signaling pathway, thus providing a potential target for the control of angiogenesis.

Purpose: To investigate the prognostic value of cavernoussinus invasion (CSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT)., Patients and Methods: Retrospective review of data from 1,087 patients with biopsy-proven, non-metastatic NPC. All patients were diagnosed using magnetic resonance imaging (MRI) scans and received IMRT as the primary treatment., Results: The incidence of cavernoussinus invasion in this cohort was 12.1%. In univariate analysis, 5-year overall survival (OS) (70.6% vs. 88.5%, P < 0.001) and distant metastasis-free survival (DMFS) (71.4% vs. 87.7%, P < 0.001), but not locoregional relapse-free survival (LRFS) (93.9% vs. 93.7%, P = 0.341), were significantly different between patients with and without cavernoussinus invasion. In the T4 subgroup, the 5-year OS, DMFS, and LRFS of patients with and without cavernoussinus extension were 70.6% vs. 81.9% (P = 0.011), 71.4% vs. 84.1% (P = 0.011), and 91.2% vs. 89.7% (P = 0.501), respectively. In multivariate analysis, cavernoussinus invasion was an independent prognostic factor for poorer OS (HR = 1.782; P = 0.013) and DMFS (HR = 1.771; P = 0.016), but not LRFS (HR = 0.632; P = 0.294). In patients with lymph node metastasis, the DMFS rates of patients with and without cavernoussinus invasion were significantly different (P < 0.001). Preliminaryanalysis indicated that neoadjuvant chemotherapy led to better DMFS and OS in patients with cavernoussinus invasion than concurrent chemotherapy or radiotherapy alone; however, the differences were not significant., Conclusions: In the IMRT era, cavernoussinus invasion remains a prognostic factor for poor DMFS and OS in NPC, even in patients with T4 disease.

The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan-Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05-1.81, P = 0.022; HR = 1.38, 95% CI 1.09-1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.

Interleukin (IL)-33, a member of the IL-1 cytokine super-family, acts as both a traditional cytokine and an intracellular nuclear factor. It is generally released from damaged immune cells and signals through its receptor ST2 in an autocrine and paracrine fashion, plays important roles in type-2 innate immunity, and functions as an "alarmin" or a danger signal for cellular damage or cellular stress. Here, we review recent advances of the role of IL-33 in lung injury and explore its potential significance as an attractive therapeutic target.

Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied., Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case-control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed., Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10(-13)). Our results also provide support for associations reported from published NPC GWAS-rs6774494 (P = 1.5 × 10(-12); located in the MECOM gene region), rs9510787 (P = 5.0 × 10(-10); located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10(-8), P = 7.0 × 10(-7), and P = 8.4 × 10(-7), respectively; located in the CDKN2A/B gene region)., Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity., Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis., (©2015 American Association for Cancer Research.)

The aim of this study was to explore the efficacy and safety of hemodialysis in interventional therapy for patients with coronary artery disease combined with chronic renal insufficiency. With the aging and social development, the number of coronary artery disease patients with chronic renal insufficiency gradually increased. Total 58 coronary heart disease patients with chronic renal dysfunction were selected. These patients were characterized with typical angina symptoms and typical electrocardiogram (ECG) changes of onset angina. Continuous oral administration of sodium bicarbonate tablets 1 g 3/day × 3 days and slow intravenous input sodium chloride 1000 ∼1500 mL 3-12 h before operation were given. By this way, all patients were treated by hydration and alkalization. After percutaneous coronary intervention (PCI) treatment, patients were immediately transferred to undergo 4 h of dialysis treatment without removing indwelling of femoral artery puncture sheath tube to protect renal function. Changes in renal function including serum creatinine, glomerular filtration rate, and urine were observed and recorded. All patients were successfully underwent PCI treatment. Within one month after PCI, there were no obvious complication and no stent thrombosis occurred. Among of 58 patients, 56 cases showed no significant increase in serum creatinine levels compared with those before operation. However, serum creatinine level of one patient increased to 251 umol/L and one patient still required permanent dialysis. Using hemodialysis in interventional therapy in coronary artery disease patients with chronic renal insufficiency could significantly improve the prognosis of the patients.

