Tianjin, China

Tianjin Medical University was founded in 1951; was the first medical institution approved by the State Council of the People's Republic of China. Hsien-I Chu, a renowned endocrinologist, was the first president of the university. The current president is Yongfeng Shang.In December 1993, with the approval of the State Education Council, the Tianjin Medical College and the Tianjin Second Medical College were integrated into the Tianjin Medical University. In December 1996, the university was accepted into Project 211, so it became one of the 97 key institutions in which there are 9 medical institutions that will be constructed emphatically by the State.In 1981, the university was approved by the Academic Degree Committee of State Council to confer the Doctorate Degree, Master's Degree and Bachelor's Degree and in 1988, was permitted to set up seven-year medical program.It is listed in International Medical Education Directory . Wikipedia.

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Zhang Q.,Tianjin Medical University | Zhang Q.,Tianjin University | Wang D.,Tianjin Medical University | Qin W.,Tianjin Medical University | And 4 more authors.
Sleep | Year: 2013

Study Objectives: Structural and functional brain changes may contribute to neural dysfunction in patients with obstructive sleep apnea (OSA). However, the effect of OSA on resting-state brain activity has not been established. The objective of this study was to investigate alterations in resting-state functional connectivity (rsFC) of the common brain networks in patients with OSA and their relationships with changes in gray matter volume (GMV) in the corresponding brain regions. Designs: Resting-state functional and structural MRI data were acquired from patients with OSA and healthy controls. Seven brain networks were identified by independent component analysis. The rsFC in each network was compared between groups and the GMV of brain regions with sig-nificant differences in rsFC was also compared. Setting: University hospital. Patients and Participants: Twenty-four male patients with untreated OSA and 21 matched healthy controls. Interventions: N/A. Measurements and Results: OSA specifically affected the cognitive and sensorimotor-related brain networks but not the visual and auditory networks. The medial prefrontal cortex and left dorsolateral prefrontal cortex (DLPFC) showed decreased rsFC and GMV in patients with OSA, suggesting structural and functional deficits. The right DLPFC and left precentral gyrus showed decreased rsFC and unchanged GMV, suggesting a functional deficit. The right posterior cingulate cortex demonstrated increased rsFC and unchanged GMV, suggesting functional compensation. In patients with OSA, the rsFC of the right DLPFC was negatively correlated with the apnea-hypopnea index. Conclusions: OSA specifically affects resting-state functional connectivity in cognitive and sensorimotor-related brain networks, which may be related to the impaired cognitive and motor functions in these patients.

Nadiminty N.,Tianjin Medical University | Lou W.,Tianjin Medical University | Sun M.,Tianjin Medical University | Chen J.,Tianjin Medical University | And 6 more authors.
Cancer Research | Year: 2010

Prostate cancer initiation and progression are uniquely dependent on the androgen receptor (AR). Even when the cancer progresses to a castration-resistant stage, AR signaling remains active via a variety of mechanisms. In the present study, we showed that NF-κB/p52 can activate the AR, resulting in increased transactivation of AR-responsive genes, such as PSA and NKX3.1, in a ligand-independent manner. NF-κB2/p52 enhances nuclear translocation and activation of AR by interacting with its NH 2-terminal domain and enhances the recruitment of coactivators such as p300 to the promoters of AR-dependent genes. These results were confirmed in three different prostate cancer cell lines: LAPC-4 (wild-type AR), LNCaP (mutant AR), and C4-2 (castration resistant). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. Comparison of the relative effects of p52 and p65 (RelA) showed that p52, but not p65, could activate the AR. Collectively, these findings, together with previous reports that the levels of NF-κB2/p52 are elevated in prostate cancer cells and that active NF-κB2/p52 promotes prostate cancer cell growth in vitro and in vivo, suggest that NF-κB2/p52 may play a critical role in the progression of castration-resistant prostate cancer. ©2010 AACR.

Yang F.,Peking University | Yang F.,China Astronaut Research and Training Center | Sun L.,Peking University | Li Q.,Peking University | And 5 more authors.
EMBO Journal | Year: 2012

SET8 is implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression, and development. As such, it is predicted that SET8 might be involved in the development and progression of tumour. However, whether and how SET8 might be implicated in tumourigenesis is currently unknown. Here, we report that SET8 is physically associated with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). We demonstrated that SET8 and TWIST are functionally interdependent in promoting EMT and enhancing the invasive potential of breast cancer cells in vitro and in vivo. We showed that SET8 acts as a dual epigenetic modifier on the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity. Significantly, in breast carcinoma samples, SET8 expression is positively correlated with metastasis and the expression of TWIST and N-cadherin and negatively correlated with E-cadherin. Together, our experiments revealed a novel role for SET8 in tumour invasion and metastasis and provide a molecular mechanism underlying TWIST-promoted EMT, suggesting SET8 as a potential target for intervention of the metastasis of breast cancer. © 2012 European Molecular Biology Organization | All Rights Reserved.

Liao Z.,Tianjin University | Liao Z.,China Institute of Technology | Wang H.,Tianjin University | Wang X.,China Institute of Technology | And 4 more authors.
Advanced Functional Materials | Year: 2011

A multifunctional nanoscale platform that is self-assembled from a hydrophobic poly(dl-lactide-coglycolide)(PLGA) core and a hydrophilic paramagnetic-folate-coated PEGylated lipid shell (PFPL; PEG=polyethylene glycol) is designed for simultaneous magnetic resonance imaging (MRI) and targeted therapeutics. The nanocomplex has a well-defined core-shell structure which is studied using confocal laser scanning microscopy (CLSM). The paramagnetic diethylenetriaminepentaacetic acid-gadolinium (DTPA-Gd) chelated to the shell layer exhibits significantly higher spin-lattice relaxivity (r1) than the clinically used small-molecular-weight MRI contrast agent Magnevist®. The PLGA core serves as a nanocontainer to load and release the hydrophobic drugs. From a drug-release study, it is found that the modification of the PLGA core with a polymeric liposome shell can be a useful tool for reducing the drug-release rate. Cellular uptake of folate nanocomplex is found to be higher than that of non-folate-nanocomplex due to the folate-binding effect on the cell membrane. This work indicates that the multifunctional platform with combined characteristics applicable to MRI and drug delivery may have great potential in cancer chemotherapy and diagnosis. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Wang J.,Tianjin Medical University | Ning X.,Tianjin Medical University | Yang L.,Tianjin Neurological Institute | Yang L.,Tianjin Medical University | And 5 more authors.
Stroke | Year: 2014

Background and Purpose: Sex differences in secular trends of stroke incidence are rarely reported. We aimed to explore sex differences in incidence and mortality of stroke in rural China from 1992 to 2012. METHODS-: In 1992, 14 920 residents were recruited to participate in the Tianjin Brain Study, a population-based study on stroke surveillance. Stroke events and all deaths were annually registered. RESULTS-: We observed 908 incident strokes (366 in women) from 1992 to 2012. Women were significantly younger than men (64±12 versus 68±11 years) in 1992 to 1998 (P=0.024). The incidence of first-ever stroke per 100 000 person-years for men was 166 in 1992 to 1998, 227 in 1999 to 2005, and 376 in 2006 to 2012; for women, the rates were 86 (1992-1998), 148 (1999-2005), and 264 (2006-2012). From 1992 to 2012, the incidence grew annually by 5.8% in men and 8.0% in women. The male/female incidence ratio declined significantly: 1.9 in 1992 to 1998, 1.5 in 1999 to 2005, and 1.4 in 2006 to 2012. There were no significant sex differences in mortality. The prevalence of obesity and diabetes mellitus, the levels of total cholesterol and triglycerides, and the age of menopause and reproductive years in women concurrently increased in 2011. CONCLUSIONS-: There was a significant increase in the incidence of first-ever stroke in women annually and a declining trend in the male/female rate ratio in rural China during the past 21 years. These results suggest that stroke will become one of the major diseases affecting women in future decades in China. © 2014 American Heart Association, Inc.

Zheng M.,Tianjin Medical University | Zheng M.,Tianjin Nankai Hospital | Qin M.,Tianjin Nankai Hospital | Zhao H.,Tianjin Nankai Hospital
Minimally Invasive Therapy and Allied Technologies | Year: 2012

This study reports the initial experience with laparoendoscopic single-site (LESS) cholecystectomy and compares it with laparoscopic cholecystectomy (LC) through a randomized controlled trial. Sixty selective patients diagnosed with cholelithiasis or polyp lesion of the gallbladder (PLG) were randomly divided into two groups undergoing either LESS cholecystectomy or LC separately. The clinical data about operations and recovery of the two groups were compared. In the LESS group 28 of 30 patients underwent LESS cholecystectomy successfully and the remaining two (6.7%) were converted to standard laparoscopic surgery. LC was successfully performed in all patients in the control group. Mean operative time of LESS cholecystectomy group and LC group was 55.6 ± 25.7 versus 42.7 ± 18.6 (p < 0.05). Mean postoperative hospital stay was 3.7 ± 1.3 versus 3.8 ± 0.8 days (p < 0.05). Mean pain index was 2.8 ± 0.6 versus 3.7 ± 1.1 (p < 0.05). A questionnaire revealed that the mean scores of satisfaction with the operation were 8.9 ± 0.7 versus 8.1 ± 1.5 (p < 0.05). LESS cholecystectomy is safe, feasible, minimally invasive, and cosmetic. It is a reasonable alternative to selective patients with uncomplicated cholelithiasis and PLG. But larger controlled studies are still needed. © 2012 Informa Healthcare.

Song X.-F.,Tianjin University of Technology | Jin C.-X.,Tianjin Medical University | Yin L.,James Cook University
Journal of the Mechanical Behavior of Biomedical Materials | Year: 2015

Enamel cutting using dental handpieces is a critical process in tooth preparation for dental restorations and treatment but the machinability of enamel is poorly understood. This paper reports on the first quantitative assessment of the enamel machinability using computer-assisted numerical control, high-speed data acquisition, and force sensing systems. The enamel machinability in terms of cutting forces, force ratio, cutting torque, cutting speed and specific cutting energy were characterized in relation to enamel surface orientation, specific material removal rate and diamond bur grit size. The results show that enamel surface orientation, specific material removal rate and diamond bur grit size critically affected the enamel cutting capability. Cutting buccal/lingual surfaces resulted in significantly higher tangential and normal forces, torques and specific energy (p<0.05) but lower cutting speeds than occlusal surfaces (p<0.05). Increasing material removal rate for high cutting efficiencies using coarse burs yielded remarkable rises in cutting forces and torque (p<0.05) but significant reductions in cutting speed and specific cutting energy (p<0.05). In particular, great variations in cutting forces, torques and specific energy were observed at the specific material removal rate of 3mm3/min/mm using coarse burs, indicating the cutting limit. This work provides fundamental data and the scientific understanding of the enamel machinability for clinical dental practice. © 2014 Elsevier Ltd.

Bruix J.,University of Barcelona | Takayama T.,Nihon University | Mazzaferro V.,Fondazione IRCCS Instituto Nazionale Tumori | Chau G.-Y.,Taipei Veterans General Hospital | And 17 more authors.
The Lancet Oncology | Year: 2015

Background: There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. Methods: We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. Findings: We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12.5 months (IQR 2.6-35.8) and 577 mg per day (SD 212.8) for sorafenib, compared with 22.2 months (8.1-38.8) and 778.0 mg per day (79.8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8.5 months (IQR 2.9-19.5) in the sorafenib group and 8.4 months (2.9-19.8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33.3 months in the sorafenib group vs 33.7 months in the placebo group; hazard ratio [HR] 0.940; 95% CI 0.780-1.134; one-sided p=0.26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. Interpretation: Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. Funding: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. © 2015 Elsevier Ltd.

Liu Y.,Tianjin Medical University | Liu Y.,College of Logistics | Wei L.-Q.,College of Logistics | Li G.-Q.,College of Logistics | And 3 more authors.
Critical Care Medicine | Year: 2016

Objectives: 1) To evaluate the ability of pulse pressure variation adjusted by respiratory changes in pleural pressure to predict fluid responsiveness compared with pulse pressure variation alone. 2) To identify factors explaining the poor performance of pulse pressure variation in acute respiratory distress syndrome. Design: Prospective study. Setting: Forty-bed university hospital general ICU. Patients: Ninety-six mechanically ventilated acute respiratory distress syndrome patients requiring fluid challenge. Interventions: Fluid challenge, 500 mL saline over 20 minutes. Measurements and Main Results: Before fluid challenge, esophageal pressure was measured at the end-inspiratory and end-expiratory occlusions. Change in pleural pressure was calculated as the difference between esophageal pressure measured at end-inspiratory and end-expiratory occlusions. Hemodynamic measurements were obtained before and after the fluid challenge. Patients were ventilated with tidal volume 7.0 ± 0.8 mL/kg predicted body weight. The fluids increased cardiac output by greater than 15% in 52 patients (responders). Adjusting pulse pressure variation for changes in pleural pressure (area under the receiver operating characteristic curve, 0.94 [0.88-0.98]) and the ratio of chest wall elastance to total respiratory system elastance (area under the receiver operating characteristic curve, 0.93 [0.88-0.98]) predicted fluid responsiveness better than pulse pressure variation (area under the receiver operating characteristic curve, 0.78 [0.69-0.86]; all p < 0.01). The gray zone approach identified a range of pulse pressure variation/changes in pleural pressure values (1.94-2.1) in 3.1% of patients for whom fluid responsiveness could not be predicted reliably. On logistic regression analysis, two independent factors affected the correct classification of fluid responsiveness at a 12% pulse pressure variation cutoff: tidal volume (adjusted odds ratio 1.57/50 mL; 95% CI, 1.05-2.34; p = 0.027) and chest wall elastance/respiratory system elastance (adjusted odds ratio, 2.035/0.1 unit; 95% CI, 1.36-3.06; p = 0.001). In patients with chest wall elastance/respiratory system elastance above the median (0.28), pulse pressure variation area under the receiver operating characteristic curve was 0.94 (95% CI, 0.84-0.99) compared with 0.76 (95% CI, 0.61-0.87) otherwise (p = 0.02). Conclusions: In acute respiratory distress syndrome patients, pulse pressure variation adjusted by changes in pleural pressure is a reliable fluid responsiveness predictor despite the low tidal volume (< 8 mL/kg). The poor predictive ability of pulse pressure variation in acute respiratory distress syndrome patients is more related to low chest wall elastance/respiratory system elastance ratios than to a low tidal volume. © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Zhang D.,Peking Union Medical College | Zhang D.,Shantou University | Sun X.,Peking Union Medical College | Liu J.,Shantou University | And 4 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015

Objective: Homocysteine can accelerate the senescence of endothelial progenitor cells or endothelial cells (ECs) via telomerase inactivation and length shortening. However, the underlying mechanism is unclear. Here, we investigated whether homocysteine promotes endothelial senescence by reducing the expression and activity of human telomerase reverse transcriptase (hTERT) by DNA methylation to reduce ECs telomerase activity.Approach and Results: When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages. Interestingly, homocysteine-stimulated but not angiotensin II-stimulated ECs senescence could be reversed by hypermethylation induced by folic acid or s-adenosylmethionine supplementation. Meanwhile, homocysteine promoted the shortening of telomere length specifically related to restoration of hTERT transcriptional expression and CCCTC-binding factor binding sites with hTERT promoter hypomethylation, as detected by quantitative real-time polymerase chain reaction, Western blot, methylation-specific polymerase chain reaction, and bisulfite sequencing assay. Electrophoretic mobility shift assay and chromatin immunoprecipitation results showed that homocysteine-reduced telomere activity and homocysteine-induced EC senescence might contribute to hTERT promoter demethylation by increasing CCCTC-binding factor repression and interfering in the SP1 binding to the demethylated hTERT promoter, which might relate with reduced of DNA methyltransferase 1. Furthermore, the CCCTC-binding factor-dependent mechanism of homocysteine-reduced hTERT expression via DNA demethylation was confirmed in aortic endothelia of mice with hyperhomocysteine levels.Conclusions: CCCTC-binding factor and SP1 cross talk may contribute to homocysteine-reduced hTERT DNA methylation and expression in endothelial senescence. © 2014 American Heart Association, Inc.

Liang J.,Tianjin Medical University | Liang J.,Peking University | Shang Y.,Tianjin Medical University | Shang Y.,Peking University
Annual Review of Physiology | Year: 2013

Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to existing antiestrogen therapies. Copyright © 2013 by Annual Reviews. All rights reserved.

Li Q.,Peking University | Shi L.,Peking University | Gui B.,Peking University | Yu W.,Peking University | And 6 more authors.
Cancer Research | Year: 2011

JARID1B is a member of the JmjC/ARID family of demethylases that specifically demethylates tri- and di-methylated forms of histone H3 lysine 4 (H3K4) that are associated with active genes. JARID1B expression is dysregulated in several cancers in which it has been implicated, but how it might affect tumor progression is unclear. In this study, we report that JARID1B is a physical component of the LSD1/NuRD complex that functions in transcriptional repression. JARID1B and LSD1 acted in a sequential and coordinated manner to demethylate H3K4. A genome-wide transcriptional analysis revealed that among the cellular signaling pathways targeted by the JARID1B/LSD1/NuRD complex is the CCL14 chemokine pathway of cell migration and angiogenesis. JARID1B repressed the expression of CCL14, an epithelial derived chemokine, suppressing the angiogenic and metastatic potential of breast cancer cells in vivo. Our findings indicate that CCL14 is a critical mediator of the JARID1B/ LSD1/NuRD complex in regulation of angiogenesis and metastasis in breast cancer, identifying a novel potential therapeutic target for breast cancer intervention. ©2011 AACR.

Dou K.,Kunming General Hospital of Chengdu Military Command | Xu Q.,Tianjin Medical University | Han X.,The First Peoples Hospital of Kunming City
Diagnostic Pathology | Year: 2013

Background: Numerous epidemiological studies have been conducted to explore the association between the Lys939Gln polymorphism of Xeroderma pigmentosum group C (XPC) gene and urinary bladder cancer susceptibility. However, the results remain inconclusive. In order to derive a more precise estimation of this relationship, a large and update meta-analysis was performed in this study.Methods: A comprehensive search was conducted through researching MEDLINE, EMBASE, PubMed, Web of Science, China Biomedical Literature database (CBM) and China National Knowledge Infrastructure (CNKI) databases before June 2013. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association.Results: A total of 12 studies with 4828 cases and 4890 controls for evaluating the XPC Lys939Gln polymorphism and urinary bladder cancer were included. Overall, there was significant associations between the XPC Lys939Gln polymorphism and urinary bladder cancer risk were found for homozygous model (OR = 1.352, 95% CL = 1.088-1.681), heterozygous model (OR = 1.354, 95% CL = 1.085-1.688), and allele comparison (OR = 1.109, 95% CL = 1.013-1.214). In subgroup analysis by ethnicity and source of controls, there were still significant associations detected in some genetic models.Conclusion: Our meta-analysis suggested that the XPC Lys939Gln polymorphism contributed to the risk of urinary bladder cancer.Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1001118393101798. © 2013 Dou et al.; licensee BioMed Central Ltd.

Jiang N.,Tianjin Medical University | Zhu S.,Tianjin Medical University | Chen J.,Tianjin Medical University | Niu Y.,Tianjin Medical University | Zhou L.,Peking University
PLoS ONE | Year: 2013

Background:Alpha-methylacyl-CoA racemase (AMACR) is a mitochondrial and peroxisomal enzyme that is overexpressed in prostate cancer. The aim of this study was to confirm and expand the findings that the PCa risk increased in men associated with AMACR expression across various geographic regions.Methods:A systematic search of databases was carried out and other relevant articles were also identified. Then the meta-analyses were conducted according to the standard guidelines.Results:A total of 22 studies with 4,385 participants were included on the basis of inclusion criteria. AMACR by IHC was significantly associated with increased diagnosis of PCa (OR = 76.08; 95% CI, 25.53-226.68; P<0.00001). Subgroup-analysis showed that findings didn't substantially change when only Caucasians or Asians (OR = 51.23; 95% CI, 19.41-135.24; P<0.00001) were considered. Expression of AMACR by PCR in relation to PCa risk suggested that AMACR was associated with PCa (OR = 33.60; 95% CI, 4.67-241.77; P<0.00001). There was also no significant publication bias observed.Conclusions:Our findings provide further evidences that the expression of AMACR contribute to PCa risk. AMACR protein overexpression was found in prostate cancers, low expression in any of the normal tissues or in benign prostatic tissue. AMACR is potentially an important prostate tumor marker. © 2013 Jiang et al.

Li H.,Tianjin Medical University | Li H.,U.S. National Institutes of Health | Yang L.,Tianjin Medical University | Fu H.,Tianjin Medical University | And 7 more authors.
Nature Communications | Year: 2013

The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis. © 2013 Macmillan Publishers Limited. All rights reserved.

Wang X.,Tianjin Medical University | Zhang Z.,Fourth Central Hospital of Tianjin | Yao C.,Jilin University
Cancer Investigation | Year: 2012

This study is to investigate the effects of bortezomib on the angiogenesis of mesenchymal stem cells (MSCs). We examined the effects of bortezomib on the cellular proliferation, migration, and capillary network formation of HUVECs cocultured with CMs of MSCs. We found that Bortezomib inhibited the cellular proliferation and tube formation of HUVECs cocultured with CMs in a dose-dependent fashion. Bortezomib also prevented the migration of HUVECs cocultured with CMs. In addition, bortezomib dose-dependently inhibited the growth of MSCs and prevented the production of angiogenic factors including VEGF (vascular endothelial growth factor), HGF (hepatocyte growth factor), and bFGF (basic fibroblast growth factor) in MSCs. In conclusion, bortezomib prevented the angiogenesis mediated by MSCs. © 2012 Informa Healthcare USA, Inc.

Hu R.,Tianjin University of Technology | Hu R.,Tianjin Medical University | Li G.,Tianjin University of Technology | Jiang Y.,Tianjin University of Science and Technology | And 4 more authors.
Langmuir | Year: 2013

In this work, we demonstrate a convenient, efficient, and environmentally benign strategy to achieving antimicrobial and antiadhesive purposes using a silver-zwitterion nanocomposite. The synthesis of the nanocomposite relies on loading zwitterionic polymer brushes with Ag+ precursor ions, followed by their in situ reduction to Ag nanoparticle by ultraviolet (UV) irradiation. Both poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA) have been studied as matrices for the embedding of silver. Well-dispersed silver nanoparticles are embedded into pCBMA matrices. The obtained pCBMA-silver hybrid (CB-Ag) is capable of killing bacteria upon contact and releasing dead bacteria under wet conditions. Results suggest the feasibility of using this nanocomposite system as a robust and reliable antimicrobial and antiadhesive platform for the prevention of microbial colonization. © 2013 American Chemical Society.