The crystal structures and magnetic behaviours of two water-bridged one-dimensional (1D) cobalt(II) chains with different isomeric naphthoate (na(-)) terminals, [Co(H2O)3(2-na)2]n (1) and {[Co(H2O)3(1-na)2]·2H2O}n (2), were reported to investigate the effect of interchain distance on their magnetic properties. Complex 1 with trans-2-na(-) blocks and dense interchain separation exhibits a metamagnetic transition from antiferromagnetic ordering to a saturated paramagnetic phase. By contrast, complex 2 possessing cis-arranged 1-na(-) spacers and good interchain isolation shows unusual single-chain magnetic behavior under a zero dc field. Thus, completely different interchain packing by isomeric naphthoate ligands governs the ratio of intra- to inter-chain magnetic interactions and further results in different magnetic phenomena, which provide significant magnetostructural information on 1D magnetic systems.

Norisoboldine (NOR), the main active constituent of Radix Linderae, was previously demonstrated to ameliorate collagen-induced arthritis in rats through regulating the imbalance of T cells in intestines, which implied its therapeutic potential in inflammatory bowel disease. Here, we investigated the effect of NOR on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice. Results showed that NOR (20, 40mg/kg) markedly reduced the symptoms of colitis, the levels of IL-1β and TNF-α, and the activation of ERK, p38 MAPK and NF-κB-p65. NOR only slightly decreased the levels of IFN-γ and IL-17A in mouse colons, but it dramatically increased the level of IL-10 at both protein and mRNA grades. Consistently, NOR increased the number of CD4(+)CD25(+)Foxp3(+) Treg cells more obviously than it decreased that of CD4(+)IL-17(+) Th17 cells in mesenteric lymph nodes (MLNs) and colonic lamina proprias (LPs) of colitis mice, and promoted the expression of Foxp3 mRNA in colon tissues. It could facilitate the in vitro differentiation of Treg cells from naive T cells and promote the phosphorylations of Smad2/3 in colon tissues of colitis mice. On the other hand, NOR did not affect the expressions of homing receptors CCR9 and α4β7 in SPs, and homing ligands CCL25 and Madcam-1 in MLNs and colonic LPs, suggesting that the increase of Treg cells in colons by NOR was not due to gut homing. In conclusion, NOR can ameliorate DSS-induced UC in mice, and the mechanisms involve reduction of pro-inflammatory cytokines and selective induction of Treg cells in colons., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 μmol·L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-κB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK., (Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Arctigenin is the main active ingredient of Fructus Arctii for the treatment of type 2 diabetes. In this study, the pharmacokinetics of arctigenin in normal and type 2 diabetic rats following oral and intravenous administration was investigated. As compared to normal rats, Cmax and AUC(0-10h) values of oral arctigenin in diabetic rats increased by 356.8% and 223.4%, respectively. In contrast, after intravenous injection, the Cmax and AUC(0-10h) values of arctigenin showed no significant difference between diabetic and normal rats. In order to explore how the bioavailability of oral arctigenin increased under diabetic condition, the absorption behavior of arctigenin was evaluated by in situ single-pass intestinal perfusion (SPIP). The results indicated that arctigenin was a substrate of P-glycoprotein (P-gp). The absorption difference of arctigenin in the normal and diabetic rats could be eliminated by the pretreatment of classic P-gp inhibitor verapamil, suggesting that P-gp might be the key factor causing the absorption enhancement of arctigenin in diabetic rats. Further studies revealed that the uptake of rhodamine 123 (Rho123) in diabetic rats was significantly higher, indicating that diabetes mellitus might impair P-gp function. Consistently, a lower mRNA level of P-gp in the intestine of diabetic rats was found. In conclusion, the absorption of arctigenin after oral administration was promoted in diabetic rats, which might be partially attribute to the decreased expression and impaired function of P-gp in intestines., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5-Fluorouracil (5-FU). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5-FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase-1 (HO-1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU-C5) and resistant (SNU-C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU-C5R cells compared with SNU-C5 cells. Elevated levels of activated Nrf2 in SNU-C5R cells resulted in the increased protein expression and activity of HO-1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten-eleven translocation (TET)1 were observed in SNU-C5R cells compared with SNU-C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine-phosphate-guanine island hypomethylation in 5-FU-treated cells. In conclusion, the results indicated that 5-FU-induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET-dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO-1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance.