Bu S.-C.,University of Groningen | Bu S.-C.,Tianjin Medical University | Kuijer R.,University of Groningen | Li X.-R.,Tianjin Medical University | And 2 more authors.
Retina | Year: 2014

Background: Idiopathic epiretinal membrane (iERM) is a fibrocellular membrane that proliferates on the inner surface of the retina at the macular area. Membrane contraction is an important sight-threatening event and is due to fibrotic remodeling.Methods: Analysis of the current literature regarding the epidemiology, clinical features, and pathogenesis of iERM and fibrotic tissue contraction.Results: Epidemiologic studies report a relationship between iERM prevalence, increasing age, and posterior vitreous detachment. Clinically, iERM progresses through different stages characterized by an increased thickness and wrinkling of the membrane. Pathophysiologically, iERM formation is a fibrotic process in which myofibroblast formation and the deposition of newly formed collagens play key roles. Anomalous posterior vitreous detachment may be a key event initiating the formation of iERM. The age-related accumulation of advanced glycation end products may contribute to anomalous posterior vitreous detachment formation and may also influence the mechanical properties of the iERM.Conclusion: Remodeling of the extracellular matrix at the vitreoretinal interface by aging and fibrotic changes, plays a significant role in the pathogenesis of iERM. A better understanding of molecular mechanisms underlying this process may eventually lead to the development of effective and nonsurgical approaches to treat and prevent vitreoretinal fibrotic diseases. Copyright © Ophthaimic Communication Society, Inc.

Dai Y.,Peking University | Jiao H.,Peking University | Teng G.,Peking University | Wang W.,Peking University | And 5 more authors.
Molecular Cancer Therapeutics | Year: 2014

The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6-induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity.Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1β, IL-17a, and IL-23a expression as well as the number of CD4+ T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC. © 2014 American Association for Cancer Research.

Li W.-B.,Tianjin Medical University | Dong L.-J.,Tianjin Medical University | Wang F.,Tianjin Medical University | Chen L.-X.,Tianjin Medical University | Li X.-R.,Tianjin Medical University
Cancer Biology and Therapy | Year: 2011

Aberrant expression of microRNAs (miRNAs) has been implicated in cancer initiation and progression. In this study, we found that microRNA-34a (miR-34a) is significantly downregulated in glioblastoma multiforme (GBM) specimens compared with normal brain tissues. Growth curve and colony formation assays revealed that miR-34a suppresses proliferation of U373MG and SHG44 glioblastoma cells. Overexpression of miR-34a could induce apoptosis of glioblastoma cells. Also, we identified notch1 as a direct target gene of miR-34a. Knockdown of notch1 showed similar cellular functions as overexpression of miR-34a both in vitro and in vivo. Collectively, our findings show that miR-34a is downregulated in GBM cells and inhibits GBM growth by targeting notch1. © 2011 Landes Bioscience.

Broeders J.A.,University of Adelaide | Roks D.J.,University of Adelaide | Ali U.A.,Cleveland Clinic | Watson D.I.,Flinders University | And 4 more authors.
Annals of Surgery | Year: 2013

OBJECTIVE: To compare short- and long-term outcome after 180-degree laparoscopic anterior fundoplication (180-degree LAF) with laparoscopic Nissen fundoplication (LNF). SUMMARY OF BACKGROUND DATA: LNF is currently the most frequently performed surgical therapy for gastroesophageal reflux disease. Alternatively, 180-degree LAF has been alleged to reduce troublesome dysphagia and gas-related symptoms, with similar reflux control. METHODS: MEDLINE, EMBASE, Cochrane Library, and web of Knowledge CPCI-S were searched for randomized clinical trials comparing primary 180-degree LAF with LNF. The methodological quality was evaluated to assess bias risk. Primary outcomes were esophageal acid exposure, esophagitis, heartburn score, dilatation for dysphagia, modified Dakkak dysphagia score (0-45), and reoperation rate. Meta-analysis was conducted at 1 and 5 years. RESULTS: Five distinct randomized clinical trials comparing 180-degree LAF (n = 227) with LNF (n = 231) were identified. At 1 year, the Dakkak dysphagia score [2.8 vs 4.8; weighted mean difference: -2.25; 95% confidence interval (CI): -2.66 to -1.83; P < 0.001], gas bloating [11% vs 18%; relative risk (RR) 0.59; 95% CI: 0.36-0.97; P = 0.04], flatulence (14% vs 25%; RR: 0.57; 95% CI: 0.35-0.91; P = 0.02), inability to belch (19% vs 31%; RR: 0.63; 95% CI: 0.40-0.99; P = 0.05), and inability to relieve bloating (34% vs 44%; RR: 0.74; 95% CI: 0.55-0.99; P = 0.04) were lower after 180-degree LAF. Esophageal acid exposure (standardized mean difference: 0.19; 95% CI: -0.07 to 0.46; P = 0.15), esophagitis (19% vs 13%; RR: 1.42; 95% CI: 0.69-2.91; P = 0.34), heartburn score (standardized mean difference: 1.27; 95% CI:-0.36 to 2.90; P = 0.13), dilatation rate (1.4% vs 2.8%; RR: 0.60; 95% CI: 0.19-1.91; P = 0.39), reoperation rate (5.7% vs 2.8%; RR: 2.08; 95% CI: 0.80-5.41; P = 0.13), perioperative outcome, regurgitation, proton pump inhibitor (PPI) use, lower esophageal sphincter pressure, and patient satisfaction were similar after 180-degree LAF and LNF. At 5 years, the Dakkak dysphagia score, flatulence, inability to belch, and inability to relieve bloating remained lower after 180-degree LAF. The 5-year heartburn score, dilatation rate, reoperation rate, PPI use, and patient satisfaction were similar. CONCLUSIONS: At 1 and 5 years, dysphagia and gas-related symptoms are lower after 180-degree LAF than after LNF, and esophageal acid exposure and esophagitis are similar, with no differences in heartburn scores, patient satisfaction, dilatations, and reoperation rate. These results lend level 1a support for the use of 180-degree LAF for the surgical treatment of gastroesophageal reflux disease. Copyright © 2013 by Lippincott Williams & Wilkins.

Li H.,Peking Union Medical College | Zhao H.,Tianjin Medical University | Wang D.,Peking University | Yang R.,Peking Union Medical College
British Journal of Haematology | Year: 2011

Megakaryocytopoiesis is governed by a complex network of haematopoietic growth factors that regulate the different stages of the process, in which haematopoietic stem cells undergo megakaryocytic lineage commitment, proliferation, maturation, and functional activation to produce platelets. MicroRNAs (miRNA) are a class of about 22-nucleotide noncoding RNAs that have been highly conserved during evolution and play a significant role in haematopoiesis, including differentiation and lineage commitment of megakaryocyte. This review summarizes the miRNAs which have changed expression during megakaryocytopoiesis, and their positive and negative functions on megakaryocytic differentiation. In addition, the abnormal miRNA expression profiles in megakaryocytic disorders are reviewed. © 2011 Blackwell Publishing Ltd.

Huang Y.,Tianjin Medical University | Li W.,Tianjin Womens and Childrens Health Center | Dong L.,Tianjin University of Traditional Chinese Medicine | Li R.,George Institute for Global Health | And 2 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2013

Aim: To evaluate the effect of statin therapy on the decrease of common carotid artery intima-media thickness (CCA-IMT) compared to placebo or usual care. Methods: A systematic search of electronic databases (MEDLINE, EMBASE, and Cochrane Center Register) up to December 2011 was performed. Two reviewers independently determined the eligibility of randomized controlled trials (RCTs) comparing statin therapy with a placebo or usual care with a minimum follow-up of 6 months. Results: Twenty-one RCTs involving 6317 individuals were included in this review. The pooled weighted mean difference (WMD) between statin therapy and placebo or usual care on CCA-IMT was -0.029 mm (95%CI: -0.045, -0.013). Subgroup analyses showed significant effects of lovastatin (WMD: -0.077; 95%CI: -0.082, -0.073) and simvastatin (WMD: -0.069; 95%CI: -0.094, -0.045), followed by pravastatin and rosuvastatin, but no significant benefits of atorvastatin, fluvastatin, or cerivastatin. A greater decrease in mean CCA-IMT was observed in the setting of secondary prevention versus primary prevention (WMD: -0.045 vs. -0.004), in younger patients versus older patients (WMD: -0.057 vs. -0.041), and in studies where the patient proportion was males ≥ females (-0.044 vs. -0.008). Meta-regression analysis showed a significant association between changes in mean CCA-IMT with decreasing triglyceride levels. A similar, but not statistically significant trend was also found between CCA-IMT decrease and the decrease in LDL-C levels or increase in HDL-C levels. Conclusion: Statin therapy is associated with a favorable decrease in CCA-IMT, an effect that seems to be mainly driven by the CCA-IMT at baseline and the extent of lipid decrease, specifically triglycerides.

Huangyang P.,Peking University | Shang Y.,Peking University | Shang Y.,Tianjin Medical University
Current Cancer Drug Targets | Year: 2013

Epithelial-mesenchymal transition (EMT) is a vital process implemented in embryo development, organ fibrosis, and cancer metastasis. Several transcription factors and signaling pathways impinge on the transcriptional program of the cell, leading to the change of cell phenotype without alteration of genotype. Accumulating evidence suggests that epigenetic mechanisms play important roles in inducing EMT and orchestrating the heredity and reversibility of EMT. In this review, we discuss how DNA methylation, histone modifications, and microRNAs (miRNAs) act in a concerted manner to regulate EMT. 'Epigenetic therapies'-inhibitors of DNA methyltransferases and histone deacetylases as well as microRNAs are emerging as promising agents for cancer intervention. © 2013 Bentham Science Publishers.

Li W.,Tianjin University of Technology | Chen B.,Tianjin University of Technology | Zhang H.,Tianjin University of Technology | Sun Y.,Tianjin Medical University | And 3 more authors.
Biosensors and Bioelectronics | Year: 2015

Bovine serum albumin (BSA) is chosen as the nucleation templates to synthesize Pt-based peroxidase nanomimetics with the average diameter of 2.0nm. The efficient Pt nanozymes consist of 57% Pt0 and 43% Pt2+, which possess highly peroxidase-like activity with the Km values of 0.119mM and 41.8mM toward 3,3',5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide (H2O2), respectively. Interestingly, Hg2+ is able to down-regulate the enzymatic activity of Pt nanoparticles, mainly through the interactions between Hg2+ and Pt0. It is the first report to explore a colorimetric Hg2+ sensing system on the basis of peroxidase mimicking activities of Pt nanoparticles. One of our most intriguing results is that BSA-stabilized Pt nanozymes demonstrate the ability to sense Hg2+ ions in aqueous solution without significant interference from other metal ions. The Hg2+ detection limit of 7.2nM is achieved with a linear response range of 0-120nM, and the developed sensing system is potentially applicable for quantitative determination of Hg2+ in drinking water. © 2014 Elsevier B.V.

Chen W.-C.,Peking University | Chen W.-C.,Key Laboratory of Vision Loss and Restoration | Wang Y.,Tianjin Medical University | Li X.-X.,Peking University | Li X.-X.,Key Laboratory of Vision Loss and Restoration
Retina | Year: 2012

PURPOSE: To evaluate photoreceptor inner/outer segment (IS/OS) defects, best-corrected visual acuity (BCVA), macular sensitivity, and fixation stability to correlate morphologic changes with visual functional outcomes at different stages after macular hole surgery using spectral-domain optical coherence tomography combined with microperimetry. METHODS: This study was an interventional, retrospective case series. Sixteen eyes of 16 patients with successfully operated idiopathic full-thickness macular holes were included in this study. The IS/OS defect maximal diameter and area, BCVA, central macular sensitivity, mean macular sensitivity, and fixation stability were measured using spectral-domain optical coherence tomography combined with microperimetry, preoperatively, and with a follow-up of 3 months postoperatively. RESULTS: Both the IS/OS defect diameter and area improved after successful macular hole surgery (P < 0.001; P < 0.001). The BCVA, central macular sensitivity, mean macular sensitivity, and fixation stability of the central 2° also improved (P = 0.001; P = 0.004; P = 0.036; P = 0.031). Stable BCVA improvement was achieved as early as 1-month postoperation despite continuous repair of the IS/OS junction defect diameter and area and improvement in fixation and macular sensitivity within the first 3 months after surgery. The postoperative central macular sensitivity and mean macular sensitivity negatively correlated with preoperative linear IS/OS junction defect diameter (P = 0.033; P = 0.006) and the defect area (P < 0.001; P = 0.002). However, the postoperative BCVA and the improvement in BCVA, macular sensitivity, and fixation stability were not correlated with preoperative IS/OS defect diameter or area. CONCLUSION: Continuous anatomical and functional improvements can be observed after successful microinvasive macular hole surgery. The preoperative extent of the IS/OS junction defect is of good predictive value for postoperative macular sensitivity. However, the factors that influence BCVA are multiple. Prediction of BCVA based on a single anatomical parameter or assessment of macular function only based on BCVA should be avoided. © Lippincott Williams & Wilkins.

Zhang D.,Shantou University | Chen Y.,Shantou University | Xie X.,Shantou University | Liu J.,Shantou University | And 4 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012

Hyperhomocysteinemia (HHcy), as an independent risk factor of atherosclerosis, facilitates endothelial dysfunction and activation of vascular smooth muscle cells (VSMCs). However, little is known about the crosstalk between endothelial cells (ECs) and VSMCs under HHcy. We investigated whether homocysteine (Hcy) activates VSMCs by aberrant secretion of mitogen platelet-derived growth factors (PDGFs) from ECs in human and in mice. In this study, we found that increased Hcy level did not affect VSMC activity in 24. hrs until the concentration reached 500μM. In contrast, Hcy at 100μM significantly promoted proliferation and migration of VSMCs co-cultured with human ECs. This effect was partially reversed by pretreatment with a PDGF receptor inhibitor. Hcy concentration-dependently upregulated the mRNA level of PDGF-A, -C and -D but not PDGF-B in ECs. Hcy reduced the expression and activity of DNA methyltransferase 1, demethylation of PDGF-A, -C and -D promoters and enhanced the binding activity of transcriptional factor SP-1 to the promoter. Hcy upregulation of PDGF was confirmed in the aortic intima of mice with HHcy. Multivariate regression analysis revealed HHcy was a predictor of increased serum PDGF level in patients. Thus, Hcy upregulates PDGF level via DNA demethylation in ECs, affects cross-talk between ECs and VSMCs and leads to VSMC activation. © 2012 Elsevier Ltd.

Hu D.,Tianjin Medical University | Du C.,Peking University | Xue W.,Peking University | Dou F.,Peking University | And 2 more authors.
Histopathology | Year: 2013

Aims: The liver and lung are the organs most commonly affected by metastasis in colorectal cancer (CRC), and the interaction of chemokines and chemokine receptors (CKRs) plays an important role in the metastatic process. The aim of this study was to investigate the organ specificity of CKRs in CRC distant metastasis. Methods and results: Surgical specimens of primary tumours from 46 patients with metachronous distant metastases were retrieved retrospectively (20 lung metastases; 26 liver metastases). As a control, the records of 29 patients without distant metastases were randomly retrieved from our database, and their specimens were reassessed. The expression rates of CKRs, including CCR6, CXCR2, and CXCR4, were determined by immunohistochemistry, and were compared among the groups. The expression rates of CCR6 and CXCR2 were both significantly higher in the metastasis group than in the non-metastasis group (P < 0.05), but there was no statistical difference between the lung metastasis and liver metastasis subgroups. The expression of CXCR4 was not significantly different between the metastasis and non-metastasis groups. Multivariable analysis suggested that preoperative serum carcinoembryonic antigen level, CCR6 and CXCR2 were independent factors associated with distant metastasis. Conclusions: The expression of CCR6 and CXCR2 in CRC could predict metachronous distant metastasis, but they have no organ specificity for metastasis. © 2013 John Wiley & Sons Ltd.

Zhang X.,Tianjin Medical University | Zhang X.,National University of Singapore | Neoh K.G.,National University of Singapore | Lin C.C.,National University of Singapore | Kishen A.,University of Toronto
Journal of Materials Science: Materials in Medicine | Year: 2012

Dentine remineralization is clinically significant for prevention and treatment of dentine caries, root caries, and dentine hypersensitivity. However, dentine remineralization is more difficult than enamel remineralization due to the abundant presence of organic matrix in dentine. The objective of this study was to develop a biomimetic method to facilitate remineralization of demineralized dentine through phosphorylation of type I collagen in demineralized dentine using sodium trimetaphosphate. The experimental results indicated that the effect of fluoride on remineralizing dentine was limited when residual mineral crystals were lacking on the surface of demineralized dentine, whereas the phosphorylation and Ca(OH)2 pretreatment enhanced surface remineralization of the partially demineralized dentine. This biomimetic methodology resulted in favorable surface properties (i.e. highly negative charge and low interfacial free energy between substrate and aqueous medium) for crystal nucleation, and thus could be a promising method to remineralize superficially demineralized dentine lesions. © 2012 Springer Science+Business Media, LLC.

Liu Y.,Chinese Academy of Sciences | Liu Y.,University of Cambridge | Yu C.,Tianjin Medical University | Duan Y.,Capital Medical University | And 7 more authors.
Cerebral Cortex | Year: 2014

Alzheimer's disease (AD) is increasingly recognized as a disconnection syndrome, which leads to cognitive impairment due to the disruption of functional activity across large networks or systems of interconnected brain regions. We explored abnormal functional magnetic resonance imaging (fMRI) resting-state dynamics, functional connectivity, and weighted functional networks, in a sample of patients with severe AD (N = 18) and age-matched healthy volunteers (N = 21). We found that patients had reduced amplitude and regional homogeneity of low-frequency fMRI oscillations, and reduced the strength of functional connectivity, in several regions previously described as components of the default mode network, for example, medial posterior parietal cortex and dorsal medial prefrontal cortex. In patients with severe AD, functional connectivity was particularly attenuated between regions that were separated by a greater physical distance; and loss of long distance connectivity was associated with less efficient global and nodal network topology. This profile of functional abnormality in severe AD was consistent with the results of a comparable analysis of data on 2 additional groups of patients with mild AD (N = 17) and amnestic mild cognitive impairment (MCI; N = 18). A greater degree of cognitive impairment, measured by the mini-mental state examination across all patient groups, was correlated with greater attenuation of functional connectivity, particularly over long connection distances, for example, between anterior and posterior components of the default mode network, and greater reduction of global and nodal network efficiency. These results indicate that neurodegenerative disruption of fMRI oscillations and connectivity in AD affects long-distance connections to hub nodes, with the consequent loss of network efficiency. This profile was evident also to a lesser degree in the patients with less severe cognitive impairment, indicating that the potential of resting-state fMRI measures as biomarkers or predictors of disease progression in AD. © 2013 The Author.

Svensson C.,Novo Nordisk AS | Ceder J.,Skåne University Hospital | Iglesias-Gato D.,Novo Nordisk AS | Chuan Y.-C.,Novo Nordisk AS | And 11 more authors.
Nucleic Acids Research | Year: 2014

The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co-localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase β-TRCP. Androgen deprivation or AR blockage with inhibitor MDV3100 (Enzalutamide) leads to neuroendocrine (NE) differentiation, a phenomenon that is mimicked by REST inactivation. Gene expression profiling revealed that REST not only acts to repress neuronal genes but also genes involved in cell cycle progression, including Aurora Kinase A, that has previously been implicated in the growth of NE-like castration-resistant tumors. The analysis of prostate cancer tissue microarrays revealed that tumors with reduced expression of REST have higher probability of early recurrence, independently of their Gleason score. The demonstration that REST modulates AR actions in prostate epithelia and that REST expression is negatively correlated with disease recurrence after prostatectomy, invite a deeper characterization of its role in prostate carcinogenesis. © 2013 The Author(s).

Zhou Q.,Tianjin Medical University | Wu Z.,Tianjin Medical University
Clinical and Experimental Dermatology | Year: 2011

A meta-analysis was performed to determine the type, incidence and risks of dermatological toxicities associated with the multikinase inhibitor sorafenib. A literature search was performed using the electronic databases PubMed and EMBASE, and conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective phase II or III clinical trials, and expanded-access programmes (i.e. outside a clinical trial) of patients with solid tumours assigned sorafenib at a starting dose of 400mg twice daily. The overall incidences and risk ratios of dermatological toxicities associated with sorafenib were analysed. For patients assigned sorafenib, the overall incidence of all-grade rash/desquamation was 35.4% (95% CI 0.29-0.43), hand-foot skin reaction (HFSR) 39.0% (95% CI 0.32-0.47), alopecia 25.5% (95% CI 0.18-0.35), pruritus 14.0% (95% CI 0.10-0.20) and dry skin 14.1% (95% CI 0.10-0.20). High-grade rash/desquamation events occurred in 5.0% (95% CI 0.04-0.07), HFSR in 9.0% (95% CI 0.082-0.098), alopecia in 4/1793, pruritus in 2/1265 and dry skin in 0/1689 of patients assigned sorafenib. Meta-analysis of risk ratio showed that sorafenib was associated with a significantly increased risk of rash/desquamation [risk ratio (RR) 2.73; 95% CI 1.66-4.49)], HFSR (RR 7.50; 95% CI 3.90-14.40) and alopecia (RR 7.55; 95% CI 5.26-10.84) in patients with solid tumours, but risk of pruritus (RR 1.80; 95% CI 0.77-4.22) or dry skin (RR 2.18; 95% CI 0.88-5.40) was not increased. In conclusion, the most frequent dermatological toxicities associated with soarfenib were HFSR, rash/desquamation, alopecia, pruritus and dry skin. There was a significantly increased risk of HFSR, rash/desquamation and alopecia with sorafenib compared with placebo. Skin toxicities were mainly mild or moderate in severity. Appropriate prevention and management are recommended. © The Author(s). CED © 2011 British Association of Dermatologists.

Zhang Y.-M.,Tianjin Medical University | Zhang S.-K.,Tianjin Nankai Hospital | Cui N.-Q.,Tianjin Nankai Hospital
World Journal of Gastroenterology | Year: 2014

AIM: To investigate whether mesenteric lymph from rats with severe intraperitoneal infection (SII) induces lung injury in healthy rats. METHODS: Twenty adult male specific pathogen-free Wistar rats were divided into two groups. Animals in the SII group received intraperitoneal injection of Escherichia coli (E. coli) at a dose of 0.3 mL/100 g. Control rats underwent the same procedure, but were injected with normal saline rather than E. coli. We ligated and drained the mesenteric lymphatic vessels and collected the mesenteric lymph. Mesenteric lymph collected from SII or control rats was infused intravenously into male healthy rats at a rate of 1 mL/h for 4 h. At the end of the infusion, all rats were sacrificed. Lungs were removed and examined histologically, and wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were determined. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. We performed Western blot to investigate the activation of Toll-like receptor (TLR)-4, and nuclear factor (NF)-κB p65. RESULTS: Compared with the control infusion group, there were obvious pathological changes in the SII group. The W/D ratio was significantly increased in the SII compared to control infusion group (5.86 ± 0.06 vs 5.37 ± 0.06, P < 0.01). MPO activity significantly increased in the SII infusion rats with a mean level of 0.86 ± 0.02 U/g compared to 0.18 ± 0.05 U/g in the control group (P < 0.01). The concentrations of TNF-α and IL-6 were significantly increased in the SII infusion group. The concentration of TNF-α was significantly increased in the SII infusion rats compared to control infusion rats (2104.46 ± 245.91 vs 1475.13 ± 137.82 pg/mL, P < 0.01). The concentration of IL-6 was significantly increased in the SII infusion rats with a mean level of 50.56 ± 2.85 pg/mL compared to 43.29 ± 2.02 pg/mL (P < 0.01). The expression levels of TLR-4 (7496.68 ± 376.43 vs 4589.02 ± 233.16, P < 0.01) and NF-κB (8722.19 ± 323.96 vs 6498.91 ± 338.76, P < 0.01) were significantly increased in the SII infusion group compared to the control infusion group. The infusion of SII lymph, but not control lymph, caused lung injury. CONCLUSION: The results indicate that SII lymph is sufficient to induce acute lung injury. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Ding G.,Tianjin Medical University | Ding G.,Tianjin Nankai Hospital | Cai W.,Tianjin Nankai Hospital | Qin M.,Tianjin Nankai Hospital
Journal of Gastrointestinal Surgery | Year: 2014

Aim: The preferred approach to the management of common bile duct (CBD) stones is uncertain, with single-stage laparoscopic cholecystectomy and CBD exploration vs. two-stage preoperative endoscopic CBD clearance followed by laparoscopic cholecystectomy being debated. To address this, a prospective randomized study which compared these two management strategies was undertaken. Methods: Between Jan 2002 and Dec 2005, patients with gallstones and common bile duct stones diagnosed by preoperative ultrasonography and magnetic resonance cholangiopancreatography were randomized to single-stage vs. two-stage treatment. In a single-stage group, laparoscopic cholecystectomy and CBD exploration were undertaken at the same operation, whereas in a two-stage group, endoscopic stone clearance was followed by laparoscopic cholecystectomy 2-5 days later. Early treatment success and complications and longer-term follow-up for the two groups were compared. Results: Two hundred twenty-one patients were enrolled in the trial, 110 in the single-stage group and 111 in the two-stage group. There was no significant difference in the success rate of CBD clearance (93.6 vs. 94.6 %, p = 0.76) or the complication rates (3.6 vs. 5.1 %, p = 0.527) between the groups. However, at longer-term follow-up, recurrent CBD stones were seen more often in the two-stage group (9.5 vs. 2.1 %, p = 0.037). Conclusion: The single-stage and two-stage approaches were equally effective in achieving initial clearance of CBD stones. However, recurrent CBD stones occurred more commonly in patients who had undergone two-stage treatment with initial endoscopic stone clearance, followed by laparoscopic cholecystectomy. © 2014 The Society for Surgery of the Alimentary Tract.

Yu J.,Tianjin Medical University | Zhao C.,Tianjin Medical University | Zhao C.,Peoples Hospital of Sichuan Province | Luo X.,Xiangyang First Peoples Hospital
Anesthesia and Analgesia | Year: 2013

BACKGROUND:: Electroacupuncture (EA), as a traditional clinical method, is widely accepted in pain clinics, but the analgesic effect of EA has not been fully demonstrated. In the present study, we investigated the effect of EA on chronic pain and expression of P2X3 receptors in the spinal cord of rats with chronic constriction injury (CCI). METHODS:: The study was conducted in 2 parts. In part 1, Sprague Dawley rats were divided into 6 groups (n = 10): sham-CCI, CCI, LEA; CCI + 2 Hz EA at acupoints), HEA; CCI + 15 Hz EA at acupoints), NA-LEA (CCI + 2 Hz EA at nonacupoints), and NA-HEA (CCI + 15 Hz EA at nonacupoints). EA treatment was performed once a day on days 4 to 9 after CCI. Nociception was assessed using von Frey filaments and a hotplate apparatus. The protein and the messenger RNA (mRNA) levels of P2X3 receptors in the spinal cord were assayed by Western blotting and real-time polymerase chain reaction, respectively. In part 2, rats were divided into 5 groups (n = 10): sham-CCI, CCI, EA (CCI + EA at acupoints), NA-EA (CCI + EA at nonacupoints), and U0126 (CCI + intrathecal injection of U0126). EA treatment was conducted similar to part 1. Rats were given 5 μg U0126 in the U0126 group and 5% dimethyl sulfoxide intrathecally. Ten microliters was used as a vehicle for the other 4 groups twice a day on days 4 to 9 after CCI. Extracellular signal-regulated kinase 1/2 (ERK1/2) and ERK1/2 phosphorylation in the spinal cord were also assayed by Western blotting. RESULTS:: EA treatment exhibited significant antinociceptive effects and reduced the CCI-induced increase of both protein and mRNA expression of P2X3 receptors in the spinal cord. Furthermore, 2 Hz EA had a better analgesic effect than 15 Hz EA, and the protein and mRNA level of P2X3 receptor in spinal cord were lower in rats treated with 2 Hz EA at acupoints than 15 Hz EA at acupoints. Either EA at acupoints or intrathecal injection of U0126 relieved allodynia and hyperalgesia and reduced the expression of P2X3 receptors and ERK1/2 phosphorylation in the spinal cord. CONCLUSIONS:: The data demonstrated that EA alleviates neuropathic pain behavior, at least in part, by reducing P2X3 receptor expression in spinal cord via the ERK1/2 signaling pathway. Low frequency EA has a better analgesic effect than high frequency HEA on neuropathic pain. Copyright © 2012 International Anesthesia Research Society.

Xu Z.,Tianjin Medical University | Xu Z.,University of North Carolina at Chapel Hill | Kim S.,Chonnam National University | Huh J.,Seoul National University
Journal of Molecular and Cellular Cardiology | Year: 2014

This study investigated if zinc plays a role in postconditioning-induced cardioprotection in rat hearts. Isolated rat hearts were subjected to 30min regional ischemia followed by 2h of reperfusion. Postconditioning was elicited by 6cycles of 10s reperfusion and 10s ischemia. Cytosolic zinc concentrations were measured with inductively coupled plasma optical emission spectroscopy (ICPOES). Infarct size was assessed by triphenyltetrazolium chloride staining. Cytosolic zinc concentrations were decreased dramatically upon reperfusion in the control hearts. In contrast, postconditioning increased cytosolic zinc levels at reperfusion. The anti-infarct effect of postconditioning was inhibited by the selective zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN). Postconditioning significantly increased phosphorylation levels of the reperfusion injury salvage kinases (RISK) including Akt (Ser473), extracellular signal-regulated kinase1/2 (ERK1/2) (Thr202/Tyr204), and glycogen synthase kinase-3β (GSK-3β) (Ser9) at reperfusion, which were nullified by TPEN. Postconditioning decreased the activity of protein phosphatase 2A (PP2A) in a zinc-dependent manner. Knockdown of the zinc transporter Zip2 inhibited the protective effect of postconditioning on hypoxia/reoxygenation injury in H9c2 cells. These results suggest that zinc plays an important role in the cardioprotective effect of postconditioning presumably by enhancing the activation of the RISK pathway. Zip2 and inactivation of PP2A by zinc may, at least in part, account for the activation of the RISK pathway. © 2013 Elsevier Ltd.

Dong X.,Tianjin Medical University | Qiu X.,Shanghai JiaoTong University | Liu Q.,Tianjin Medical University | Jia J.,Temple University
Annals of Thoracic Surgery | Year: 2013

In this article, we assessed the pooled sensitivity and specificity of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in studies during the last 10 years that have solely used EBUS-TBNA as a minimally invasive technique, with or without computed tomography or positron-emission tomography screening. The meta-analysis included 1,066 patients from 9 studies who underwent EBUS-TBNA. The results show EBUS-TBNA is a potential technique for the investigation, diagnosis, and staging of non-small cell lung cancer among patients with suspected lung cancer. It has excellent sensitivity, specificity, accuracy, positive predictive value, and negative predictive value. EBUS-TBNA is well tolerated and does not lead to complications in patients. © 2013 The Society of Thoracic Surgeons.

Dai Y.,Institute of Robotics and Automatic Information System | Xue Y.,Tianjin Medical University | Zhang J.,Institute of Robotics and Automatic Information System
Annals of Biomedical Engineering | Year: 2014

In order to prevent possible damages to soft tissues, reliable monitoring methods are required to provide valuable information on the condition of the bone being cut. This paper describes the design of an electrical impedance sensing drill developed to estimate the relative position between the drill and the bone being drilled. The two-electrode method is applied to continuously measure the electrical impedance during a drill feeding movement: two copper wire brushes are used to conduct electricity in the rotating drill and then the drill is one electrode; a needle is inserted into the soft tissues adjacent to the bone being drilled and acts as another electrode. Considering that the recorded electrical impedance is correlated with the insertion depth of the drill, we theoretically calculate the electrode-tissue contact impedance and prove that the rate of impedance change varies considerably when the drill bit crosses the boundary between two different bone tissues. Therefore, the rate of impedance change is used to determine whether the tip of the drill is located in one of cortical bone, cancellous bone, and cortical bone near a boundary with soft tissue. In vitro experiments in porcine thoracic spines were performed to demonstrate the feasibility of the impedance sensing drill. The experimental results indicate that the drill, used with the proposed data-processing method, can provide accurate and reliable breakthrough detection in the bone-drilling process. © 2013 Biomedical Engineering Society.

Chen P.,Tianjin Medical University | Li L.,CAS Institute of Physics
Chinese Journal of Clinical Oncology | Year: 2013

Lung cancer is the most common cancer worldwide, accounting for approximately 18% of all cancer-related deaths. Circulating tumor cells (CTCs) have the capacity to spread into the blood stream. This capacity of CTCs is one of the most critical factors for unfavorable clinical outcome of patients with NSCLC. Detection of CTCs using a simple blood test may assist in early detection of lung cancer. Researchers have attempted to isolate CTCs from peripheral blood using various techniques. Although reports on CTC detection are abundant, methodological aspects concerning sensitivity, specificity, and reproducibility have prevented a clear appraisal of the clinical impact. This paper gives a brief description of each CTC detection method.

Wang H.,Nanjing University | Du Y.-C.,Arizona State University | Du Y.-C.,Sichuan Cancer Hospital and Institute | Zhou X.-J.,Nanjing University | And 3 more authors.
Cancer and Metastasis Reviews | Year: 2014

The major functions of Hippo (Hpo) signaling pathway are to control cell growth, proliferation, and apoptosis. As its important downstream player, yes-associated protein (YAP)-1 was originally found to promote cell proliferation and transformation. Overexpression of YAP-1 has been linked to tumor progression and worse survival in certain malignancies. However, it has been recently recognized as a tumor suppressor gene as well since it also induces apoptosis. Decreased or absent expression of YAP-1 is highly correlated with tumor progression and worse survival in other tumors such as breast cancer. It is clear that YAP-1 plays a dual role as oncogene and tumor suppressor gene in human oncogenesis, depending on the specific tissue type involved. Here, we reviewed the recent research on both the oncogenic and tumor suppressor function of YAP-1 and its significance in human malignancy. The clinical implication of YAP-1 expression in cancer prognosis and the development of targeted therapy will also be discussed. © 2013 Springer Science+Business Media New York.

He W.,Vanderbilt University | Lin J.,Vanderbilt University | Lin X.,CAS Institute of Physics | Lu N.,Tianjin Medical University | And 2 more authors.
Analyst | Year: 2012

An analytical expression of Coulomb interaction between a sphere and a cylindrical rod was derived. Along with a recently reported van der Waals interaction expression, the derived Coulomb interaction expression, for the first time, allows one to quantitatively evaluate the activation energy in the oriented attachment growth of colloidal nanorods. © 2012 The Royal Society of Chemistry.

Niu Y.,Tianjin Institute of Physical Education | Yuan H.,Tianjin Institute of Physical Education | Fu L.,Tianjin Medical University
International Journal of Sport Nutrition and Exercise Metabolism | Year: 2010

Insulin resistance (IR) is a common pathophysiological feature of Type 2 diabetes. Although the mechanisms leading to IR are still elusive, evidence has shown that aerobic exercise can reverse this process. To investigate the effects of aerobic exercise on IR, the authors created an IR animal model by feeding C57BL/6 mice a high-fat diet for 8 wk. They then compared the effect of 6 wk of treadmill training (60 min/d) at 75% VO 2max on mice in normal-diet (NE) and high-fat-diet (HE) groups with their sedentary control groups. Levels of skeletal-muscle AMPKα (AMP-activated protein kinase α), ACC (acetyl-CoA carboxylases), and CPT1 (carnitine palmitoyltransferase 1) mRNA and AMPKα, pAMPK-Thr 172, ACC, pACC-Ser 79, and CPT1 protein expressions were analyzed. In addition, fasting serum levels of insulin, triglyceride, and cholesterol were measured. The results demonstrate that 6 wk of exercise increased AMPKα mRNA expression by 11% and 25 % (p < .01) in the NE and HE groups, respectively, and AMPKα protein expression by 37.9% and 20.1% (p < .01) in NE and HE compared with their sedentary control. In addition, ACC mRNA and protein expressions declined, whereas CPT1 mRNA and protein expressions were elevated in both exercise groups compared with sedentary control groups. In addition, pAMPK-Thr 172 and pACC-Ser 79 expression increased significantly in the NE and HE groups compared with sedentary control groups. In conclusion, our results demonstrate that 6 wk of aerobic exercise can effectively ameliorate IR by increasing the expression of AMPKα and pAMPK-Thr 172, thereby activating the key enzymes that facilitate lipid metabolism. © 2010 Human Kinetics, Inc.

Fan Q.,People's Care | Yang J.,Tianjin Medical University | Wang G.,Tianjin Medical University
Clinical and Translational Oncology | Year: 2014

Objective: Malignant peripheral nerve sheath tumors (MPNST) are relatively rare sarcomas and poorly understood. We sought to find clinicopathological and molecular predictors of survival for Chinese MPNST patients. Methods: Clinical information from 146 MPNST patients treated in the Tianjin Medical University Cancer Institute and Hospital was collected and 56 cases of formalin-fixed and paraffin-embedded tissues were available for immunohistochemical examination of expression of hepatocyte growth factor receptor (c-MET), E3 ubiquitin-protein ligase Mdm2 (MDM2), and TP53. Results: The 5-year tumor-free survival rate was 24 % and the median tumor-free survival time was 25.64 months. The 5-year overall survival rate was 57 % and the median overall survival time was 132.57 months. The expression patterns of c-MET, TP53, and MDM2 were heterogeneous with total positivity rates of 82.1 % (46/56), 55.4 % (31/56), and 73.2 % (41/56), respectively. The univariate analysis not only showed that tumor size, Neurofibromin 1 (NF1) status, the American Joint Committee on Cancer (AJCC) stage, surgery, MDM2 expression, and TP53 expression had significant correlation with the tumor-free survival, but also demonstrated that radiotherapy, chemotherapy, tumor size, and NF1 status had significant correlation with the overall survival. Even though multivariate analysis found no independent prognostic predictor of MPNST, tumor size and NF1 status had significant correlation with the tumor-free survival and overall survival of MPNST patients. Conclusions: With this, the largest documented Chinese cohort, our data supply powerful Chinese evidence of the prognostic role of tumor size and NF1 status in MPNST. © 2013 Federación de Sociedades Españolas de Oncología (FESEO).

Wang J.,Tianjin Hospital | Wang H.,Tianjin Public Security Hospital | Liu A.,Tianjin Medical University | Fang C.,Advanced Personalized Diagnostics | And 2 more authors.
Oncotarget | Year: 2015

Reprogramming metabolism of tumor cells is a hallmark of cancer. Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumor cells. Previous studies has shown higher levels of LDHA is related with colorectal cancer (CRC), but its role in tumor maintenance and underlying molecular mechanisms has not been established. Here, we investigated miRNAs-induced changes in LDHA expression. We reported that colorectal cancer express higher levels of LDHA compared with adjacent normal tissue. Knockdown of LDHA resulted in decreased lactate and ATP production, and glucose uptake. Colorectal cancer cells with knockdown of LDHA had much slower growth rate than control cells. Furthermore, we found that miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b target LDHA and regulate glycolysis in cancer cells. There is a negative correlation between these miRNAs and LDHA expression in colorectal cancer tissues. More importantly, we identified a genetic loci newly associated with increased colorectal cancer progression, rs18407893 at 11p15.4 (in 3'-UTR of LDHA), which maps to the seed sequence recognized by miR-374a. Cancer cells overexpressed miR-374a has decreased levels of LDHA compared with miR-374a-MUT (rs18407893 at 11p15.4). Taken together, these novel findings provide more therapeutic approaches to the Warburg effect and therapeutic targets of cancer energy metabolism.

Liu X.,Tianjin Medical University | Ru J.,Tianjin Medical University | Zhang J.,Tianjin Medical University | Zhu L.-H.,Tianjin Medical University | And 4 more authors.
PLoS ONE | Year: 2013

MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR-23a bound to the IRF1 mRNA 3′UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently up-regulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level. © 2013 Liu et al.

He X.,Tianjin Medical University | Li B.,Binzhou Medical University | Shao Y.,Feixian Hospital | Zhao N.,Tianjin Medical University | And 3 more authors.
BMC Cancer | Year: 2015

Background: The discovery of cancer stem cells and tumor heterogeneity prompted the exploration of additional mechanisms aside from genetic mutations for carcinogenesis and cancer progression. The aim of the present study was to investigate the effect of cell fusion between mesenchymal stem cells and the gastric epithelial cells in tumorigenesis. Methods: Cell fusion between cord blood mesenchymal stem cells and human gastric epithelial cells was performed in vitro. Cell scratch and transwell assays were performed to determine migration and invasion abilities of the hybrids. The expressions of epithelial-mesenchymal transition-related proteins and genes were analyzed by immunocytochemistry and real time quantitative PCR. Tumorigenesis of the hybrids was evaluated through in vivo inoculation in nude mice. Results: Hybrids expressed the phenotypes of both donor cells. Aneuploidy was observed in 84.1% of cells. The hybrids showed increased proliferation, migration and invasion abilities compared with the parental cells. In addition, the expression of N-cadherin and vimentin in the hybrids was significantly higher than that of the epithelial cells, and the mRNA expression of the epithelial-mesenchymal transition-related genes, Twist and Slug, in the hybrids was also increased compared with that of the parental epithelial cells. Furthermore, the hybrids formed masses of epithelial origin with glandular structures in BALB/c nude mice. Conclusions: These findings suggest that cell fusion between gastric epithelial cells and mesenchymal stem cells may result in epithelial to mesenchymal transition and malignant transformation. © He et al.