Introduction: The current metastatic category (M) of nasopharyngeal carcinoma (NPC) is a "catch-all" classification, covering a heterogeneous group of tumors ranging from potentially curable to incurable. The aim of this study was to design an M categorization system that could be applied in planning the treatment of NPC with synchronous metastasis., Methods: A total of 505 NPC patients diagnosed with synchronous metastasis at Sun Yat-sen University Cancer Center between 2000 and 2009 were involved. The associations of clinical variables, metastatic features, and a proposed M categorization system with overall survival (OS) were determined by using Cox regression model., Results: Multivariate analysis showed that Union for International Cancer Control (UICC) N category (N1-3/N0), number of metastatic lesions (multiple/single), liver involvement (yes/no), radiotherapy to primary tumor (yes/no), and cycles of chemotherapy (>4/≤4) were independent prognostic factors for OS. We defined the following subcategories based on liver involvement and the number of metastatic lesions: M1a, single lesion confined to an isolated organ or location except the liver; M1b, single lesion in the liver and/or multiple lesions in any organs or locations except the liver; and M1c, multiple lesions in the liver. Of the 505 cases, 74 (14.7%) were classified as M1a, 296 (58.6%) as M1b, 134 (26.5%) as M1c, and 1 was not specified. The three M1 subcategories showed significant difference in OS [M1b vs. M1a, hazard ratio (HR) = 1.69, 95% confidence interval (CI) = 1.16-2.48, P = 0.007; M1c vs. M1a, HR = 2.64, 95% CI = 1.75-3.98, P < 0.001]., Conclusions: We developed an M categorization system based on the independent factors related to the prognosis of patients with metastatic NPC. This system may be helpful to further optimize individualized care for NPC patients.

Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.

There is an urgent need to develop new antibacterial agents because of multidrug resistance by bacteria and fungi. Schiff bases (aldehyde or ketone-like compounds) exhibit intense antibacterial characteristics, and are therefore, promising candidates as antibacterial agents. To investigate the mechanism of action of newly designed benzaldehyde Schiff bases, a series of high-yielding benzaldehyde Schiff bases were synthesized, and their structures were determined by NMR and MS spectra data. The structure-microbicidal activity relationship of derivatives was investigated, and the antibacterial mechanisms were investigated by gene assays for the expression of functional genes in vitro using Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The active compounds were selective for certain active groups. The polar substitution of the R2 group of the amino acids in the Schiff bases, affected the antibacterial activity against E. coli and S. aureus; specific active group at the R3 or R4 groups of the acylhydrazone Schiff bases could improve their inhibitory activity against these three tested organisms. The antibacterial mechanism of the active benzaldehyde Schiff bases appeared to regulate the expression of metabolism-associated genes in E. coli, hemolysis-associated genes in B. subtilis, and key virulence genes in S. aureus. Some benzaldehyde Schiff bases were bactericidal to all the three strains and appeared to regulate gene expression associated with metabolism, hemolysis, and virulence, in vitro. The newly designed benzaldehyde Schiff bases possessed unique antibacterial activity and might be potentially useful for prophylactic or therapeutic intervention of bacterial infections., (Copyright © 2015. Published by Elsevier Masson SAS.)

Objective: The soluble form of major histocompatibility complex class I-related chain A (MICA) is released from the surface of tumor cells of epithelial origin. Serum levels of soluble MHC class I-related chain A (sMICA) is related with the prognosis of various types of cancer. However, there are studies on the prognostic value of sMICA in non-small cell carcinoma (NSCLC). In this study, we retrospectively investigated the relationship between sMICA levels and clinical features of NSCLC, and we assessed the prognostic value of sMICA in NSCLC., Patients and Methods: sMICA levels were detected in 207 NSCLC patients and 207 normal control individuals with using enzyme-linked immunosorbent assay (ELISA), and its associations with clinicopathological parameters were evaluated. Survival curves were compared using the Kaplan-Meier method and log-rank tests. Univariate Cox regression was used on each clinical covariate to examine its influence on patient survival. Multivariate models were based on step-wise addition., Results: Serum sMICA levels were significantly higher in NSCLC patients than in healthy controls (mean ± SD [pg/ml], 143.52 ± 27.6 vs. 32.4 ± 7.53 p < 0.01) and were significantly correlated with TNM stage, poorer differentiation, lymph node metastases and distant metastases. Survival analysis showed that a low sMICA level had longer survival time than those with high serum sMICA. Multivariate analyses indicated that high sMICA proved to be an independent predictor of survival time., Conclusions: Serum sMICA level in NSCLC patients is associated with metastasis. It is an indicator of a poorer survival probability. Serum sMICA levels may be an independent prognostic factor for NSCLC.