The antibodies used for western blotting included anti-YAP/TAZ (1:1,000; 8418; Cell Signaling Technology, USA), anti-YAP (1:1,000; Cell Signaling Technology, USA), anti-pYAP (1:1,000; Ser 127, 4911S; Cell Signaling Technology, USA), anti-TAZ (1:1,000; ab84927; Abcam, UK), anti-JNK (1:1,000; 9252h; Cell Signaling Technology, USA), anti-pJNK (1:1,000; 9255; Cell Signaling Technology, USA), anti-CTGF (1:1,000; ab6992; Abcam, UK), anti-Gα (1:1,000; ab128900; Abcam, UK), anti-integrin β (1:1,000; 4702; Cell Signaling Technology, USA), anti-RhoA (1:1,000; ab54835; Abcam, UK) and anti-eNOS (1:1,000; BD Biosciences, USA). The antibodies used for immunostaining included anti-pYAP (1:100; Ser 127, 4911S; Cell Signaling Technology, USA), anti-YAP (1:100; Cell Signaling Technology, USA) and anti-pJNK (1:100; 9255; Cell Signaling Technology, USA). RNA was extracted by using TRIzol Reagent (Thermo) according to the manufacturer’s protocol. cDNA was synthesized using a High-Capacity cDNA Reverse Transcription Kit (Thermo). Quantitative PCR was performed using SYBR Select (Thermo) following the manufacturer’s protocol. GAPDH was used as the internal control. Primers used for quantitative real-time PCR were included in Supplementary Table 1. Cells or tissues were homogenized in cold RIPA lysis buffer supplemented with cOmplete Protease Inhibitors cocktail and phosSTOP phosphatase inhibitor (Roche). The protein concentration was determined using Bradford Assay (Bio-Rad). Ten micrograms of protein were resolved by SDS–polyacrylamide gel electrophoresis and transferred to the PVDF membrane (Bio-Rad). Target protein was detected using specific primary antibody. Bound antibodies were detected by horseradish-peroxidase-conjugated secondary antibody and visualized by enhanced chemiluminescence (Cell Signaling Technology). Experiments were repeated three times and the target protein level was quantified by ImageJ and normalized to internal control (or pYAP was normalized to total YAP) (Extended Data Figs 6 and 7). Original western blot scans are included in Supplementary Fig. 1. HUVECs and human aortic ECs were purchased from Lonza (EGM, Clonetics, Lonza, Walkersville, Maryland, USA). Lonza guarantees that the cells express CD31/105, von Williebrand Factor VIII, and are positive for acetyated low-density lipoprotein uptake. We did not test for mycoplasma contamination during the experiments. HUVECs were maintained in EGM supplemented with EGS and FBS at 37 °C in an incubator with 95% humidified air and 5% CO and passaged every 3 days. Cells within seven passages were used for the in vitro study. GST-RBD recombinant protein was purified from BL21 (DE3) Escherichia coli and affinity conjugated to glutathione sepharose beads (Pharmacia). For GST affinity pull-down, 107 cells were lysed in 1 ml Weak Lysis Buffer (Beyotime) supplemented with protease inhibitors (Roche). Cell lysates were centrifuged at 15,000 g at 4 °C for 20 min to remove cell debris. Cell lysates were incubated in sepharose beads conjugated with 1 μg GST–RBD and incubated at 4 °C for 2 h with constant agitation, and precipitated by centrifugation at 1,000 r.p.m. for 10 min. After three washes, beads were collected by centrifugation and boiled in 2× SDS loading buffer for 5 min. The active RhoA was determined by western blotting. Animals were supplied by the University Laboratory Animal Services Centre and their use approved by the Ethical Committee of Animal Research (CUHK). The animals used in the present study included Sprague-Dawley rats, apolipoprotein E deficient (ApoE−/−) mice and EC-specific YAP overexpression transgenic mice. Male mice or rats were used in all in vivo studies. The animals were kept at a constant temperature (21 ± 1 °C) under 12/12-h light/dark cycle and had free access to water and standard chow unless specified. CAG loxp-stop-loxp-Yap mice were generated in a C57BL/6 background in Model Animal Research Center (Nanjing, China). Yap-COE mice were crossed with ApoE−/− mice and then Tie-2-Cre+/− mice. The 6-week-old ApoE−/−;Yap-COE;Tie-2-Cre+/− and ApoE−/−;Yap-COE;Tie-2-Cre+/− mice were bred and housed in temperature-controlled cages under a 12/12-h light/dark cycle with free access to water in Tianjin Medical University Animal Center. Study protocols and the use of animals were approved by the Institutional Animal Care and Use Committee of Tianjin Medical University (Tianjin, China). The mice were fed a Western diet (Research Diets, D12109) containing 40 kcal% fat, 1.25% cholesterol and 0.5% cholic acid for 4 weeks before being killed. Aortas were isolated to assess lesion formation and distribution by Oil Red O staining. Aortic roots were stained for pJNK, α-SMA and macrophages. Mouse aortas were fixed with 4% paraformaldehyde for 15 min. After permeabilization/blocking in 0.05% Triton X-100 (in PBS) and 1% BSA and for 0.5 h at room temperature, aortas were incubated at 4 °C overnight in incubation buffer containing 1% BSA and the primary antibody including YAP1 (Abcam, ab52771), CD31 (Abcam, ab24590). After being washed in PBS three times, aortas were incubated with Alexa-Fluor 488-, Alexa-Fluor 594-conjugated secondary antibodies (ZSGB-BIO, Beijing) for 1 h at room temperature. The fluorescent signal was detected by a Leica confocal laser scanning microscopy. Stenosis of the abdominal aorta of rats was induced using a U-shaped titanium clip, as described29, 30. Briefly, after anaesthetization with isoflurane, the rat was laid supine and a lower midline abdomen incision was made; the part of the intestine was gently lifted out of the abdominal cavity and kept moist with saline throughout the surgical procedure. The aorta, left and right common iliac artery were exposed and the accompanying vein was carefully separated. The clip was held with a pair of forceps and placed around the isolated segment (1 cm from the arterial bifurcation) to partly constrict the abdominal aorta. The extent of clipping was controlled by placing a stopper of given size between the two arms of the forceps. Two weeks later, the rat was euthanized by intoxication with 100% carbon dioxide, and the aorta was perfusion-fixed with 4% (w/v) paraformaldehyde at 120 mm Hg. The fixed aorta was embedded in paraffin blocks for immunohistochemical staining. Partial ligation of carotid artery was generated as described before31. Briefly, ApoE−/− mice were anaesthetized by intraperitoneal injection of xylazine (10 mg/kg) and ketamine (80 mg/kg) mixture. A ventral midline incision (4–5 mm) was made in the neck. Left carotid artery was exposed by ventral midline incision (4–5 mm) in the neck. Left external carotid, internal carotid and occipital arteries were ligated, while the superior thyroid artery was left intact. Mice were monitored until recovery in a chamber on a heating pad after surgery and fed the Western diet immediately after surgery until killed. Immunohistochemical staining was performed on serial sections (5 μm thick) of paraffin-embedded rat abdominal aortas and ApoE−/− mouse aortas using pYAP (Cell Signaling), EC- and SMC-specific markers (that is, vWF and α-SMA, respectively) (Merck Millipore). Briefly, the sections were de-waxed in xylene, rehydrated in descending grades of alcohol and permeabilized by incubating for 10 min in sodium citrate for 10 min at 95 °C. Sections were cooled down to room temperature and blocked with blocking reagent (Merck Millipore) for 30 min. One section was incubated with antibody against pYAP (1:100) overnight at 4 °C, followed by Alexa-Fluor 594-conjugated goat-anti-rabbit IgG (1:1,000; Invitrogen) secondary antibody in blocking reagent for 1 h at room temperature. The secondary section was incubated with antibodies against vWF and α-SMA (1:100 each) overnight at 4 °C, followed by Alexa-Fluor 594-conjugated goat-anti-rabbit IgG and Alexa-Fluor 488-conjugated goat-anti-mouse IgG (1:1,000; Invitrogen) secondary antibodies in blocking reagent for 1 h at room temperature. Nuclei were co-stained by DAPI (Invitrogen) in PBS for 5 min. The sections were spin-dried and mounted with ProLong Gold (Invitrogen) on glass coverslips. Images were acquired and analysed using a Zeiss fluorescence microscope with Axiovision image analysis software. ApoE−/− mice (male, 12 weeks old) were fed a Western diet, and MnCl was administered through voluntary water consumption. Water consumption rate was predetermined by monitoring the volume of water remained. MnCl was supplemented to drinking water to achieve 5 mg/kg body weight. Mice body weight and water consumption were adjusted weekly to adapt to the change of body weight and water consumption. After feeding on the Western diet for 3 months, the mice were killed and the atherosclerotic plaque formation was determined by Oil Red O staining. The ApoE−/− mice were killed by CO asphyxiation. Mouse aortas were dissected in cold PBS and cut open to expose the atherosclerotic plaques. After fixation in 4% formaldehyde for 16 h at 4 °C, the tissues were first rinsed in water for 10 min and then in 60% isopropanol. The aortas were stained with Oil Red O for 15 min with gentle shaking, and rinsed again in 60% isopropanol and then in water for three rinses. The samples were fixed on the cover slides with the endothelial surface facing upwards. The images were recorded using an HP Scanjet G4050. The plaque areas were determined using National Institutes of Health ImageJ software and calculated by expressing the plaque area relative to the total vascular area. The experiments were approved by the Hospital Human Subjects Review Committee (IRB approval number TSGHIRB 2-103-05-132) of Tri-Service General Hospital in Taipei and were conducted under the guidelines established by the Ethics Review Board of National Health Research Institutes, Taiwan. Written informed consent was obtained from all individuals. Human aortic tissue specimens were from patients with acute type-A aortic dissection. These samples were collected during emergency aortic surgery. The diseased segments of aorta (that is, dissecting aortic aneurysm) in these patients were all resected and replaced by an artificial inter-position graft. Specimens were fixed in paraformaldehyde, paraffin-embedded and cut into 5 μm sections. YAP Ser127 phosphorylation was determined by immunofluorescence imaging. HUVECs were transfected with pWCXIH-Flag-YAP-S127A (a gift from K. Guan, Addgene 33092) and 3× Flag pCMV5-TOPO TAZ (S89A) (a gift from J. Wrana, Addgene 24815) or pEGFP-N1 by Neon transfection system (Invitrogen, USA)32, 33. Four hours after transfection, cells were harvested and RNA was extracted using RNeasy Mini Kit (Qiagen, Germany). The extracted RNA samples were sent to Beijing Genomics Institute (BGI) for RNA-sequencing analysis. P < 0.05 and fold change >1.5 was used as a threshold for different regulated genes. DAVID tools were used for the pathways enrichment analysis and GlueGo was used for the Gene Ontology analysis. Ibidi flow system (IBIDI, Germany) was used to generate USS and disturbed flow (12 dyn cm−2 for USS and 0.5 ± 6 dyn cm−2, 1 Hz for disturbed flow). μ-slide I 0.4 Luers (IBIDI, LLC) was used for immunofluorescence studies. The slide was coated with 50 μg/ml fibronectin for 24 h. Seven thousand HUVECs were seeded onto the slide. After cells were adapted to medium containing 2% FBS (10% fatty acid free BSA for disturbed flow) for 6 h, the slides were mounted onto the Ibidi flow system. For immunostaining of USS-induced YAP/TAZ nuclear exportation, cells were subjected to USS for 6 h. For western blotting and reverse transcription real-time PCR analysis, the μ-slides were replaced with a custom-built flow chamber, which could accommodate more cells. Glass slides (75 mm × 38 mm; Corning) were coated with fibronectin (50 μg/ml). HUVECs were seeded on slides and allowed to attach on the bottom for 16 h. For USS, the medium was replaced with EGM supplemented with 2% FBS for 6 h. For disturbed flow, cells were incubated in EGM supplemented with 10% fatty-acid-free BSA (Sigma). The slides were mounted onto the flow chamber and connected to the Ibidi flow system. The cells were then subjected to USS or disturbed flow. For USS-induced YAP phosphorylation, 15 min of shear force was applied unless otherwise noted. For USS-induced YAP translocation, 6 h of shear force was applied. For reverse transcription real-time PCR analysis, 4 h of shear stress was sufficient to inhibit the expression of YAP/TAZ target genes. For reporter gene assay, 48 h of shear forces were applied to HUVECs. To construct the reporter plasmids for adhesion molecules, human genomic DNA was purified from HUVECs using a Universal Genomic DNA Extraction Kit Ver 3.0 (Takara, Japan). The promoters of ICAM1, SELE, CCL2 and CXCL1 were PCR amplified from human genomic DNA using the primers listed in Supplementary Table 1. A 2.1 kb fragment (−1784 to +328) from the ICAM1 promoter, a 2.2 kb fragment (−1807 to +475) from the SELE promoter, a 4 kb fragment (−3992 to +73) from CCL2 promoter and a 1.3 kb fragment (−1256 to +84) from CXCL1 promoter were amplified. The PCR products were gel purified by gel extraction kit (Takara, Japan) and digested with restriction enzymes. The digested fragments were gel purified and ligated to pGL3 reporter plasmid digested by corresponding restriction enzymes. The ligation products were then heat inactivated at 65 °C for 15 min and transformed into the DH5α competent cells. The Pro32Pro33 integrin was derived from pcDNA3.1-beta-3 (a gift from T. Springer, Addgene plasmid 27289) by point mutation34. Primers used for plasmids construction were included in Supplementary Table 1. To generate the adenovirus shuttle vector pShuttle-U6, the U6 promoter and 1.9 kb stuffer sequence was excised from pLKO.1 (a gift from D. Root, Addgene plasmid 10878) with NotI/XhoI and ligated into pShuttle plasmid pre-digested with restriction enzymes accordingly. Short hairpin RNA targeting mouse Taz was generated using a protocol similar to pLKO.1 shRNA plasmids (Addgene) construction protocol. Taz shRNA sequence, TRCN0000095951, which was validated by Mission shRNA (Sigma Aldrich), was used to generate shuttle plasmids for Taz shRNA. Recombinant adenovirus was generated using the AdEasy system35. Briefly, pShuttle-U6 vector containing shRNA was digested with PmeI and co-transformed with adenoviral backbone plasmid pAdEasy-1 for homologous recombination in E. coli BJ5183 cells. Positive recombinants were linearized by PacI digestion and transfected into HEK-293A cells for virus packaging. The medium and cells were collected until the cytopathic effect was apparent. After three cycles of freeze and thaw to release the virus, the cell debris was removed by centrifugation at 3,000 r.p.m. for 15 min. The virus-containing supernatant was collected by PEG precipitation, followed by dialysis against saline with 100K MWCO dialysis tubing (Spectrum Labs). Lentiviral shuttle plasmids for YAP (TRCN0000300325), TAZ (TRCN0000370007), Gα (TRCN0000036885) and ITGB3 (TRCN0000003236) shRNA were purchased from Sigma. Plasmid cocktail containing 1 μg of resultant shuttle plasmid, 750 ng of psPAX2 packaging plasmid and 250 ng of pMD2.G envelope plasmid were co-transfected to HEK-293FT cells. The medium was changed 15 h after transfection; 48 and 72 h after transfection, the medium containing the lentiviral particles was harvested then passed through 0.45 μm filters to remove cell debris. The virus was precipitated with PEG and suspended in PBS containing 4% sucrose. The lentiviral solutions were then aliquoted to vials and stored at −80 °C. YAP1 S127A was amplified from pWCXIH-Flag-YAP-S127A (a gift from K. Guan, Addgene 33092) and ligated to pAAV-MCS (Stratagene) to generate the pAAV-YAP1 S127A shuttle plasmid. A similar strategy was used to generate the pAAV-TAZ S89A from 3× Flag pCMV5-TOPO TAZ (S89A) (a gift from J. Wrana, Addgene 24815). pX601-AAV-CMV: NLS-SaCas9-NLS-3xHA-bGHpA;U6::BsaI-sgRNA (a gift from F. Zhang, Addgene plasmid 61591) was used to generate the EC-specific Cas9 for Yap in vivo genome editing28. Three sgRNA sequences for Yap were predicted by CCTop (CRISPR/Cas9 target online predictor)36. ICAM2 endothelium-specific promoter from human was synthesized by GenScript and replaced the CMV promoter in pX601-AAV-CMV14. Primers used for sgRNA were included in Supplementary Table 1. The shuttle plasmids were co-transfected into HEK-293T with endothelial enhanced RGDLRVS-AAV9-cap plasmid (provided by O. J. Müller, Universität Heidelberg, Germany) and pHelper plamid (Stratagene)37. After co-transfection for 72 h, the AAV viral particles were isolated according to the protocol reported in ref. 38. Briefly, the cells were harvested and re-suspended in 1× restore buffer and the nuclei were extracted by homogenization. Viral particles were extracted by using nuclear lysis buffer. The viral particles were purified by PEG concentration, followed by dialysis against saline with 100K MWCO dialysis tubing (Spectrum Labs) to remove impurities, and concentrated. The viral titration was determined by qPCR and adjusted to 1010 plaque-forming units per ml in PBS containing 4% sucrose. For adenovirus-mediated Taz shRNA, viruses (109 plaque-forming units) were administered to ApoE−/− mice (male, 12 weeks old) that had been fed on Western diet (Research Diets) for 4 weeks, through tail vein injection. The mice were then fed on Western diet for 2 more months. The atherosclerotic plaque formation was visualized by Oil Red O staining. For AAV-mediated CA-YAP/TAZ overexpression and YAP-Cas9, the viruses (109 plaque-forming units) were administrated to ApoE−/− mice (male, 12 weeks old) through tail vein injection before feeding on Western diet or receiving the carotid partial ligation surgery. Statistics analyses were performed using GraphPad Prism 5.0. The sample sizes were not predetermined by statistical methods. The samples were not randomized and the investigators were not blinded to allocation during experiments and outcome assessment. At least three independent experiments were performed for all biochemical experiments and the representative images were shown. Results represent mean ± s.e.m. Student’s t-test (unpaired two-tailed) was used in the analysis. No samples, mice or data points were excluded from the reported analysis. Levels of probabilities less than 0.05 were regarded as significant. The RNA-seq data that support the findings of this study have been deposited in BioSamples database (https://www.ebi.ac.uk/biosamples/) under accession number SAMN04565728. All other data are available from the corresponding authors upon reasonable request.

Wu M.,University of South China | Chen S.-W.,University of South China | Jiang S.-Y.,Tianjin Medical University
Mediators of Inflammation | Year: 2015

An increase in the prevalence and severity of gingival inflammation during pregnancy has been reported since the 1960s. Though the etiology is not fully known, it is believed that increasing plasma sex steroid hormone levels during pregnancy have a dramatic effect on the periodontium. Current works of research have shown that estrogen and progesterone increasing during pregnancy are supposed to be responsible for gingivitis progression. This review is focused not only on epidemiological studies, but also on the effects of progesterone and estrogen on the change of subgingival microbiota and immunologic physiological mediators in periodontal tissue (gingiva and periodontal ligament), which provides current information about the effects of pregnancy on gingival inflammation. © 2015 Min Wu et al.

Wang X.,Tianjin Medical University | Zhang Z.,Dalian Central Hospital | Yao C.,Jilin University
Cancer Investigation | Year: 2011

The pathophysiology of multiple myeloma-induced angiogenesis is complex and involves both direct production of angiogenic cytokines by plasma cells and their induction within the microenvironment. In this research, we investigated whether mesenchymal stem cells participated in inducing the angiogenic response in multiple myeloma, and explored the mechanism by which MSCs influence myeloma angiogenesis. We detected the concentration of angiogenic factors (bFGF, HGF, and VEGF) in the conditioned medium of mesenchymal stem cells and the capillary formation ability of mesenchymal stem cells in vitro. We found that conditioned medium of MSCs derived from MM significantly promoted the proliferation, chemotaxis, and capillary formation of human umbilical vein endothelial cells compared with that from normal donors. ELISA and RT-PCR were used to detect the mRNA and protein levels of angiogenic factors (bFGF, HGF, and VEGF) in the conditioned medium. We found that mRNA and protein levels of angiogenic factors were elevated in MSCs from multiple myeloma compared with normal donors. © 2011 Informa Healthcare USA, Inc.

Fu W.,University of Pennsylvania | Fu W.,Tianjin Medical University | Madan E.,University of Pennsylvania | Yee M.,University of Pennsylvania | Zhang H.,University of Pennsylvania
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients. © 2011 Elsevier B.V.

Schernhammer E.S.,Harvard University | Schernhammer E.S.,Ludwig Boltzmann Research Institute | Feskanich D.,Harvard University | Liang G.,Harvard University | And 3 more authors.
American Journal of Epidemiology | Year: 2013

The risk of lung cancer among night-shift workers is unknown. Over 20 years of follow-up (1988-2008), we documented 1,455 incident lung cancers among 78,612 women in the Nurses' Health Study. To examine the relationship between rotating night-shift work and lung cancer risk, we used multivariate Cox proportional hazard models adjusted for detailed smoking characteristics and other risk factors. We observed a 28% increased risk of lung cancer among women with 15 or more years spent working rotating night shifts (multivariate relative risk (RR) = 1.28, 95% confidence interval (CI): 1.07, 1.53; Ptrend = 0.03) compared with women who did not work any night shifts. This association was strongest for small-cell lung carcinomas (multivariate RR = 1.56, 95% CI: 0.99, 2.47; Ptrend = 0.03) and was not observed for adenocarcinomas of the lung (multivariate RR = 0.91, 95% CI: 0.67, 1.24; Ptrend = 0.40). Further, the increased risk associated with 15 or more years of rotating night-shift work was limited to current smokers (RR = 1.61, 95% CI: 1.21, 2.13; Ptrend < 0.001), with no association seen in nonsmokers (P interaction = 0.03). These results suggest that there are modestly increased risks of lung cancer associated with extended periods of night-shift work among smokers but not among nonsmokers. Though it is possible that this observation was residually confounded by smoking, our findings could also provide evidence of circadian disruption as a "second hit" in the etiology of smoking-related lung tumors. © The Author 2013.

Hao Y.,Sichuan University | Gu J.,CAS Shanghai Institute of Materia Medica | Guo Y.,Neijiang Normal University | Zhang M.,Tianjin Medical University | And 2 more authors.
Physical Chemistry Chemical Physics | Year: 2014

Using the CCSD(T) method with relativistic correlation consistent basis sets up to cc-pVQZ-PP, the entrance complex, transition state, and exit complex for the endothermic reaction I + H2O → HI + OH have been studied. The vibrational frequencies and the zero-point vibrational energies of the five stationary points for the title reaction are reported and compared with the limited available experimental results. Opposite to the valence isoelectronic F + H2O system, but similar to the Cl + H2O and Br + H2O reactions, the I + H2O reaction is endothermic, in this case by 46 kcal mol-1. After the zero-point vibrational energy and spin-orbit coupling corrections, the endothermic reaction energy is predicted to be 48 kcal mol-1, which agrees well with experimental values. For the reverse reaction HI + OH → I + H2O the transition state lies below the reactants, consistent with the experimental negative temperature dependence for the rate constants. © 2014 the Owner Societies.

Lin X.,Nanjing Southeast University | Lin X.,State Key Laboratory of Bioelectronics | Li Y.,Tianjin Medical University | Gu N.,Nanjing Southeast University | Gu N.,State Key Laboratory of Bioelectronics
Soft Matter | Year: 2011

We have performed coarse grained molecular dynamics simulations (CGMD) to investigate the interactions of generation 7, 5 and 3 (G7, G5 and G3) charge-neutral polyamidoamine (PAMAM) dendrimers with a DPPC (dipalmitoylphosphatidylcholine) monolayer at the air-water interface (model pulmonary surfactant) during the end-expiration process. Our results show that different generations of PAMAM dendrimers have different influences on the DPPC monolayer. Generally, G3 PAMAM dendrimers show little influence on the DPPC monolayer's structure and relative properties. While G7 and G5 PAMAM dendrimers tend to induce the formation of largely deformed structures of the DPPC monolayer and inhibit or even reverse the normal phase transition of the interfacial DPPC molecules during the process of compression. Besides, we find that the formation processes of these disrupted structures are energy-favorable based on analyzing van der Waals interaction energy between PAMAM dendrimers and the whole system. © The Royal Society of Chemistry 2011.

Li C.-J.,Tianjin Medical University | Lv L.,Tianjin Medical University | Li H.,University of Pennsylvania | Yu D.-M.,Tianjin Medical University
Cardiovascular Diabetology | Year: 2012

Background: Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model.Methods: Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot.Results: DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation.Conclusions: These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation. © 2012 Li et al.; licensee BioMed Central Ltd.

Wang J.,Tianjin Medical University | Wang J.,Hong Kong University of Science and Technology | Tse N.,Hong Kong University of Science and Technology | Gao Z.,Tianjin University
Energy Conversion and Management | Year: 2011

In this paper, proportional and integral (PI) pitch controller is analyzed and designed for a large wind turbine generator (WTG) by using graphical approach. Firstly, the transfer function of the wind turbine which including a time delay in the hydraulic pressure driven unit of pitch control system is derived. The complete stabilizing set in the plain of proportional-integral gains can then be drawn and identified immediately based on the presented method, rather than computed mathematically. The influence of the time delay in hydraulic pressure driven of pitch unit on the stability region of PI controller is analyzed as well. Finally, the proposed techniques are verified by using simulation results to the actual model of WTG. © 2010 Elsevier Ltd. All rights reserved.

Li T.,Shandong University | Su L.,Shandong University | Zhong N.,Shandong University | Hao X.,Shandong University | And 3 more authors.
Autophagy | Year: 2013

Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells. This novel agent can selectively eliminate breast and other cancer stem cells, though the mechanism of action remains unclear. In this study, we found that salinomycin induced autophagy in human non-small cell lung cancer (NSC LC) cells. Furthermore, we demonstrated that salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CH OP-TRIB3-AKT1-MTOR axis. Moreover, we found that the autophagy induced by salinomycin played a prosurvival role in human NSC LC cells and attenuated the apoptotic cascade. We also showed that salinomycin triggered more apoptosis and less autophagy in A549 cells in which CDH1 expression was inhibited, suggesting that the inhibition of autophagy might represent a promising strategy to target cancer stem cells. In conclusion, these findings provide evidence that combination treatment with salinomycin and pharmacological autophagy inhibitors will be an effective therapeutic strategy for eliminating cancer cells as well as cancer stem cells. © 2013 Landes Bioscience.

Yang P.,Shaanxi Normal University | Yang P.,Duke University | Zhang X.,Tianjin Medical University
Chemical Communications | Year: 2012

In Nature, certain organisms can perform microbial corrosion on base metals by oxidation of neutral metallic atoms (H. L. Ehrlich, Appl. Microbiol. Biotechnol., 1997). Herein we describe the first discovery of biological nucleic acids able to catalyze and mediate gold oxidation from neutral Au0 to trivalent Au(iii) under certain oxidative environments provided by mild oxidizing reagent N-bromosuccinimide or amino acids. A new biolithography technique for gold patterning is further developed. © 2012 The Royal Society of Chemistry.

Liu G.,Shandong University | Su L.,Shandong University | Hao X.,Shandong University | Zhong N.,Shandong University | And 3 more authors.
Journal of Cellular and Molecular Medicine | Year: 2012

Sirtuins (a class III histone deacetylase) have emerged as novel targets for cancer therapy. Salermide, a reverse amide compound that inhibits Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2), has been shown to induce apoptosis in human cancer cells. The mechanism underlying cellular apoptotic signalling by salermide remains unclear. In this study, we show that salermide up-regulates the expression of death receptor 5 (DR5) in human non-small cell lung cancer (NSCLC) cells. Blocking DR5 expression by gene silencing technology results in a decrease in activated forms of several pro-apoptotic proteins (caspase-8, caspase-9, caspase-3, PARP). Increasing DR5 protein expression correlates with salermide-induced apoptosis in human NSCLC cells. We discovered that IRE-1α, Bip, activating transcription factor 3 (ATF4), activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP) are induced by salermide, which suggests that DR5-dependent apoptosis is induced by endoplasmic reticulum stress. Moreover, knockdown of Sirt1 and Sirt2 expression resulted in up-regulation of ATF4, CHOP and DR5. Transfected NSCLC cells with ATF4, ATF3 or CHOP siRNA results in a decline in pro-apoptotic proteins (such as caspase-8, caspase-9, caspase-3 and PARP) despite salermide treatment. We demonstrate that salermide induces expression of ATF4, and ATF4 up-regulates ATF3 and subsequently modulates CHOP. This suggests that DR5 is modulated by the ATF4-ATF3-CHOP axis in NSCLC after Sirt1/2 inhibition or salermide treatment. This study highlights the importance of DR5 up-regulation in apoptosis induced by Sirt1/2 inhibition and elucidates the underlying mechanism in human NSCLC cells. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Ye Y.,Tianjin Medical University | Xu W.,Peking Union Medical College | Zhong W.,Glaxosmithkline | Li Y.,Tianjin Medical University | Wang C.,Tianjin Medical University
Molecular and Cellular Biochemistry | Year: 2012

The aim of this study was to investigate the effect of dihydrotanshinone I (DI) in inhibiting the growth of human cervical cancer cells both in vitro and in vivo, and molecular targets in HeLa cells when treated by DI or irradiation with or without being combined. In this study, MTT, clonogenic assay, flow cytometry, and Western blotting were performed to assess the effect of treatment on cells. After treatment with IR, DI, and DI + IR, the apoptosis was 5.8, 13.3 and 22.5% (P < 0.05 vs. control), respectively. Clonogenic assay revealed that the survival of irradiated HeLa cell was significantly reduced by DI treatment. Combination treatment with IR and DI could down-regulate HPV E6 gene expression. Effect of DI on up-regulation of p21 expression and down-regulation of cyclin B1, p34 cdc2 expression in irradiated HeLa cell was concomitant with cell cycle arrest in G 2 phase. The significant increase in caspase-3 activity was also observed in the combination treatment. When HeLa cells were grown as xenografts in nude mice, combination treatment with DI and IR induced a significant decrease in tumor growth, and without signs of general or organ toxicity. These data suggest DI should be tested as the radiosensitizer in vitro and in vivo, which has potential in the treatment of human cervical cancer. © 2011 Springer Science+Business Media, LLC.

Cao X.,Tianjin Medical University | Han Z.-B.,Peking Union Medical College | Zhao H.,Tianjin University of Commerce | Liu Q.,Peking Union Medical College
International Journal of Biochemistry and Cell Biology | Year: 2014

Alleviation of hyperglycemia in chemical-induced diabetic mice has been reported after bone marrow transplantation. Nevertheless, the underlying mechanism remains elusive. In the present study, we transplanted genetically labeled primary mouse mesenchymal stem cells into the pancreas of the streptozotocin-treated hyperglycemic isogeneic mice, resulting in a decrease in blood glucose due to a recovery in beta cell mass. Further analysis revealed that the increase in beta cell mass was predominantly attributable to beta cell replication. The grafted mesenchymal stem cells did not transdifferentiate into beta cells themselves but recruited and polarized macrophages in a Stromal cell-derived factor 1-dependent manner, which in turn promoted beta cell replication. Our finding thus suggests that transplantation of autogenic mesenchymal stem cells may increase functional beta cell mass by boosting beta cell replication in diabetes. © 2014 Elsevier Ltd.

Fu Y.,Tianjin Medical University | Liu Q.,Tianjin Medical University | Anrather J.,New York Medical College | Shi F.-D.,Tianjin Medical University
Nature Reviews Neurology | Year: 2015

Approaches for the effective management of acute stroke are sparse, and many measures for brain protection fail. However, our ability to modulate the immune system and modify the progression of multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In patients with acute stroke, microglial activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions. © 2015 Macmillan Publishers Limited.

Wang X.,Tianjin Medical University | Zhang Z.,Dalian Central Hospital | Yao C.,Jilin University
Leukemia Research | Year: 2010

In this study we investigated the influence of the mesenchymal stem cells on the survival of U266 and H929 myeloma cell lines. We found that both soluble factors and direct cell contact inhibited daunorubicin-induced apoptosis of U266 and H929 cells. The mRNA and protein levels of survivin were upregulated in U266 and H929 cells cocultured with mesenchymal stem cells, whereas not increased in that separated by TW insert. Antisense oligonucleotides targeting survivin downregulated the expression of survivin and increased the apoptosis of U266 and H929 cells. The results indicated that MSCs had anti-apoptotic effect on U266 and H929 cells that was mediated by survivin. © 2010 Elsevier Ltd.

Wang Z.,Hong Kong University of Science and Technology | Wu T.,Hong Kong University of Science and Technology | Shi L.,Hong Kong University of Science and Technology | Zhang L.,Tianjin Medical University | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

As the primary microtubule-organizing centers, centrosomes require γ-tubulin for microtubule nucleation and organization. Located in close vicinity to centrosomes, the Golgi complex is another microtubule-organizing organelle in interphase cells. CDK5RAP2 is a γ-tubulin complex-binding protein and functions in γ-tubulin attachment to centrosomes. In this study, we find that CDK5RAP2 localizes to the Golgi complex in an ATP-and centrosome-dependent manner and associates with Golgi membranes independently of microtubules. CDK5RAP2 contains a centrosome-targeting domain with its core region highly homologous to the Motif 2 (CM2) of centrosomin, a functionally related protein in Drosophila. This sequence, referred to as the CM2-like motif, is also conserved in related proteins in chicken and zebrafish. Therefore, CDK5RAP2 may undertake a conserved mechanism for centrosomal localization. Using a mutational approach, we demonstrate that the CM2-like motif plays a crucial role in the centrosomal and Golgi localization of CDK5RAP2. Furthermore, the CM2-like motif is essential for the association of the centrosome-targeting domain to pericentrin and AKAP450. The binding with pericentrin is required for the centrosomal and Golgi localization of CDK5RAP2, whereas the binding with AKAP450 is required for the Golgi localization. Although the CM2-like motif possesses the activity of Ca2+-independent calmodulin binding, binding of calmodulin to this sequence is dispensable for centrosomal and Golgi association. Altogether, CDK5RAP2 may represent a novel mechanism for centrosomal and Golgi localization. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Zhou W.,Beckman Research Institute | Zhou W.,Chongqing Medical University | Fong M.Y.,Beckman Research Institute | Min Y.,U.S. National Cancer Institute | And 23 more authors.
Cancer Cell | Year: 2014

Cancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer. © 2014 Elsevier Inc.

Cheng H.,University of Texas M. D. Anderson Cancer Center | Zhang L.,Tianjin Medical University | Cogdell D.E.,University of Texas M. D. Anderson Cancer Center | Zheng H.,Tianjin Medical University | And 6 more authors.
PLoS ONE | Year: 2011

Background: Colorectal cancer (CRC) remains one of the major cancer types and cancer related death worldwide. Sensitive, non-invasive biomarkers that can facilitate disease detection, staging and prediction of therapeutic outcome are highly desirable to improve survival rate and help to determine optimized treatment for CRC. The small non-coding RNAs, microRNAs (miRNAs), have recently been identified as critical regulators for various diseases including cancer and may represent a novel class of cancer biomarkers. The purpose of this study was to identify and validate circulating microRNAs in human plasma for use as such biomarkers in colon cancer. Methodology/Principal Findings: By using quantitative reverse transcription-polymerase chain reaction, we found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. Conclusions/Significance: We propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis. © 2011 Cheng et al.

Chen Z.,China Agricultural University | Chen Y.-Z.,Tianjin Medical University | Wang X.-F.,China Agricultural University | Wang C.,China Agricultural University | And 2 more authors.
PLoS ONE | Year: 2011

As one of the most important reversible protein post-translation modifications, ubiquitination has been reported to be involved in lots of biological processes and closely implicated with various diseases. To fully decipher the molecular mechanisms of ubiquitination-related biological processes, an initial but crucial step is the recognition of ubiquitylated substrates and the corresponding ubiquitination sites. Here, a new bioinformatics tool named CKSAAP_UbSite was developed to predict ubiquitination sites from protein sequences. With the assistance of Support Vector Machine (SVM), the highlight of CKSAAP_UbSite is to employ the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input. When trained and tested in the dataset of yeast ubiquitination sites (Radivojacet al, Proteins, 2010, 78: 365-380), a 100-fold cross-validation on a 1:1 ratio of positive and negative samples revealed that the accuracy and MCC of CKSAAP_UbSite reached 73.40% and 0.4694, respectively. The proposed CKSAAP_UbSite has also been intensively benchmarked to exhibit better performance than some existing predictors, suggesting that it can be served as a useful tool to the community. Currently, CKSAAP_UbSite is freely accessible at http://protein.cau.edu.cn/cksaap_ubsite/. Moreover, we also found that the sequence patterns around ubiquitination sites are not conserved across different species. To ensure a reasonable prediction performance, the application of the current CKSAAP_UbSite should be limited to the proteome of yeast. © 2011 Chen et al.

Shen J.,Rush University | Shen J.,University of Rochester | Li J.,Rush University | Li J.,Liaoning University of Traditional Chinese Medicine | And 8 more authors.
Arthritis and Rheumatism | Year: 2013

Objective: While transforming growth factor β (TGFβ) signaling plays a critical role in chondrocyte metabolism, the TGFβ signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFβ signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling. Methods: TGFβ receptor type II (TGFβRII)-conditional knockout (KO) (TGFβRII Col2ER) mice were generated by breeding TGFβRII flox/flox mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFβ signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling, TGFβRII/matrix metalloproteinase 13 (MMP-13)- and TGFβRII/ADAMTS-5-double-KO mice were generated and analyzed. Results: Inhibition of TGFβ signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up-regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFβRIICol2ER mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRIICol2ER mice with an MMP-13 inhibitor also slowed OA progression. Conclusion: Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA. Copyright © 2013 by the American College of Rheumatology.

Wang X.,Tianjin Medical University | Zhang Z.,Dalian Central Hospital | Yao C.,Jilin University
Medical Oncology | Year: 2011

In this study, we investigated ILK expression in myeloma cell lines U266 and H929 kept in suspension and cocultured with BMSCs, and studied the pharmacologic inhibitors of ILK on the apoptosis, invasive potential of myeloma cell lines, and production of pro-angiogenic factors of bone marrow stromal cells. We found that ILK protein was expressed in U266 and H929 cells and kinase activity was elevated when cocultured with BMSCs. ILK inhibitor QLT0267 reduced ILK kinase activity and increased apoptosis both in myeloma cell lines kept in suspension and cocultured with BMSCs. ILK inhibition by ILK inhibitor decreased the in vitro invasive capability of myeloma cell lines. In addition, QLT0267 significantly decreased VEGF and IL-6 secretion in BMSCs in a dose-dependent fashion. The results indicated that inhibition of ILK may provide a potential target for myeloma therapy. © 2010 Springer Science+Business Media, LLC.

Shen J.-W.,Nankai University | Yang C.-X.,Nankai University | Dong L.-X.,Nankai University | Sun H.-R.,Tianjin Medical University | And 2 more authors.
Analytical Chemistry | Year: 2013

Rational design and fabrication of multimodal imaging nanoprobes are of great significance for in vivo imaging. Here we report the fabrication of a multishell structured NaYF4:Yb/Tm@NaLuF4@NaYF 4@NaGdF4 nanoprobe via a seed-mediated epitaxial growth strategy for upconversion luminescence (UCL), X-ray computed tomography (CT), and magnetic resonance (MR) trimodal imaging. Hexagonal phase NaYF 4:Yb/Tm is used as the core to provide UCL, while the shell of NaLuF4 is epitaxially grown on the core not only to provide an optically inert layer for enhancing the UCL but also to serve as a contrast agent for CT. The outermost NaGdF4 shell is fabricated as a thin layer to give the high longitudinal relaxivity (r1) desired for MR imaging. The transition shell layer of NaYF4 not only provides an interface to facilitate the formation of NaGdF4 shell but also inhibits the energy transfer from inner upconversion activator to surface paramagnetic Gd3+ ions. The fabricated multishell structured nanoprobe shows intense near-infrared UCL, high r1 value of 3.76 mM-1 s-1, and in vitro CT contrast effect. The multishell structured nanoprobe offers great potential for in vivo UCL/CT/MR trimodal imaging. Further covalent bonding of folic acid makes the multishell structured nanoprobe promising for in vivo targeted UCL imaging of tumor-bearing mice. © 2013 American Chemical Society.

Feng J.,Tianjin Medical University | Feng J.,Duke University | Zhang D.,Chinese Academy of Sciences | Zhang D.,Peking Union Medical College | Chen B.,Tianjin Medical University
Sleep and Breathing | Year: 2012

Background: Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men in the general population and the prevalence is much higher in specific patient groups. Intermittent hypoxia (IH, oxygen desaturation and re-oxygenation) cycle, a major pathophysiologic character of OSA, and the physiological responses this evokes are thought to be responsible for its association with increased cardiovascular morbidity and mortality. Endothelial dysfunction, resulting from IH and as a key early event in atherosclerosis, was demonstrated repeatedly in patients with OSA and in animal models of IH, providing an important mechanistic link between the acute cyclical IH during sleep and the increased prevalence of chronic vascular diseases. Conclusions: From this work, we conclude that IH from OSA may result in endothelial dysfunction, as a potential promoter of atherosclerosis, through nitric oxide unavailability, oxidative stress and inflammation, cell apoptosis, the crosstalk between endothelial cells and circulating inflammatory cells, microparticles, and damage repairing process. Though effective continuous positive airway pressure (CPAP) may specifically improve endothelial function, more controlled larger interventional trials that will include multiple centers and randomized allocation of CPAP therapy are needed to see if such changes are reversible before cause and effect can be implied finally, while further studies on cellular and animal level are also needed to elucidate molecular biologic/pathologic pathways. © Springer-Verlag 2011.

Hao Y.,CAS Institute of Automation | Wang T.,Shanghai East Hospital | Zhang X.,Capital Medical University | Duan Y.,Capital Medical University | And 3 more authors.
Human Brain Mapping | Year: 2014

Automatic and reliable segmentation of subcortical structures is an important but difficult task in quantitative brain image analysis. Multi-atlas based segmentation methods have attracted great interest due to their promising performance. Under the multi-atlas based segmentation framework, using deformation fields generated for registering atlas images onto a target image to be segmented, labels of the atlases are first propagated to the target image space and then fused to get the target image segmentation based on a label fusion strategy. While many label fusion strategies have been developed, most of these methods adopt predefined weighting models that are not necessarily optimal. In this study, we propose a novel local label learning strategy to estimate the target image's segmentation label using statistical machine learning techniques. In particular, we use a L1-regularized support vector machine (SVM) with a k nearest neighbor (kNN) based training sample selection strategy to learn a classifier for each of the target image voxel from its neighboring voxels in the atlases based on both image intensity and texture features. Our method has produced segmentation results consistently better than state-of-the-art label fusion methods in validation experiments on hippocampal segmentation of over 100 MR images obtained from publicly available and in-house datasets. Volumetric analysis has also demonstrated the capability of our method in detecting hippocampal volume changes due to Alzheimer's disease. © 2013 Wiley Periodicals, Inc.

Cui Y.,Johns Hopkins University | Cui Y.,Tianjin Medical University | Elahi D.,University of Pennsylvania | Andersen D.K.,Johns Hopkins University
Journal of Gastrointestinal Surgery | Year: 2011

Introduction: Hyperinsulinemic hypoglycemia with severe neuroglycopenia has been identified as a late complication of Roux-en-Y gastric bypass (RYGB) in a small number of patients. Discussion: The rapid resolution of type 2 diabetes mellitus after RYGB is probably related to increased secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and patients with post-RYGB hypoglycemia demonstrate prolonged elevations of GIP and GLP-1 compared to non-hypoglycemic post-RYGB patients. Nesidioblastosis has been identified in some patients with post-RYGB hypoglycemia and is likely due to the trophic effects of GIP and GLP-1 on pancreatic islets. Conclusions: Treatment of hypoglycemia after RYGB should begin with strict dietary (low carbohydrate) alteration and may require a trial of diazoxide, octreotide, or calcium-channel antagonists, among other drugs. Surgical therapy should include consideration of a restrictive form of bariatric procedure, with or without reconstitution of gastrointestinal continuity. Partial or total pancreatic resection should be avoided. © 2011 The Society for Surgery of the Alimentary Tract.

Liu Y.,Peking Union Medical College | Li Q.,Tianjin First Center Hospital | Zhu L.,Tianjin Medical University
Tumori | Year: 2012

Aim and background. The hepatocyte growth factor (HGF)/c-Met signaling system has been implicated in the development and progression of colon cancer, but the relationship between the expression of HGF or c-MET and clinicopathologic features remains controversial. In the study, we analyzed the expression of HGF and c-Met in colon cancer and assessed the influence of the expression of this growth factor and its receptor on clinical and histological parameters and patient survival. Methods and study design. We investigated the mRNA expression of HGF and c-Met with real-time PCR in 90 unselected colon carcinomas and the corresponding normal mucosa. Furthermore, HGF and c-Met protein expression was investigated with immunohistochemistry in all the samples. Results. The mRNA and protein expression levels of HGF and c-Met were significantly higher in colon cancer than in matched normal mucosa. The protein level in most of the cases investigated was correlated with the mRNA level. Overexpression of HGF and c-Met, at both protein and mRNA levels, was correlated with depth of invasion, lymph node metastases and overall AJCC stage. According to univariate analysis, the mean survival time was shorter in the HGF-positive and c-Met-positive groups. Multivariate Cox analysis showed that high M stage and the expression of c-Met independently had a negative impact on overall survival. Conclusions. The HGF/c-Met signaling pathway may be involved in the pathogenesis and progression of colon cancer. C-Met overexpression can be used as a useful parameter to evaluate the prognosis of colon cancer. © Il Pensiero Scientifico Editore.

Zhang M.,Peking Union Medical College | Xiong Q.,Peking Union Medical College | Chen J.,Tianjin Medical University | Wang Y.,Tianjin Medical University | And 2 more authors.
Polymer Chemistry | Year: 2013

A novel cyclodextrin-containing star polymer was synthesized by atom transfer radical polymerization using the arm-first approach. Copolymerization of a mixture of mono- and multi-methacrylate substituted cyclodextrin and 2-(dimethylamino) ethyl methacrylate initiated by poly(ethylene glycol) macroinitiator produced a core cross-linked star polymer. The star polymer could self-assemble into nanostructures via host-guest interactions between the cyclodextrin polymer and hydrophobic guest molecules. The morphologies of these nanostructures showed regular transitions by altering the type of guest molecule, the ratio of star polymer to guest, and the pH of the solution. Furthermore, doxorubicin (DOX) was entrapped into the star polymer for the purpose of drug delivery. In vitro experiments demonstrated that the DOX-loaded nanoparticles could release their payload in response to the endosomal-pH after being internalized by HeLa cell via endocytosis. At high DOX concentration, DOX-loaded nanoparticles showed significantly higher cell cytotoxicity compared to the free drug. The results indicate that the star polymer has great promise for potential anticancer treatment. © 2013 The Royal Society of Chemistry.

Zhang Q.,Tianjin Medical University | Lou S.,Tianjin Normal University | Meng Z.,Tianjin Medical University | Ren X.,Tianjin Medical University
Clinical Rheumatology | Year: 2011

Prevalence of both metabolic syndrome (MS) and hyperuricemia are increasing. However, findings regarding their relationships are inconsistent. We aimed to explore correlations between MS and hyperuricemia in a large Chinese population, emphasizing the impacts from gender and age. Data analyses were performed in 17,762 subjects randomly recruited from Tianjin municipality in China. Hyperuricemia was defined as serum uric acid (SUA) >420 μmol/L for men, >360 μmol/L for women. MS was diagnosed by the consensus criterion released in 2009 from a joint collaboration between American Heart Association and other organizations. MS was also diagnosed by Chinese Diabetes Society (CDS) criterion. Total hyperuricemic prevalence was 12.16%, with male significantly higher than female. Total MS prevalence by consensus criterion was much higher than by CDS criterion (25.56% versus 14.09%). Correlation coefficients were much greater in women than in men. SUA was significantly positively related with body mass index and waist circumference. Generally, binary logistic regression models disclosed females with high SUA were twice likely to suffer from MS than males. Young females (≤44 years old) with hyperuricemia had the highest odd ratio of 7.857 by consensus criterion; and after further adjustment by body mass index, this odd ratio was 3.040. SUA and MS were much more closely related in females than in males. Young women with hyperuricemia had the highest risk of MS. © 2010 Clinical Rheumatology.

Doiron B.,University of Texas Health Science Center at San Antonio | Hu W.,University of Texas Health Science Center at San Antonio | Hu W.,Tianjin Medical University | Norton L.,University of Texas Health Science Center at San Antonio | Defronzo R.A.,University of Texas Health Science Center at San Antonio
Diabetologia | Year: 2012

Aims/hypothesis: The physiological significance of growth factor receptor-bound protein-10 (GRB10) in the pancreas is unclear. We hypothesised that GRB10 is involved in pancreatic apoptosis, as GRB10 binds with a family of cell-survival-related proteins implicated in apoptosis. Methods: Lentiviral vector small hairpin RNA (shRNA) targeting Grb10 was injected in vivo via an intraductal pancreatic route to target pancreatic tissues in adult mice, which were studied 2 weeks post-injection. Results: Using the TUNEL assay, we demonstrated for the first time that in vivo injection of lentivirus shRNA Grb10 directly into the adult mouse pancreas induced apoptosis in both exocrine and endocrine (alpha and beta) cells. This effect was more pronounced in alpha cells. Levels of the pro-apoptotic protein BCL2-interacting mediator of cell death (BIM) in islets was higher in lentivirus shRNA Grb10 than in lentivirus shRNA scramble mice. In the apoptotic pathway, BIM initiates apoptosis signalling, leading to activation of the caspase cascade. We propose that, when complexed with GRB10, BIM is inactive. On activation by stress signalling or, in the present study, following injection of lentivirus shRNA Grb10 into pancreas, BIM becomes unbound from GRB10 and activates the caspase cascade. Indeed, caspase-3 activity in islets was higher in the experimental than in the control group. Apoptosis induced by shRNA Grb10 resulted in a 34% decrease in fasting plasma glucagon. Mice injected with shRNA Grb10 had improved glucose tolerance despite reduced insulin secretion compared with shRNA scramble control mice. Conclusions/interpretation: GRB10 is critically involved in alpha cell survival and, as a result, plays an important role in regulating basal glucagon secretion and glucose tolerance in adult mice. © 2012 Springer-Verlag.

Niu Y.,University of Rochester | Niu Y.,Tianjin Medical University | Chang T.-M.,University of Rochester | Yeh S.,University of Rochester | And 4 more authors.
Oncogene | Year: 2010

Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells. © 2010 Macmillan Publishers Limited All rights reserved.