Introduction: Thrombocytosis has been identified as an unfavorable prognostic factor in several types of cancer. This study aimed to evaluate the prognostic value of pretreatment platelet count in association with the TNM staging system and therapeutic regimens in patients with nasopharyngeal carcinoma (NPC)., Methods: A total of 2,626 patients with NPC were retrospectively analyzed. Platelet count >300 × 10(9)/L was defined as thrombocytosis. Matched-pair analysis was performed between patients receiving chemoradiotherapy and radiotherapy., Results: Multivariate analysis showed that platelet count was an independent unfavorable prognostic factor for overall survival (OS) [hazard ratio (HR) = 1.810, 95% confidence interval (CI) = 1.531-2.140, P < 0.001] and distant metastasis-free survival (DMFS) (HR = 1.873, 95% CI = 1.475-2.379, P < 0.001) in the entire patient cohort. Further subgroup analysis revealed that increased platelet count was an independent unfavorable prognostic factor for OS and DMFS in patients with NPC stratified by early and advanced T category, N category, or TNM classification (all P ≤ 0.001). Receiver operating characteristic (ROC) curves verified that the predictive value of TNM classification for OS was improved when combined with pretreatment platelet count (P = 0.030). Matched-pair analysis showed that chemoradiotherapy significantly improved OS only in advanced-stage NPC with thrombocytosis (HR = 0.416, 95% CI = 0.226-0.765, P = 0.005)., Conclusions: Pretreatment platelet count, when combined with TNM classification, is a useful indicator for metastasis and survival in patients with NPC. It may improve the predictive value of the TNM classification and help to identify patients likely to benefit from more aggressive therapeutic regimens.

The aim of the present study was to investigate the prognostic value of different pretreatment platelet (PLT) counts on the treatment outcome in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone. A total of 1,501 NPC patients, including 412 receiving CCRT and 1,089 receiving RT, were enrolled in the present study. The PLT count cut-off points for the CCRT and RT groups were 150 and 300×10 9 /l, respectively, and the PLT counts were categorized it into three groups: Low (PLT≤150×10 9 /l), moderate (150×10 9 /l9 /l) and high (PLT>300×10 9 /l). To identify independent predictors of overall survival (OS), the Cox proportional hazards model was used to determine local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates in the CCRT and RT patients. Furthermore, univariate and multivariate analysis indicated that compared with a moderate PLT count, a low PLT count was an independent unfavorable prognostic factor for OS rate in CCRT patients [hazard ratio (HR), 2.024; 95% confidence interval (CI), 1.165-3.516], and a high PLT count was an independent unfavorable prognostic factor for OS and DMFS rates in CCRT (OS: HR, 1.742; 95% CI, 1.090-2.786; DFMS: HR, 2.110; 95%CI, 1.084-4.108) and RT (OS: HR, 1.740; 95%CI, 1.283-2.362; DMFS: HR, 2.819; 95% CI, 1.766-4.497) patients. Compared with a low PLT count, a high PLT count was significantly and independently associated with a poor DMFS rate in the RT patients (P=0.025; HR, 2.454; 95% CI, 1.121-5.372). Therefore, the present study indicates that low and high PLT counts may be useful indicators of survival and distant metastasis in NPC patients who have undergone radiation treatment.