Deng S.X.,University of California at Los Angeles | Chen L.,Tianjin Medical University
American Journal of Ophthalmology | Year: 2015

Purpose To investigate the outcomes of Descemet membrane endothelial keratoplasty (DMEK) using prestripped donor tissue prepared by an eye bank. Design Retrospective, noncomparative case series. Methods This retrospective, noncomparative, observational study investigated the outcomes of the first 40 consecutive DMEK procedures performed by a single surgeon using prestripped tissues prepared by a single eye bank during the period September 17, 2013 to July 1, 2014. A new technique to unfold the Descemet membrane grafts using a single cannula was described. Medical records were reviewed to obtain the prestripped and poststripped endothelial cell counts (ECC), postoperative ECC, visual acuity measurements, and complications. Results Of the 43 prestripped tissues received, 40 were transplanted. The leading indications for DMEK were Fuchs endothelial corneal dystrophy (n = 28) and bullous keratopathy (n = 11). Nine DMEK procedures were performed in combination with phacoemulsification and posterior chamber intraocular lens implantation. Six patients had undergone prior glaucoma surgeries. The mean follow-up duration was 5.3 months (range, 1 week to 11 months). Preoperative spectacle-corrected visual acuity was ≤20/200 in 8 patients (20%) and ≤20/40 in 37 patients (92.5%). Primary graft failure occurred in the first case. Thirty-eight patients had improved vision postoperatively. Among the 39 patients who had successful DMEK, postoperative BCVA was ≥20/20 in 20 patients (51.2%), ≥20/25 in 30 patients (76.9%), and ≥20/40 in 34 patients (87.2%) by the last follow-up. There was no secondary graft failure. Rejection occurred in 2 patients because of self-discontinuation of topical corticosteroid. The most common complication was partial detachment requiring air injection (11 of 40 patients; 27.5%). Mean ECC loss after stripping of Descemet membrane was 3.9% (range, 6.5% gain to 14.5% loss). During the first 6 months after transplantation, the average ECC loss was 30.5% (range, 3.8%-67.4% loss). Conclusions DMEK using eye bank-prepared tissue achieved outcomes comparable to those reported for DMEK using surgeon-prepared tissue.

Wen S.,Tianjin Medical University | Wen S.,University of Rochester | Niu Y.,Tianjin Medical University | Lee S.O.,University of Rochester | And 2 more authors.
Cancer Treatment Reviews | Year: 2014

Androgen/androgen receptor (AR) signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer (PCa). Androgen deprivation therapy (ADT) with anti-androgens remains as the main treatment for later stage PCa, and it has been shown to effectively suppress PCa growth during the first 12-24. months. However, ADT eventually fails and tumors may re-grow and progress into the castration resistant stage. Recent reports revealed that AR might play complicated and even opposite roles in PCa progression that might depend on cell types and tumor stages. Importantly, AR may influence PCa progression via differential modulation of various cell deaths including apoptosis, anoikis, entosis, necrosis, and autophagic cell deaths. Targeting AR may induce PCa cell apoptosis, autophagic cell deaths and programmed necrosis, yet targeting AR may suppress cell deaths via anoikis and entosis that may potentially lead to increased metastasis. These differential functions of AR in various types of PCa cell death might challenge the current ADT with anti-androgens treatment. Further detailed dissection of molecular mechanisms by which AR modulates different PCa cell deaths will help us to develop a better therapy to battle PCa. © 2013 Elsevier Ltd.

Geng X.,Tsinghua University | Hu G.,Tsinghua University | Tian X.,Tianjin Medical University
Neurocomputing | Year: 2010

Neural spike sorting is an indispensable first step for the analysis of multiple spike train data. As it is very common that noises degrade the performance of most of the available spike sorting method, in this paper we have proposed a novel spike sorting algorithm framework which seems less susceptible to heavy noises. At first, mathematical morphology operation is used to facilitate the spike event detection process, especially in strong noisy situations. Then, multiwavelets transform is performed to the detected spike waveforms to extract discriminative features. Finally, hierarchical clustering with an outlier removal process proceeds to separate the first 10 distinguishable multiwavelets coefficients. The results show that our spike sorting method performs quite well even for the heavy noisy simulated spike data. © 2009 Elsevier B.V. All rights reserved.

Huang C.,Tohoku University | Niu K.,Tianjin Medical University | Momma H.,Tohoku University | Kobayashi Y.,Tohoku University | And 2 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2014

Background and aims: Increased levels of circulating adiponectin in the elderly cause a negative impact on physical function and health status, which suggests that circulating adiponectin may be related to skeletal muscle function. However, data on the relationship between circulating adiponectin levels and skeletal muscle function is limited. Our objective was to investigate the association between serum adiponectin levels and muscle strength in adults. Methods and results: This cross-sectional study is a part of the Oroshisho Study of adult employees in Japan from 2008 to 2011. In our study, we used data gathered in 2008-2010 that had included serum adiponectin measurements (n=1378; age, 19-83 years). From this population, 1259 subjects were evaluated for grip strength (949 men, 310 women), and 965 subjects were evaluated for leg extension power (716 men, 249 women). Multivariate linear regression analyses showed that adiponectin was associated significantly and negatively with both grip strength (β and standard error [SE]: men, -0.09 [0.01], p=0.010; women, -0.20 [0.03], kg, p=0.002) and leg extension power (men, -0.09 [0.02], p=0.014; women, -0.14 [0.07], W, p=0.032) after adjusting for age, physical activity, nutrient intake, depressive symptoms, metabolic syndrome, C-reactive protein, body mass index, and other lifestyle-related potential confounders. Conclusion: This population-based cross-sectional study indicates an inverse association between serum adiponectin levels and muscle strength in adults. Further studies are necessary to confirm this association and to clarify causality. © 2013 Elsevier B.V.

Yang D.,University of Houston | Yang D.,Thomas Jefferson University | Sun Y.,University of Houston | Sun Y.,Tianjin Medical University | And 21 more authors.
Cancer Cell | Year: 2013

Integrated genomic analyses revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth. © 2013 Elsevier Inc.

Hou S.,University of Texas Health Science Center at San Antonio | Hou S.,Tianjin Medical University | Lei L.,University of Texas Health Science Center at San Antonio | Yang Z.,University of Texas Health Science Center at San Antonio | And 3 more authors.
Journal of Bacteriology | Year: 2013

We previously reported that the Chlamydia trachomatis outer membrane complex protein B (OmcB) was partially processed in Chlamydia-infected cells. We have now confirmed that the OmcB processing occurred inside live cells during chlamydial infection and was not due to proteolysis during sample harvesting. OmcB processing was preceded by the generation of active CPAF, a serine protease known to be able to cross the inner membrane via a Sec-dependent pathway, suggesting that active CPAF is available for processing OmcB in the periplasm. In a cell-free system, CPAF activity is both necessary and sufficient for processing OmcB. Both depletion of CPAF from Chlamydia-infected cell lysates with a CPAF-specific antibody and blocking CPAF activity with a CPAF-specific inhibitory peptide removed the OmcB processing ability of the lysates. A highly purified wild-type CPAF but not a catalytic residue-substituted mutant CPAF was sufficient for processing OmcB. Most importantly, in chlamydial culture, inhibition of CPAF with a specific inhibitory peptide blocked OmcB processing and reduced the recovery of infectious organisms. Thus, we have identified OmcB as a novel authentic target for the putative chlamydial virulence factor CPAF, which should facilitate our understanding of the roles of CPAF in chlamydial biology and pathogenesis. © 2013, American Society for Microbiology.

Wang Z.,Tianjin Medical University | Gao F.,Tianjin Medical University | Men J.,Tianjin Medical University | Ren J.,Tianjin Medical University | And 2 more authors.
European Journal of Cardio-thoracic Surgery | Year: 2012

Objective: Anti-platelet therapy with aspirin is the cornerstone of treatment after coronary artery bypass grafting (CABG). Aspirin resistance describes the clinical observation of the inability of aspirin to prevent thrombotic complications or the laboratory phenomenon of absence of the effect of aspirin on platelet inhibition tests. Off-pump CABG (OPCAB) is associated with reduced platelet activation and turnover compared to on-pump surgery which may indicate that aspirin is more effective after OPCAB. Our aim was to evaluate the efficacy of aspirin and incidence of aspirin resistance in patients undergoing OPCAB. Methods: A total of 331 patients was recruited, of which 111 underwent primary OPCAB (group A) and 220 controls with ischaemic heart disease received medical therapy. Arachidonic acid-induced platelet aggregation and urinary 11-dehydro thromboxane B2 (11-dehydroTxB2) were measured at baseline and following aspirin administration on days 1, 4 and 10. A 6-month follow-up was completed in patients who developed aspirin resistance. Results: On the first postoperative day, 78 patients (70.3%) were aspirin sensitive (AS) and 33 (29.7%) were aspirin resistant (AR). Of the latter, 18 (16.2%) and five (4.5%) patients remained resistant on days 4 and 10, respectively. AR patients had significantly greater platelet aggregation and urinary 11-dehydroTxB2 levels at all time points than those in the AS group. All patients in the AR group were AS by 6 months. All controls were sensitive to aspirin with similar platelet aggregation and 11-dehydroTxB2 to those in the AS group. Conclusions: Aspirin resistance is a transient phenomenon during the early postoperative period in approximately 30% of patients undergoing OPCAB. © The Author 2011. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Li X.,Moffitt Cancer Center | Li X.,Tianjin Medical University | Gilkes D.,Moffitt Cancer Center | Li B.,Moffitt Cancer Center | And 5 more authors.
Oncogene | Year: 2012

MDMX is a heterodimeric partner of MDM2 and a critical regulator of p53. The MDMX level is generally elevated in tumors with wild-type p53 and contributes to p53 inactivation. MDMX degradation is controlled in part by MDM2-mediated ubiquitination. Here, we show that MDMX turnover is highly responsive to changes in MDM2 level in non-transformed cells, but not in tumor cells. We found that loss of alternate reading frame (ARF) expression, which occurs in most tumors with wild-type p53, significantly reduces MDMX sensitivity to MDM2. Restoration of ARF expression in tumor cells enables MDM2 to degrade MDMX in a dose-dependent manner. ARF binds to MDM2 and stimulates a second-site interaction between the central region of MDM2 and MDMX, and thus increases MDMX-MDM2 binding and MDMX ubiquitination. These results reveal an important abnormality in the p53-regulatory pathway as a consequence of ARF deficiency. Loss of ARF during tumor development not only prevents p53 stabilization by proliferative stress but also causes accumulation of MDMX that compromises p53 activity. This phenomenon may reduce the clinical efficacy of MDM2-specific inhibitors by preventing MDMX downregulation. © 2012 Macmillan Publishers Limited All rights reserved.

Xu X.-M.,Tianjin Medical University | Wang X.-B.,Tianjin Medical University | Chen M.-M.,Tianjin Medical University | Liu T.,Tianjin Medical University | And 5 more authors.
Cancer Letters | Year: 2012

MicroRNAs (miRNAs) play a key role in the regulation of gene expression. In this study, we demonstrate that microRNA-19a and -19b (miR-19a/b) are highly expressed in human cervical cancer cells and are involved in maintaining the malignant phenotypes of HeLa and C33A cells. Up-regulation of miR-19a and miR-19b promoted cell growth and invasion, whereas knockdown of miR-19a and miR-19b yielded the reverse phenotype. CUL5 was identified as a novel target gene of both miR-19a and miR-19b. CUL5 ectopic over-expression without its 3' untranslated region (UTR) abolished the effect of miR-19a/b on HeLa and C33A cell proliferation and invasion. These results indicated that miR-19a/b directly and negatively regulate CUL5 expression in cervical cancer cells, highlighting the importance of miR-19a and miR-19b and their target genes in tumorigenesis. © 2012 Elsevier Ireland Ltd.

Liu Y.,University of Texas Health Science Center at San Antonio | Liu Y.,Tianjin Medical University | Chen C.,University of Texas Health Science Center at San Antonio | Gong S.,University of Texas Health Science Center at San Antonio | And 5 more authors.
Journal of Bacteriology | Year: 2014

Transformation of Chlamydia trachomatis should greatly advance the chlamydial research. However, significant progress has been hindered by the failure of C. trachomatis to induce clinically relevant pathology in animal models. Chlamydia muridarum, which naturally infects mice, can induce hydrosalpinx in mice, a tubal pathology also seen in women infected with C. trachomatis. We have developed a C. muridarum transformation system and confirmed Pgp1,-2,-6, and-8 as plasmid maintenance factors, Pgp3,-5, and-7 as dispensable for in vitro growth, and Pgp4 as a positive regulator of genes that are dependent on plasmid for expression. More importantly, we have discovered that Pgp5 can negatively regulate the same plasmid-dependent genes. Deletion of Pgp5 led to a significant increase in expression of the plasmid-dependent genes, suggesting that Pgp5 can suppress the expression of these genes. Replacement of pgp5 with a mCherry gene, or premature termination of pgp5 translation, also increased expression of the plasmid-dependent genes, indicating that Pgp5 protein but not its DNA sequence is required for the inhibitory effect. Replacing C. muridarum pgp5 with a C. trachomatis pgp5 still inhibited the plasmid-dependent gene expression, indicating that the negative regulation of plasmid-dependent genes is a common feature of all Pgp5 regardless of its origin. Nevertheless, C. muridarum Pgp5 is more potent than C. trachomatis Pgp5 in suppressing gene expression. Thus, we have uncovered a novel function of Pgp5 and developed a C. muridarum transformation system for further mapping chlamydial pathogenic and protective determinants in animal models. © 2014, American Society for Microbiology.

Osorio-Fuentealba C.,University of Chile | Contreras-Ferrat A.E.,University of Chile | Altamirano F.,University of Chile | Espinosa A.,University of Chile | And 7 more authors.
Diabetes | Year: 2013

Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. © 2013 by the American Diabetes Association.

Qi M.,University of Texas Health Science Center at San Antonio | Qi M.,Tianjin Medical University | Gong S.,University of Texas Health Science Center at San Antonio | Lei L.,University of Texas Health Science Center at San Antonio | And 2 more authors.
Infection and Immunity | Year: 2011

The Chlamydia trachomatis outer membrane complex protein B (OmcB) is an antigen with diagnostic and vaccine relevance. To further characterize OmcB, we generated antibodies against OmcB C-terminal (OmcBc) and N-terminal (OmcBn) fragments. Surprisingly, the anti-OmcBc antibody detected dominant signals in the host cell cytosol, while the anti-OmcBn antibody exclusively labeled intrainclusion signals in C. trachomatisinfected cells permeabilized with saponin. Western blot analyses revealed that OmcB was partially processed into OmcBc and OmcBn fragments. The processed OmcBc was released into host cell cytosol, while the OmcBn and remaining full-length OmcB were retained within the chlamydial inclusions. The organism-associated OmcB epitopes became detectable only after the C. trachomatis-infected cells were permeabilized with strong detergents such as SDS. However, the harsh permeabilization conditions also led to the leakage of the already secreted OmcBc and chlamydia-secreted protease (CPAF) out of the host cells. The OmcBc processing and release occurred in all biovars of C. trachomatis. Moreover, the released OmcBc but not the retained OmcBn was highly immunogenic in C. trachomatis-infected women, which is consistent with the concept that exposure of chlamydial proteins to host cell cytosol is accompanied by increased immunogenicity. These observations have provided important information for further exploring/optimizing OmcB as a target for the development of diagnosis methods and vaccines. © 2011, American Society for Microbiology.

Yang R.,Tianjin Medical University | Yeh A.,Wang Vision Cataract and Center | George M.R.,Tylock Eye Care and Laser Center | Rahman M.,University of Tennessee at Knoxville | And 2 more authors.
Journal of Cataract and Refractive Surgery | Year: 2013

Purpose: To compare the accuracy of intraocular lens (IOL) power calculation methods for post-myopic excimer laser surgery patients without previous refractive surgery data using the Holladay IOL Consultant Program and the American Society of Cataract and Refractive Surgery (ASCRS) IOL Power Calculator. Setting: Wang Vision Cataract and LASIK Center, Nashville, Tennessee, USA. Design: Case series. Methods: Eight methods were used to calculate IOL power: Holladay 2 partial coherence interferometry (PCI)-K, Holladay 2 FlatK, Wang-Koch-Maloney, Shammas No-History, Haigis-L, ASCRS-Average, ASCRS-Min, and ASCRS-Max. The optimum IOL power corresponding to the target refraction was back-calculated using the stable post-cataract surgery refraction and implanted IOL power. Using the optimum IOL power, the predicted IOL power error and the resultant refractive error with each method were calculated and compared. Results: The Holladay 2 FlatK method was most accurate for IOL power calculation, followed by the Holladay 2 PCI-K, ASCRS-Min, Wang-Koch-Maloney, ASCRS-Average, Shammas No-History, Haigis-L, and ASCRS-Max. Statistically significant differences were observed between Holladay 2 FlatK and Holladay 2 PCI-K (P<.05), Wang-Koch-Maloney and ASCRS-Average (P<.05), and Haigis-L and ASCRS-Max (P<.01). No statistically significant differences were observed between the Holladay 2 PCI-K, ASCRS-Min, and Wang-Koch-Maloney or between the ASCRS-Average, Shammas No-History, and Haigis-L (both P>.05). Conclusions: The Holladay 2 FlatK method provided the most accurate IOL power in eyes without previous myopic laser surgery data. If the Holladay IOL Consultant Program is unavailable, the ASCRS methods can be used; the ASCRS-Min represents the most accurate method. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2013 ASCRS and ESCRS Published by Elsevier Inc.

Su S.,Sun Yat Sen University | Liu Q.,Sun Yat Sen University | Chen J.,Sun Yat Sen University | Chen J.,Guangzhou Medical College | And 13 more authors.
Cancer Cell | Year: 2014

The close vicinity of cancer cells undergoing epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) at the invasive front of tumors suggests that these two cell type may mutually interact. We show that mesenchymal-like breast cancer cells activate macrophages to a TAM-like phenotype by GM-CSF. Reciprocally, CCL18 from TAMs induces cancer cell EMT, forming a positive feedback loop, in coculture systems and humanized mice. Inhibition of GM-CSF or CCL18 breaks this loop and reduces cancer metastasis. High GM-CSF expression in breast cancer samples is associated with more CCL18+ macrophages, cancer cell EMT, enhanced metastasis, and reduced patient survival. These findings suggest that a positive feedback loop between GM-CSF and CCL18 is important in breast cancer metastasis. © 2014 Elsevier Inc.

Luo M.,Tianjin Medical University | Li L.,Tianjin Medical University | Lu C.-Z.,Tianjin Infection Disease Hospital | Cao W.-K.,Tianjin Infection Disease Hospital
European Journal of Gastroenterology and Hepatology | Year: 2011

OBJECTIVE: To evaluate the clinical efficacy of lactulose in patients with minimal hepatic encephalopathy (MHE). METHODS: Randomized controlled trials (RCTs) comparing lactulose with placebo or with no intervention in the management of MHE that were conducted from January 1990 to July 2011 were searched from MEDLINE, EMBASE, SCI, Cochrane Controlled Trials Register, and China Biological Medicine Database. Studies with a Jadad score higher than 3 were included in the meta-analysis and evaluated using RevMan5.0 software for relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (95% CI). Sensitivity analysis was performed on the ethnical differences and quality of the trials. Publication bias was observed using an inverted funnel plot. RESULTS: Nine studies with 434 patients were included in the meta-analysis. Compared with placebo or no intervention, lactulose significantly reduced the risk of no improvement in neuropsychological tests (RR: 0.52, 95% CI: 0.44-0.62, P<0.00001), the time required for the completion of the number connection test-A (WMD:-26.95, 95% CI:-37.81 to-16.10, P<0.00001), and the mean number of abnormal neuropsychological tests (WMD:-1.76, 95% CI:-1.96 to-1.56, P<0.00001). Furthermore, the meta-analysis also showed that lactulose prevented the progression to overt hepatic encephalopathy (RR: 0.17, 95% CI: 0.06-0.52, P=0.002), reduced blood ammonia levels (WMD:-9.89 μmol/l, 95% CI:-11.01 to-8.77 μmol/l, P<0.00001), and improve health-related quality of life (WMD:-6.05, 95% CI:-6.30 to-5.20, P<0.00001). However, no significant difference was observed in the mortality of patients with MHE (RR: 0.75, 95% CI: 0.21-2.72, P=0.66), and lactulose significantly increased the incidence of diarrhea (RR: 4.38, 95% CI: 1.35-14.25, P=0.01). CONCLUSION: Lactulose has significant beneficial effects for patients with MHE compared with placebo or no intervention. © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins.

Yan Y.,Tianjin Medical University | Luo Y.-C.,Tianjin Medical University | Wan H.-Y.,Tianjin Medical University | Wang J.,Sun Yat Sen University | And 5 more authors.
Hepatology | Year: 2013

MicroRNAs (miRNAs) have been reported to be associated with the development of cancers. However, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. Here we found that overexpression of miR-10a promoted the migration and invasion of QGY-7703 and HepG2 cells in vitro but suppressed metastasis in vivo. Cell adhesion assays showed that miR-10a suppressed HCC cell-matrix adhesion, which could explain the results of the in vivo animal experiments. The Eph tyrosine kinase receptor, EphA4, was identified as the direct and functional target gene of miR-10a. Knockdown of EphA4 phenocopied the effect of miR-10a and ectopic expression of EphA4 restored the effect of miR-10a on migration, invasion, and adhesion in HCC cells. We further demonstrated that miR-10a and EphA4 regulated the epithelial-mesenchymal transition process and the β1-integrin pathway to affect cell invasion and adhesion. Conclusion: Our findings highlight the importance of miR-10a in regulating the metastatic properties of HCC by directly targeting EphA4 and may provide new insights into the pathogenesis of HCC. © 2012 American Association for the Study of Liver Diseases.

Zhang T.,Tianjin Medical University | Zhang T.,Yale University | Pang C.,Tianjin Cancer Institute and Hospital | Li N.,Tianjin Medical University | And 2 more authors.
BMC Medicine | Year: 2013

Background: Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes.Methods: Data were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations.Results: Nine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57).Conclusions: The present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10 years) indicated a gene-environment interaction in determining the risk of diabetic retinopathy. © 2013 Zhang et al; licensee BioMed Central Ltd.

Zhang X.,Tianjin Medical University | Zhang X.,Key laboratory of breast cancer prevention and therapy of ministry of education | Zhang X.,Key laboratory of cancer prevention and therapy in Tianjin | Li X.-r.,Chinese People's Liberation Army | And 3 more authors.
Current Cancer Drug Targets | Year: 2013

The PI3K/Akt/mTOR signaling pathway is involved in the inhibition of tumor cell apoptosis, the promotion of cell survival, cell cycle regulation, tumor angiogenesis, invasion, and metastasis and therefore plays an important role in tumorigenesis, tumor growth, patient prognosis, and tumor treatment. Recent studies have identified this signaling pathway in breast cancer, and the PI3K/Akt/mTOR pathway is therefore being considered as a new therapeutic target and a hotspot in breast cancer research. Pre-clinical studies have confirmed that PI3K inhibitors and mTOR inhibitors achieve anticancer effects by targeting different levels of the PI3K/Akt/mTOR signaling pathway. Among the PI3K inhibitors, some molecules target only PI3K, whereas others target both PI3K and mTOR. Currently, researchers tend to focus on molecular targets based on the different PI3K subtypes to achieve more targeted and specific inhibition of the PI3K pathway. However, the clinical efficacy and efficiency of these inhibitors need to be further studied. The mTOR inhibitors target mTORC1 and have become relatively well-developed targeted therapies for the PI3K/AKT/mTOR pathway. Rapamycin derivatives have been studied in Phase II / III clinical trials in breast cancer, and these derivatives achieved positive results in the treatment of metastatic breast cancer when combined with endocrine therapy or HER2-targeted therapies. This review summarizes the activation of the PI3K/AKT/mTOR pathway, its role in breast cancer, and the latest clinical trials of a variety of PI3K and mTOR inhibitors to improve the understanding of the role of these drugs in breast cancer treatment. © 2013 Bentham Science Publishers.