Background: During mechanical ventilation, high end-inspiratory lung volume results in a permeability type pulmonary oedema, called ventilator-induced lung injury (VILI). The pathophysiology of ventilator-induced lung injury involves multiple mechanisms, such as excessive inflammation. And pycnogenol is a mixture of flavonoid compounds extracted from pine tree bark that have anti-inflammatory activity., Objective: We investigated the effects of pyncogenol on ventilator-induced lung injury in rats., Methods: Rats were orally administrated with pycnogenol once (30 mg/kg) 2 days before lung injury induction with mechanical ventilation, then the rats were divided into three groups: lung-protective ventilation (LV group, n = 20), injurious ventilation (HV group, n = 20), HV + pycnogenol group (HV + Pyc group, n = 20). Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses., Results: Pretreatment with pycnogenol could markedly decrease lung wet/dry ratio, lower myeloperoxidase (MPO) activity and total protein concentration and reduce the production of TNF-α, IL-6, IL-1β and MIP-2 in the BALF in ventilator-induced lung injury rats. Additionally, pycnogenol improved the histology of the lung and significantly inhibited the phosphorylation of NF-κB p65 and the degradation of IκB-α., Conclusion: Pycnogenol treatment could attenuate ventilator-induced lung injury in rats, at least in part, through its ability to reduce the production of inflammatory cytokines via inhibiting the activation of NF-κB, indicating it as a potential therapeutic candidate for ventilator-induced lung injury.

Objective: To explore the changes of intestinal mucosal immunity in collagen-induced arthritis rats and the impact of madecassoside on these changes., Methods: Collagen-induced arthritis was established in female Wistar rats. Treatment group was orally administrated madecassoside once daily for consecutive 21 days, while blank control and model groups were orally administered saline at the same volume. The concentrations of sIgA in small intestine content and IFN-γ in small intestinal tissue homogenate were determined by ELISA. The proportions of CD4+ T and CD8+ T in the epithelium and laminar propria of small intestine were detected by flow cytometry, and the ratios of CD4+/CD8+ were calculated. The relative expressions of CD80, CD86, IL-6, IL-12 and Foxp3 mRNA in the small intestine were determined by real-time PCR., Results: Compared with blank control rats, the concentrations of sIgA in small intestine content and IFN-γ in small intestinal tissue homogenate from model rats were increased, the ratios of CD4+/CD8+ in the epithelium and laminar propria of small intestine were higher and the relative expressions of CD80, CD86, IL-6 and IL-12 mRNA in the small intestine were increased. Madecassoside treatment decreased the concentrations of sIgA in small intestine content and IFN-γ in small intestinal tissue, downregulated the ratios of CD4+/CD8+ in the epithelium and laminar propria and decreased the relative expressions of CD80, CD86, IL-6 and IL-12 mRNA, while upregulated the relative expression of Foxp3 mRNA in the small intestine., Conclusion: The intestinal mucosal immune response is enhanced in collagen-induced arthritis rats, the antigen presenting cells are activated abnormally and the immune tolerance is disturbed. Madecassoside treatment can downregulate the intestinal mucosal immune response and benefit for the induction and maintenance of intestinal immune tolerance.

Background: A moderate dose of radiation is the recommended treatment for solitary plasmacytoma (SP), but there is controversy over the role of surgery. Our study aimed at comparing different treatment modalities in the management of SP., Materials and Methods: Data from 38 consecutive patients with solitary plasmacytoma, including 16 with bone plasmacytoma and 22 with extramedullary plasmacytoma, were retrospectively reviewed. 15 patients received radiotherapy alone; 11 received surgery alone, and 12 received both. The median radiation dose was 50Gy. All operations were performed as radical resections. Local progression-free survival (LPFS), multiple myeloma-free survival (MMFS), progression-free survival (PFS) and overall survival (OS) were calculated and outcomes of different therapies were compared., Results: The median follow-up time was 55 months. 5-year LPFS, MMFS, PFS and OS were 87.0%, 80.9%, 69.8% and 87.4%, respectively. Univariate analysis revealed, compared with surgery alone, radiotherapy alone was associated with significantly higher 5-year LPFS (100% vs 69.3%, p=0.016), MMFS (100% vs 51.4%, p=0.006), PFS (100% vs 33.7%, p=0.0004) and OS (100% vs 70%, p=0.041)., Conclusions: Radiotherapy alone can be considered as a more effective treatment for SP over surgery. Whether a combination of radiotherapy and surgery improves outcomes requires further study.