Xu S.,Tongji University | Fu G.-B.,Nanjing Medical University | Tao Z.,Tianjin Medical University | OuYang J.,Nanjing Medical University | And 5 more authors.
Oncotarget | Year: 2015

The mechanism of cisplatin resistance in ovarian cancer is not clearly understood. In the present investigation, we found that the expression levels of miR-497 were reduced in chemotherapy-resistant ovarian cancer cells and tumor tissues due to hypermethylation of miR-497 promoter. Low miR-497 expression levels were associated with chemo-resistant phonotype of ovarian cancer. By analyzing the expression levels of miR-497, mTOR and p70S6K1 in a clinical gene-expression array dataset, we found that mTOR and p70S6K1, two proteins correlated to chemotherapyresistance in multiple types of human cancers, were inversely correlated with miR-497 levels in ovarian cancer tissues. By using an orthotopic ovarian tumor model and a Tet-On inducible miR-497 expression system, our results demonstrated that overexpression of miR-497 sensitizes the resistant ovarian tumor to cisplatin treatment. Therefore, we suggest that miR-497 might be used as a therapeutic supplement to increase ovarian cancer treatment response to cisplatin.

Liu R.,Barrow Neurological Institute | Zhou Q.,Tianjin Medical University | La Cava A.,University of California at Los Angeles | Campagnolo D.I.,Barrow Neurological Institute | And 3 more authors.
European Journal of Immunology | Year: 2010

Human autoimmune diseases are often characterized by a relative deficiency in CD4+CD25+ regulatory T cells (Treg). We therefore hypothesized that expansion of Treg can ameliorate autoimmune pathology. We tested this hypothesis in an experimental model for autoimmune myasthenia gravis (MG), a B-cell-mediated disease characterized by auto-Ab directed against the acetylcholine receptorwithin neuromuscular junctions.We showed that injection of immune complexes composed of the cytokine IL-2 and anti-IL-2 mAb (JES6-1A12) induced an effective and sustained expansion of Treg, via peripheral proliferation of CD4+CD25+Foxp3+ cells and peripheral conversion of CD4+CD25-Foxp3- cells. The expanded Treg potently suppressed autoreactive T- and B-cell responses to acetylcholine receptor and attenuated themuscular weakness that is characteristic ofMG. Thus, IL-2/anti-IL-2 mAb complexes can expand functional Treg in vivo, providing a potential clinical application of this modality for treatment of MG and other autoimmune disorders. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Li S.-Y.,Tianjin Medical University | Xu Y.-W.,Sun Yat Sen University | Liu J.-M.,Sun Yat Sen University | Su C.-Y.,Sun Yat Sen University
International Journal of Molecular Sciences | Year: 2011

Inherently chiral calixarenes, whose chirality is based on the absence of a planar symmetry or an inversion center in the molecules as a whole through the asymmetric array of several achiral groups upon the three-dimensional calix-skeletons, are challenging and attractive chiral molecules, because of their potential in supramolecular chemistry. The synthesis and optical resolution of all varieties of inherently chiral calixarenes are systematically discussed and classified, and their applications in chiral recognition and asymmetric catalysis are thoroughly illustrated in this review. © 2010 by the authors; licensee MDPI, Basel, Switzerland.

Liu Q.,Tianjin Medical University | Liu Q.,Barrow Neurological Institute | Sanai N.,Barrow Neurological Institute | Jin W.-N.,Tianjin Medical University | And 5 more authors.
Nature Neuroscience | Year: 2016

Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair. © 2016 Nature America, Inc. All rights reserved.

Hao J.,Tianjin Medical University | Hao J.,Barrow Neurological Institute | Hao J.,Nankai University | Liu R.,Barrow Neurological Institute | And 9 more authors.
Journal of Experimental Medicine | Year: 2010

Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention. © 2010 Hao et al.

He Q.,Louisiana State University | He Q.,Tianjin Medical University | Gao Z.,Louisiana State University | Yin J.,Louisiana State University | And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

The transcription factor HIF-1α activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter. © 2011 the American Physiological Society.

Wen S.,Tianjin Medical University | Shang Z.,Tianjin Medical University | Zhu S.,Tianjin Medical University | Chang C.,Tianjin Medical University | And 2 more authors.
Prostate | Year: 2013

BACKGROUND Cell-in-cell phenomenon has been found for more than a century. Entosis, which is a newly found homogeneous cell-in-cell phenomenon and a non-apoptosis cell death progress, has unclear function in prostate cancer progression. Here, we dissected mechanism of AR signaling related to entosis incidence in PCa progression. METHODS Two stable PCa cell lines, named LNCaP-ARsi and C4-2-ARsi were established with stably transfected AR-shRNA to knockdown AR mRNA expression in LNCaP and C4-2 cells, respectively. PC3-AR9 cell line was also established after stably transfecting full-length AR-cDNA into PC3 cells. All these cells were cultured in poly-HEME-coated plates to induce entosis, which is demonstrated via double staining. RESULTS Androgen-DHT could enhance entosis in LNCaP, C4-2 and PC3-AR9 PCa cells in a dose dependent manner. Knock-down of AR in LNCaP and C4-2 significantly suppressed entosis as compared to LNCaP-ARsc and C4-2-ARsc cells at both 1 and 10 nM DHT condition (P < 0.05). And suppression of Rho/ROCK expression resulted in interruption of AR-mediated entosis. Human PCa samples surveys demonstrated that entosis was found only in CRPC but not in BPH and ADPC where AR was less expressed as compared to CRPC. CONCLUSIONS These results indicated that AR might play a negative role during PCa progression via influencing entosis by modulating Rho/ROCK pathway. This newly identified AR role of enhancing entosis might help us to better understand the multiple and opposite roles of AR, which could either promote or suppress PCa cell progression via different mechanisms. Copyright © 2013 Wiley Periodicals, Inc.

Song F.,Tianjin Medical University | Yang D.,University of Houston | Liu B.,Tianjin Medical University | Guo Y.,Tianjin Medical University | And 11 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Our aim was to investigate whether microRNAs can predict the clinical outcome of patients with gastric cancer. We used integrated analysis of microRNA and mRNA expression profiles to identify gastric cancer microRNA subtypes and their underlying regulatory scenarios. Experimental Design: MicroRNA-based gastric cancer subtypes were identified by consensus clustering analysis of microRNA profiles of 90 gastric cancer tissues. Activated pathways in the subtypes were identified by gene expression profiles. Further integrated analysis was conducted to model a microRNA regulatory network for each subtype. RNA and protein expression were analyzed by RT-PCR and tissue microarray, respectively, in a cohort of 385 gastric cancer cases (including the 90 cases for profiling) to validate the key microRNAs and targets in the network. Both in vitro and in vivo experiments were carried out to further validate the findings. Results: MicroRNA profiles of 90 gastric cancer cases identified two microRNA subtypes significantly associated with survival. The poor-prognosis gastric cancer microRNA subtype was characterized by overexpression of epithelial-to-mesenchymal transition (EMT) markers. This gastric cancer "mesenchymal subtype" was further validated in a patient cohort comprising 385 cases. Integrated analysis identified a key microRNA regulatory network likely driving the gastric cancer mesenchymal subtype. Three of the microRNAs (miR-200c, miR-200b, and miR-125b) targeting the most genes in the network were significantly associated with survival. Functional experiments demonstrated that miR-200b suppressed ZEB1, augmented E-cadherin, inhibited cell migration, and suppressed tumor growth in a mouse model. Conclusions: We have uncovered a key microRNA regulatory network that defines the mesenchymal gastric cancer subtype significantly associated with poor overall survival in gastric cancer. © 2014 American Association for Cancer Research.

Gao R.,Tianjin Medical University | Cai C.,Tianjin Medical University | Gan J.,Tianjin Medical University | Yang X.,Tianjin Medical University | And 4 more authors.
Oncotarget | Year: 2015

Alpha fetoprotein (AFP) is a clinical biomarker of hepatocellular carcinoma (HCC). Here, we found that miR-1236 is down-regulated, whereas AFP is highly expressed in HCC tissues and cells. We demonstrated that miR-1236 directly targets the 3'UTR of AFP and down-regulates its expression. Also, miR-1236 inhibited and AFP stimulated proliferation, migration, invasion and vasculogenic mimicry (VM) of HCC. In agreement, AFP over-expression counteracted the inhibitory effect of miR-1236. We demonstrated that AFP promoted the ubiquitination of PTEN, thus decreasing PTEN levels, while miR-1236 inhibited the PI3K/Akt pathway.

Zhang S.,CAS Research Center for Eco Environmental Sciences | Zhang S.,Massachusetts Institute of Technology | Chen Y.,CAS Research Center for Eco Environmental Sciences | Chen Y.,Tianjin Medical University | And 7 more authors.
Cellular Signalling | Year: 2014

Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth. © 2014 Elsevier Inc.

Yang X.,Jilin University | Yang B.,Tianjin Medical University | Li B.,Jilin University | Liu Y.,Jilin University
Archives of Dermatological Research | Year: 2013

Single-nucleotide polymorphism of CLPTM1L-rs401681(C > T) at the 5p15.33 locus is significantly associated with cancer risk as reported in genome-wide association studies, but the reported studies for non-melanoma skin cancer (NMSC) are inconclusive. To assess the association between rs401681[C] allele and NMSC risk, we performed this meta-analysis with four case-control studies involving 5,469 cases and 39,715 controls. Our meta-analysis showed that rs401681[C] allele was associated with NMSC susceptibility in the overall subjects (C vs. T, OR 1.13, 95 % CI 1.07-1.20). In the stratified analysis, the rs401681[C] allele confers susceptibility in Icelanders (C vs. T, OR 1.15, 95 % CI 1.06-1.26) and non-Icelanders (C vs. T, OR 1.13, 95 % CI 1.03-1.24). In the subtype analysis, we found that rs401681[C] allele was a risk factor for BCC, but not SCC in the overall subjects. © 2012 Springer-Verlag.

Chen X.,Guangzhou University | Guo Z.,Guangdong Women and Children Hospital | Wang P.,Tianjin Medical University | Xu M.,Guangzhou University
Heart Lung and Circulation | Year: 2014

Background: Doxorubicin (DOX) is a highly effective anti-cancer drug with limited clinical use due to its serious cardiotoxicity. Recent studies reported that erythropoietin (EPO) could exert a cardioprotective effect by non-erythropoietic effects. This study was to investigate fibrosis of DOX-induced cardiotoxicity and determine mechanisms of EPO against extracellular matrix (ECM) remodelling. Methods: Rats were grouped as the control group, the DOX group and the DOX+EPO group. DOX (2.5. mg/kg/dose, six doses for two weeks) was administered to induce cardiotoxicity by intraperitoneal injections in the DOX group and the DOX+EPO group, and EPO (2500U/kg/dose, six doses for two weeks) was administered simultaneously in the DOX+EPO group. Two weeks after the last administration, rats were killed with cardiac tissues used for histological analyses and immunological detections for matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2). Results: Rats treated with DOX showed degenerative changes with cardiac fibrosis. Compared to the control group, the expression of MMP-2 was up-regulated whereas that of TIMP-2 was down-regulated in the DOX group. EPO administration improved cardiac fibrosis, decreased MMP-2 expression, increased TIMP-2 expression and ameliorated imbalance of MMP-2/TIMP-2 ratio. Conclusions: The present study suggests that EPO can exert a cardioprotective effect on DOX-induced cardiotoxicity which may be associated with improving MMP-2/TIMP-2 imbalance. © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).

Liu B.,CAS Institute of Automation | Zhang X.,CAS Institute of Automation | Hou B.,CAS Institute of Automation | Li J.,CAS Institute of Automation | And 6 more authors.
Neuropsychopharmacology | Year: 2014

A recent mega-analysis combining genome-wide association study data revealed that a variant of microRNA 137 (MIR137) exhibits the most significant association with schizophrenia. Other biological evidence also consistently suggests that MIR137 may have a pivotal role in the pathogenesis of schizophrenia. However, the underlying neural mechanism remains unclear. As the disrupted dorsolateral prefrontal cortex (DLPFC) coupling with the hippocampal formation (HF) has been widely observed in schizophrenia patients, DLPFC-HF dysconnectivity can therefore be thought of as a pivotal intermediate phenotype that links genetic variants of psychiatric risk genes to schizophrenia. This study used resting-state functional magnetic resonance imaging to test whether the MIR137 variant (rs1625579) impacts DLPFC-HF functional connectivity and cognitive performance in 290 young, healthy Han Chinese individuals. To identify functional connectivity between DLPFC and HF, a seed-based functional connectivity analysis was used. The association between DLPFC-HF connectivity and working memory performance was further examined in individuals with different MIR137 genotypes. The individuals who are homozygous for the MIR137 risk allele (TT), which confers a high risk for schizophrenia, exhibited significantly different DLPFC-HF functional connectivity compared with TG individuals. Moreover, the DLPFC-HF connectivity could predict the working memory performance in MIR137 TG individuals, but not in TT individuals. The current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking MIR137 with the risk of developing schizophrenia via the intermediate phenotype of DLPFC-HF connectivity. © 2014 American College of Neuropsychopharmacology. All rights reserved.

Fan L.,CAS Institute of Automation | Wang J.,University of Electronic Science and Technology of China | Zhang Y.,CAS Institute of Automation | Han W.,Tianjin Medical University | And 4 more authors.
Cerebral Cortex | Year: 2014

The temporal pole (TP) is an association cortex capable of multisensory integration and participates in various high-order cognitive functions. However, an accepted parcellation of the human TP and its connectivity patterns have not yet been well established. Here, we sought to present a scheme for the parcellation of human TP based on anatomical connectivity and to reveal its subregional connectivity patterns. Three distinct subregions with characteristic fiber pathways were identified, including the dorsal (TAr), the medial (TGm), and lateral (TGl) subregions, which are located ventrally. According to the connectivity patterns, a dorsal/ventral sensory segregation of auditory and visual processing and the medial TGm involved in the olfactory processing were observed. Combined with the complementary resting-state functional connectivity analysis, the connections of the TGm with the orbitofrontal cortex and other emotion-related areas, the TGl connections with the MPFC and major default mode network regions, and the TAr connections with the perisylvian language areas were observed. To the best of our knowledge, the present study represents the first attempt to parcel the human TP based on its anatomical connectivity features, which may help to improve our understanding of its connectional anatomy and to extend the available knowledge in TP-related clinical research. © The Author 2013. Published by Oxford University Press. All rights reserved.

Ma X.-L.,Tianjin Hospital | Sun X.-L.,Tianjin Hospital | Wan C.-Y.,Tianjin Hospital | Ma J.-X.,Tianjin Medical University | Tian P.,Tianjin Hospital
Journal of Orthopaedic Research | Year: 2012

Fracture healing is a complex bone formation process, and neovascularization may contribute to new bone regeneration. The circulating endothelial progenitor cell (EPC) mobilization and homing could involve in neovascularization and vasculogenesis. In this study, we investigate the changes of circulating EPC during bone fracture healing, and the possible contribution of EPCs to increased neovascularization and fracture healing. The number of circulating EPCs was monitored in twenty-four patients with long bone traumatic fracture within the first 48 h and at 3, 5, 10, and 14 days post-fracture. The mononuclear cells which isolated from peripheral blood were analyzed by flow cytometry. Peripheral blood counts of leukocytes and platelets were measured by hematology analyzer. The amount of peripheral EPCs significantly increased in patients with fracture compared to age-matched healthy control subjects within the first 48 h after injury, and peaked at 3 days post-fracture. There was no significant difference in the change trend of early EPCs between male and female, but the number of early EPCs was significantly greater in younger patients compared to older patients. A comparison of the EPCs levels between patients with severe injury (ISS > 16) and patients with mild injury (ISS ≤ 16) revealed no statistically significant difference. The level of early EPCs was inverse correlation with the level of plate after fracture, but no correlation with the level of peripheral leucocytes. These findings suggest traumatic fracture may induce the mobilization of EPCs into the peripheral circulation. The increased EPCs may contribute to neovascularization and involve in fracture healing. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1860-1866, 2012.

Thorn D.A.,State University of New York at Buffalo | Jing L.,State University of New York at Buffalo | Jing L.,Tianjin Medical University | Qiu Y.,State University of New York at Buffalo | And 5 more authors.
Neuropsychopharmacology | Year: 2014

Animal knockout studies suggest that trace amine-associated receptor (TAAR) 1 is involved in behavioral effects of psychostimulants such as cocaine. Recently, several highly selective TAAR 1 agonists have been discovered. However, little is known of the impact of TAAR 1 agonists on abuse-related effects of cocaine. Here, we report the effects of a TAAR 1 agonist RO5263397 on several abuse-related behavioral effects of cocaine in rats. RO5263397 was evaluated for its effects on cocaine-induced behavioral sensitization, conditioned place preference (CPP), cue- and cocaine prime-induced reinstatement of cocaine-seeking behavior, and cocaine self-administration using behavioral economic analysis. RO5263397 reduced the expression of cocaine behavioral sensitization, cue- and cocaine prime-induced reinstatement of cocaine seeking, and expression but not development of cocaine CPP. Behavioral economic analysis showed that RO5263397 increased the elasticity of the cocaine demand curve, but did not change cocaine consumption at minimal prices. Taken together, this is the first systematic assessment of a TAAR 1 agonist on a range of behavioral effects of cocaine, showing that RO5263397 was efficacious in reducing cocaine-mediated behaviors. Collectively, these data uncover essential neuromodulatory roles of TAAR 1 on cocaine abuse, and suggest that TAAR 1 may represent a novel drug target for the treatment of cocaine addiction. © 2014 American College of Neuropsychopharmacology.

Yang F.,Tianjin Medical University | Chu X.,Tianjin Hospital | Yin M.,Tianjin Huanhu Hospital | Liu X.,Tianjin Medical University | And 3 more authors.
Behavioural Brain Research | Year: 2014

Defect of autophagy is common to many neurodegenerative disorders because it serves as a major degradation pathway for the clearance of various aggregate-prone proteins. Mammalian target of rapamycin (mTOR) signaling, which is recognized as the most important negative regulator of autophagy, is also involved in neurodegenerative diseases. However, the role of mTOR and its dependent autophagy in normal brain during aging remains unknown. Furthermore, caloric restriction (CR) is frequently used as a tool to study mechanisms behind aging and age-associated diseases because CR can prevent age-related diseases and prolong lifespan in several model organisms. Inhibiting mTOR and promoting autophagy activity play roles in aging delayed by CR. However, whether CR can ameliorate age-related cognition deficits by inhibiting mTOR and activate autophagy in hippocampus needs to be further investigated. Here we showed a decline of autophagic degradation in mice hippocampus in correlation with age-dependent cognitive dysfunction, whereas the activity of mTOR and its upstream brain-derived neurotrophic factor (BDNF)/phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was decreased with aging. In addition, facilitating the mTOR pathway successfully declines and sustains autophagic degradation with aging in hippocampus by CR treatment and is involved in CR by ameliorating age-related cognitive deficits. © 2014 Elsevier B.V.

Shen C.,Hebei Medical University | Zhao C.-Y.,Hebei Medical University | Zhang R.,Tianjin Medical University | Qiao L.,University of Sydney
Frontiers in Bioscience | Year: 2012

Epidemiological data have demonstrated that the prevalence of either obesity or hepatocellular carcinoma (HCC) is increasing worldwide during past decades, and obesity has been unequivocally shown to be a risk factor for HCC. It has been reported that a significant proportion of HCC in obesity develops in cryptogenic cirrhosis, which is largely associated with the progression of nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis. Since the HCC is a highly malignant tumor with a poor prognosis, a better understanding of the molecular mechanisms may help researchers to explore new approaches for preventing and treating the obesity-related HCC, and thereby facilitating a substantial reduction of morbidity and mortality. In this article, we reviewed the mechanisms underlying the relationship between obesity and HCC, with an emphasis on the roles of insulin/insulinlike growth factor axis, adipose tissue derived hormones, oxidative stress, and liver stem cells. In addition, we will discuss the impact of life-style modification on obesityrelated HCC.

Zhao J.-G.,Tianjin Hospital | Zhao J.-G.,Tianjin Medical University | Wang J.,Tianjin Hospital | Wang J.,Tianjin Medical University | Zhang P.,Soochow University of China
Clinical Orthopaedics and Related Research | Year: 2013

Background: Closed reduction and percutaneous pin fixation is considered standard management for displaced supracondylar fractures of the humerus in children. However, controversy exists regarding whether to use an isolated lateral entry or a crossed medial and lateral pinning technique. Questions/purposes: We performed a meta-analysis of randomized controlled trials (RCTs) to compare (1) the risk of iatrogenic ulnar nerve injury caused by pin fixation, (2) the quality of fracture reduction in terms of the radiographic outcomes, and (3) function in terms of criteria of Flynn et al. and elbow ROM, and other surgical complications caused by pin fixation. Methods: We searched PubMed, Embase, the Cochrane Library, and other unpublished studies without language restriction. Seven RCTs involving 521 patients were included. Two authors independently assessed the methodologic quality of the included studies with use of the Detsky score. The median Detsky quality score of the included trials was 15.7 points. Dichotomous variables were presented as risk ratios (RRs) or risk difference with 95% confidence intervals (CIs) and continuous data were measured as mean differences with 95% CI. Statistical heterogeneity between studies was formally tested with standard chi-square test and I 2 statistic. For the primary objective, a funnel plot of the primary end point and Egger's test were performed to detect publication bias. Results: The pooled RR suggested that iatrogenic ulnar nerve injury was higher with the crossed pinning technique than with the lateral entry technique (RR, 0.30; 95% CI, 0.10-0.89). No publication bias was further detected. There were no statistical differences in radiographic outcomes, function, and other surgical complications. No significant heterogeneity was found in these pooled results. Conclusions: We conclude that the crossed pinning fixation is more at risk for iatrogenic ulnar nerve injury than the lateral pinning technique. Therefore, we recommend the lateral pinning technique for supracondylar fractures of the humerus in children. Level of Evidence: Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. © 2013 The Association of Bone and Joint Surgeons®.

Wang F.,Tianjin Medical University | Chang G.-M.,Tianjin Medical University | Yu Q.,Tianjin Medical University | Geng X.,Tianjin Medical University | Geng X.,Tianjin Key Laboratory of Cellular and Molecular Immunology
Journal of Molecular Neuroscience | Year: 2015

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that could interfere cortical excitability though brief electric currents induced by alternating magnetic fields from the inductive coil. Currently, it has been applied in many fields of basic and clinical neuro-research. The aims of the present study are to investigate the effect of rTMS pre-treatment on cognitive function in vascular dementia (VaD) rats and further explore the molecular mechanism of rTMS neuroprotection on VaD. We found that rTMS pre-treated VaD rats showed significantly better memory and learning abilities in Morris water maze test compared to the untreated group. Moreover, the mRNA and protein expression levels of BDNF, TrkB, and SYN were significantly higher in the rTMS pre-treated group, indicating that rTMS pre-treatment has neuroprotective effect for VaD, which may have resulted from the increased level of BDNF, TrkB, and SYN in the hippocampal CA1 area. © 2015, Springer Science+Business Media New York.

Wang F.,Tianjin Peoples Hospital | Liu J.,Tianjin Peoples Hospital | Lv Z.,Tianjin Medical University
Scandinavian Journal of Infectious Diseases | Year: 2013

Background: Helicobacter pylori infects more than half of the world's population. The aim of this study was to quantify the association between H. pylori infection and the risk of diabetes mellitus and diabetic nephropathy, and to detect at which stage the infection might have higher pathogenicity in the disease-free status-diabetes mellitus-diabetic nephropathy process. Methods: A literature search was performed to identify studies published between 1997 and 2012 for relative risk estimates. Fixed and random effects meta-analytical techniques were conducted for diabetes mellitus and diabetic nephropathy. Results: Thirty-seven case-control studies and 2 cohort studies were included. H. pylori was associated with an increased risk of each type of diabetes mellitus (odds ratio (OR) 2.00, 95% confidence interval (CI) 1.82-2.20, p for heterogeneity = 0.07). The infection was also associated with increased risks of type 1 and type 2 diabetes mellitus, separately (OR 1.99, 95% CI 1.52-2.60, p for heterogeneity = 0.15, and OR 2.15, 95% CI 1.81-2.55, p for heterogeneity = 0.24, respectively). In addition, we found a significant association between H. pylori infection and diabetic nephropathy risk (OR 1.60, 95% CI 1.10-2.33, p for heterogeneity = 0.44). Conclusions: Our meta-analyses suggest a relationship between H. pylori infection and the risk of diabetes mellitus and diabetic nephropathy. The bacterium may be able to play its pathogenic role in the whole disease process, and this action may be stronger in type 2 diabetic patients than in type 1 diabetic patients. © 2013 Informa Healthcare.

Liu J.,Tianjin Peoples Hospital | Wang F.,Tianjin Medical University | Shi S.,Tianjin Peoples Hospital
Helicobacter | Year: 2015

Background: Myocardial infarction is a fatal cardiovascular disease and one of the most common death causes all around the world. The aim of the meta-analysis was to quantify the risk of myocardial infarction associated with Helicobacter pylori infection. Methods: A literature search was performed to identify studies published before 14 July, 2014, for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for myocardial infarction. Results: Twenty-six case-control studies involving 5829 myocardial infarction patients and more than 16,000 controls were included. Helicobacter pylori infection was associated with an increased risk of myocardial infarction (OR: 2.10, 95%CI: 1.75-2.53, p = .06). We also discovered a significant association between the bacteria and risk of myocardial infarction in young people (OR: 1.93, 95% CI: 1.41-2.66, p = .07), in elder people (OR: 2.02, 95% CI: 1.60-2.54, p = .29), in Caucasians (OR: 2.29, 95% CI: 1.99-2.63, p = .12), and in Asians (OR: 1.75, 95% CI: 1.12-2.73, p = .08). Conclusion: Our meta-analyses suggested a possible indication of relationship between Helicobacter pylori infection and the risk of myocardial infarction. The pathogenicity might not be affected by age and race. More researches should be conducted to explore the mechanisms involved. © 2014 John Wiley & Sons Ltd.

Qin W.,Tianjin Medical University | Liu Y.,CAS Institute of Automation | Jiang T.,CAS Institute of Automation | Yu C.,Tianjin Medical University | Yu C.,Capital Medical University
PLoS ONE | Year: 2013

Visual experience plays an important role in the development of the visual cortex; however, recent functional imaging studies have shown that the functional organization is preserved in several higher-tier visual areas in congenitally blind subjects, indicating that maturation of visual areas depend unequally on visual experience. In this study, we aim to validate this hypothesis using a multimodality MRI approach. We found increased cortical thickness in the congenitally blind was present in the early visual areas and absent in the higher-tier ones, suggesting that the structural development of the visual cortex depends hierarchically on visual experience. In congenitally blind subjects, the decreased resting-state functional connectivity with the primary somatosensory cortex was more prominent in the early visual areas than in the higher-tier ones and were more pronounced in the ventral stream than in the dorsal one, suggesting that the development of functional organization of the visual cortex also depends differently on visual experience. Moreover, congenitally blind subjects showed normal or increased functional connectivity between ipsilateral higher-tier and early visual areas, suggesting an indirect corticocortical pathway through which somatosenroy information can reach the early visual areas. These findings support our hypothesis that the development of visual areas depends differently on visual experience. © 2013 Qin et al.

Wang J.,Tianjin Medical University | Li J.,Tangshan Peoples Hospital | Li J.,Hebei Medical University | Wang X.,Tianjin Medical University | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

miR-214 is one of the most significantly downregulated microRNAs (miRNAs) in hepatocellular carcinoma (HCC). Fibroblast growth factor receptor 1 (FGFR-1) is a miR-214 target gene implicated in the progression of HCC. However, the roles of miR-214 and FGFR-1 in HCC are not fully understood. Here, we analyzed the expression of miR-214 and FGFR-1 in 65 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR and Western blot (WB), respectively. Our data indicated that miR-214 was downregulated and FGFR-1 was overexpressed in HCC compared to the paired non-neoplastic tissues. The low miR-214 expression was correlated with portal vein invasion (p=0.016) and early recurrence (p=0.045) in HCC patients. Moreover, the low miR-214 expression was correlated with high positive rate of FGFR-1 in HCC cases (p=0.020). Our data further demonstrated that miR-214 overexpression in SK-HEP1 and HepG2 cells downregulated FGFR-1 expression and inhibited liver cancer cell invasion. The Luciferase assay results further demonstrated the targeted regulation of FGFR-1 by miR. -214. In conclusion, our data indicate that the downregulation of miR-214 in HCC and the upregulation of its target gene FGFR-1 is associated with HCC progression. Therefore, miR-214 and FGFR-1 are potential prognostic markers and therapeutic targets in HCC. © 2013 Elsevier Inc.

He X.,Tianjin Medical University | Qin W.,Tianjin Medical University | Liu Y.,CAS Institute of Automation | Zhang X.,Capital Medical University | And 5 more authors.
Human Brain Mapping | Year: 2014

The salience network (SN) serves to identify salient stimuli and to switch between the central executive network (CEN) and the default-mode network (DMN), both of which are impaired in Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI). We hypothesized that both the structural and functional organization of the SN and functional interactions between the SN and CEN/DMN are altered in normal aging and in AD/aMCI. Gray matter volume (GMV) and resting-state functional connectivity (FC) were analyzed from healthy younger (HYC) to older controls (HOC) and from HOC to aMCI and AD patients. All the SN components showed significant differences in the GMV, intranetwork FC, and internetwork FC between the HYC and HOC. Most of the SN components showed differences in the GMV between the HOC and AD and between the aMCI and AD. Compared with the HOC, AD patients exhibited significant differences in intra- and internetwork FCs of the SN, whereas aMCI patients demonstrated differences in internetwork FC of the SN. Most of the GMVs and internetwork FCs of the SN and part of the intranetwork FC of the SN were correlated with cognitive differences in older subjects. Our findings suggested that structural and functional impairments of the SN may occur as early as in normal aging and that functional disconnection between the SN and CEN/ DMN may also be associated with both normal aging and disease progression. Hum Brain Mapp 35:3446-3464, 2014. © 2013 Wiley Periodicals, Inc.

Wang D.,Tianjin Medical University | Qin W.,Tianjin Medical University | Liu Y.,CAS Institute of Automation | Zhang Y.,Tianjin Medical University | And 2 more authors.
Human Brain Mapping | Year: 2014

The brain of congenital blind (CB) has experienced a series of structural and functional alterations, either undesirable outcomes such as atrophy of the visual pathway due to sight loss from birth, or compensatory plasticity to interact efficiently with the environment. However, little is known, so far, about alterations in the functional architecture of resting-state networks (RSNs) in CB. This study aimed to investigate intra- and internetwork connectivity differences between CB and sighted controls (SC), using independent component analysis (ICA) on resting state functional MRI data. Compared with SC, CB showed significantly increased network connectivity within the salience network (SN) and the occipital cortex. Moreover, CB exhibited enhanced internetwork connectivity between the SN and the frontoparietal network (FPN) and between the FPN and the occipital cortex; however, they showed decreased internetwork connectivity between the occipital cortex and the sensorimotor network. These findings suggest that CB experience large scale reorganization at the level of the functional network. More importantly, the enhanced intra- and internetwork connectivity of the SN, FPN, and occipital cortex in CB may improve their abilities to identify salient stimuli, to initiate the executive function, and to top-down control of attention, which are critical for the CB to guide appropriate behavior and to better adaption to the environment. © 2013 Wiley Periodicals, Inc.

Wang Y.,Beckman Research Institute | Yu Y.,Beckman Research Institute | Yu Y.,Tianjin Medical University | Tsuyada A.,Beckman Research Institute | And 6 more authors.
Oncogene | Year: 2011

Recent studies indicate that a subset of cancer cells possessing stem cell properties, referred to as cancer-initiating or cancer stem cells (CSCs), have crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. Transforming growth factor (TGF)-Β and their family members have been implicated in both normal (embryonic and somatic) stem cells and CSCs. In this study, we observed that exposure to TGF-Β increased the population of breast cancer (BC) cells that can form mammospheres in suspension, a feature endowed by stem cells. This was mediated by the micro (mi)RNA family miR-181, which was upregulated by TGF-Β at the post-transcriptional level. Levels of the miR-181 family members were elevated in mammospheres grown in undifferentiating conditions, compared with cells grown in two-dimensional conditions. Ataxia telangiectasia mutated (ATM), a target gene of miR-181, exhibited reduced expression in mammospheres and upon TGF-Β treatment. Overexpression of miR-181a/b, or depletion of ATM or its substrate CHK2, was sufficient to induce sphere formation in BC cells. Finally, knockdown of ATM enhanced in vivo tumorigenesis of the MDA361 BC cells. Our results elucidate a novel mechanism through which the TGF-Β pathway regulates the CSC property by interfering with the tumor suppressor ATM, providing insights into the cellular and environmental factors regulating CSCs, which may guide future studies on therapeutic strategies targeting these cells. © 2011 Macmillan Publishers Limited All rights reserved.

Zhang Z.,Tianjin Medical University | Zhang Z.,Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry of China | Zhang Z.,Metabolic Diseases Hospital | Zhang R.,Tianjin Medical University | And 2 more authors.
Autoimmunity Reviews | Year: 2015

Epigenetics is the study of heritable changes in genome function without underlying modifications in their nucleotide sequence. Disorders of epigenetic processes, which involve DNA methylation, histone modification, non-coding RNA and nucleosome remodeling, may influence chromosomal stability and gene expression, resulting in complicated syndromes. In the past few years, it has been disclosed that identified epigenetic alterations give rise to several typical human autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). These emerging epigenetic studies provide new insights into autoimmune diseases. The identification of specific epigenetic dysregulation may inspire more discoveries of other uncharacterized mechanisms. Further elucidation of the biological functions and clinical significance of these epigenetic alterations may be exploited for diagnostic biomarkers and therapeutic benefits. © 2015 Elsevier B.V.

Liu T.-B.,Rutgers University | Kim J.-C.,University of Kansas Medical Center | Wang Y.,Rutgers University | Wang Y.,Tianjin Medical University | And 5 more authors.
PLoS Pathogens | Year: 2013

Cryptococcus neoformans is the most common cause of fungal meningitis, with high mortality and morbidity. The reason for the frequent occurrence of Cryptococcus infection in the central nervous system (CNS) is poorly understood. The facts that human and animal brains contain abundant inositol and that Cryptococcus has a sophisticated system for the acquisition of inositol from the environment suggests that host inositol utilization may contribute to the development of cryptococcal meningitis. In this study, we found that inositol plays an important role in Cryptococcus traversal across the blood-brain barrier (BBB) both in an in vitro human BBB model and in in vivo animal models. The capacity of inositol to stimulate BBB crossing was dependent upon fungal inositol transporters, indicated by a 70% reduction in transmigration efficiency in mutant strains lacking two major inositol transporters, Itr1a and Itr3c. Upregulation of genes involved in the inositol catabolic pathway was evident in a microarray analysis following inositol treatment. In addition, inositol increased the production of hyaluronic acid in Cryptococcus cells, which is a ligand known to binding host CD44 receptor for their invasion. These studies suggest an inositol-dependent Cryptococcus traversal of the BBB, and support our hypothesis that utilization of host-derived inositol by Cryptococcus contributes to CNS infection. © 2013 Liu et al.

Wang F.,Tianjin Peoples Hospital | Fu Y.,Tianjin Medical University | Lv Z.,Tianjin Medical University
Endocrine Research | Year: 2014

Background. Helicobacter pylori (HP) infects more than half of the world's population. The aim of the study was to quantify the association between HP and the risk of diabetic complications. Methods: A literature search was performed to identify studies published between 1998 and 2012 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for ischemic heart disease, retinopathy, neuropathy and nephropathy. Results: Eight studies were included. HP was associated with an increase risk of nephropathy and neuropathy (relative risk [RR]: 1.35, 95% CI: 1.06-1.73, p=0.45 and RR: 1.20, 95% CI: 1.03-1.40, p=0.29). We also discovered significant associations between bacterial infection and nephropathy risk in Oriental people (RR: 1.73, 95% CI: 1.19-2.50, p=0.82) and in type 2 diabetic patients (RR: 1.50, 95% CI: 1.11-2.02, p=0.29). Conclusions: Our meta-analyses suggest a possible relationship between HP and the risk of nephropathy and neuropathy. Our results also suggest that the effect of HP on the risk of nephropathy is stronger in Oriental people and in type 2 DM patients. © 2014 Informa Healthcare USA, Inc.

Wang D.,Tianjin Medical University | Qin W.,Tianjin Medical University | Liu Y.,CAS Institute of Automation | Zhang Y.,Tianjin Medical University | And 2 more authors.
Neural Plasticity | Year: 2013

The blind subjects have experienced a series of brain structural and functional alterations due to the visual deprivation. It remains unclear as to whether white matter changes differ between blind subjects with visual deprivation before and after a critical developmental period. The present study offered a direct comparison in changes of white matter fractional anisotropy (FA) between congenital blind (CB) and late blind (LB) individuals. Twenty CB, 21 LB (blindness onset after 18 years old), and 40 sight control (SC) subjects were recruited. Both the tract-based spatial statistics (TBSS) and voxel-based analysis (VBA) showed lower FA in the bilateral optic radiations in both blind groups, suggesting that the loss of white matter integrity was the prominent hallmark in the blind people. The LB group showed more extensive white matter impairment than the CB group, indicating the mechanisms of white matter FA changes are different between the CB and LB groups. Using a loose threshold, a trend of an increased FA was found in the bilateral corticospinal tracts in the LB but with a smaller spatial extent relative to the CB. These results suggest that white matter FA changes in the blind subjects are the reflection of multiple mechanisms, including the axonal degeneration, deafferentation, and plasticity. © 2013 Dawei Wang et al.

Chen C.,Tianjin Hospital | Zhao M.,Tianjin Medical University | Tian A.,Tianjin Hospital | Zhang X.,Tianjin Hospital | And 2 more authors.
Oncotarget | Year: 2015

Bone sarcomas such as osteosarcoma and chondrosarcoma are frequently refractory to conventional chemotherapy and radiotherapy that exhibit poor prognosis. The Wnt signaling are evolutionarily conserved and implicated in cell proliferation and sarcomagenesis. However, the potential role of the Wnt signaling in bone sarcomas is still unclear. Here we demonstrate aberrant activation of Wnt/β-catenin signaling in bone sarcoma cells, involving an autocrine Wnt signaling loop with upregulation of specific Wnt ligands and receptors. Activation of Wnt/β-catenin signaling with Wnt3a or GSK-3β inhibitor drives the proliferation of bone sarcoma cells, whereas downregulation of activated Wnt signaling with dnTCF4 or siLEF1 suppresses bone sarcoma proliferation and induces cell cycle arrest. Taken together, our findings establish the evidence that aberrant activation of Wnt/β-catenin pathway involving an autocrine Wnt singaling drives the proliferation of bone sarcoma cells, and identify the autocrine activation of the Wnt/β-catenin signaling as a potential novel therapeutic target for bone sarcomas.

Wang J.,Tianjin Medical University | Li J.,Tangshan Peoples Hospital | Li J.,Hebei Medical University | Shen J.,Qingdao Agricultural University | And 3 more authors.
BMC Cancer | Year: 2012

Background: miR-182 is one of the most significantly up-regulated miRNAs in hepatocellular carcinoma (HCC). Metastasis suppressor 1 (MTSS1), one target gene of miR-182, plays an important role in the metastasis of cancers. However, it remains unclear what role does function and mechanism of miR-182 and MTSS1play in HCC.Methods: miR-182 expression was tested in 86 cases of paired HCC and normal tissues by real-time PCR and the relationships between miR-182 expression and clinicopathological parameters were analyzed. The expression of MTSS1 was evaluated by immunohistochemistry and western blot in the above tissues and its correlation with miR-182 expression was analyzed. Moreover, western blot and invasion assays were performed after transfection of pre-miR-182 or anti-miR-182 to HCC cell lines. In addition, luciferase assays was performed to confirm the regulation of miR-182 on MTSS1.Results: Compared with normal tissue, miR-182 was up-regulated and MTSS1 was down-regulated in HCC tissues. Moreover, the over-expression of miR-182 was correlated with intrahepatic metastasis (p = 0.034) and poor prognosis (p = 0.039) of HCC patients. There was a negative correlation between miR-182 and MTSS1 expression in both HCC tissues (r = -0.673, p < 0.01) and HCC cell lines (r = -0.931, p = 0.021). Furthermore, the up-regulation of miR-182 resulted in the down-regulation of MTSS1 and increased invasive potential of HUH-1, and reverse results were also confirmed when the expression of miR-182 was inhibited. In addition, the results of the luciferase assay demonstrated the targeted regulation of miR-182 on MTSS1.Conclusions: miR-182 could promote metastasis of HCC and inhibit the expression of MTSS1. miR-182 and MTSS1 are potential prognostic markers and/or therapeutic targets in HCC. © 2012 Wang et al.; licensee BioMed Central Ltd.

Liu T.,Tianjin Medical University | Zhao H.,Tianjin Hospital | Li J.,Tianjin Medical University | Korantzopoulos P.,University of Ioannina | Li G.,Tianjin Medical University
Cardiovascular Therapeutics | Year: 2014

Summary: Introduction: The pleiotropic effects of glitazones may favorably affect atrial remodeling. We sought to investigate the effects of peroxisome proliferator-activated receptor-γ (PPAR-γ) activator rosiglitazone on atrial structural remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. Methods: Twenty alloxan-induced diabetic rabbits were randomly divided into two groups (10 animals in each group), namely the diabetic rosiglitazone group (treated with rosiglitazone 2 mg/day/kg for 4 weeks) and the nontreated diabetic group, while 10 additional healthy rabbits served as controls. Moreover, isolated Langendorff-perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF, examined by burst pacing. Histological examination was also performed, whereas plasma oxidative stress and inflammatory biomarkers were measured. Results: The duration of induced AF was significantly prolonged in the alloxan-induced diabetic rabbits compared with controls (1.6 ± 0.4 s vs. 0 s; P < 0.05). Rosiglitazone treatment significantly reduced the duration of induced AF in the treated rabbits (1.6 ± 0.4 s vs. 1.2 ± 0.05 s; P < 0.05). Moreover, rosiglitazone attenuated atrial structural remodeling reducing the interatrial activation time (35.4 ± 12.1 ms vs. 24.2 ± 10.8 ms, P < 0.05; control 23.3 ± 10.4 ms) and the atrial interstitial fibrosis as well (collagen volume fraction: 5.6 ± 3.9% vs. 2.4 ± 2.1%, P < 0.05; control 1.6 ± 0.8%). Rosiglitazone increased plasma superoxide dismutase (SOD) activity and, on the other hand, decreased malondialdehyde (MDA), hs-C-reactive protein, and tumor necrosis factor-α levels. Conclusion: Rosiglitazone attenuates arrhythmogenic atrial structural remodeling and AF promotion in alloxan-induced diabetic rabbits. Also, it seems to modulate oxidative stress and inflammation in this experimental model. © 2014 John Wiley & Sons Ltd.

Zhou K.J.,State University of New York at Stony Brook | Chen J.,Tianjin Medical University
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2016

The current growing of food industry for low production costs and high efficiency needs for maintenance of high-quality standards and assurance of food safety while avoiding liability issues. Quality and safety of food depend on physical (texture, color, tenderness etc.), chemical (fat content, moisture, protein content, pH, etc.), and biological (total bacterial count etc.) features. There is a need for a rapid (less than a few minutes) and accurate detection system in order to optimize quality and assure safety of food. However, the fluorescence ranges for known fluorophores are limited to ultraviolet emission bands, which are not in the tissue near infrared (NIR) "optical window". Biological tissues excited by far-red or NIR light would exhibit strong emission in spectral range of 650-1,100 nm although no characteristic peaks show the emission from which known fluorophores. The characteristics of the auto-fluorescence emission of different types of tissues were found to be different between different tissue components such as fat, high quality muscle food. In this paper, NIR auto-fluorescence emission from different types of muscle food and fat was measured. The differences of fluorescence intensities of the different types of muscle food and fat emissions were observed. These can be explained by the change of the microscopic structure of physical, chemical, and biological features in meat. The difference of emission intensities of fat and lean meat tissues was applied to monitor food quality and safety using spectral polarized imaging, which can be detect deep depth fat under the muscle food up to several centimeter. © 2016 SPIE.

Wang R.,Tanggu Blood Center | Hu W.,Tianjin Medical University | Qiang L.,Beijing University of Chinese Medicine
Journal of Investigative Medicine | Year: 2012

Objective: Previous studies demonstrated that G1359A polymorphism of cannabinoid receptor-1 (CNR1) was associated with cardiovascular risk factors including obesity, insulin resistance, dyslipidemia, and inflammation, which are also risk factors for developing type 2 diabetes mellitus (T2DM). Therefore, this study was aimed to determine whether G1359A polymorphism of CNR1 is associated with T2DM and the presence of coronary artery disease (CAD) in patients with T2DM. Methods: A total of 450 patients with T2DM (259 patients with CAD and 191 patients without CAD) and 94 healthy subjects were genotyped using polymerase chain reaction and restriction fragment length polymorphism method. Results: No significant differences in genotype frequency of CNR1 were found between normal controls and patients with T2DM without CAD. GG genotype frequency of CNR1 was significantly higher in the patients with T2DM with CAD compared with those without CAD and healthy subjects (P = 0.003 and P = 0.005, respectively). Unconditional logistic regression analysis revealed that GG genotype was significantly associated with the presence of CAD in the patients with T2DM compared with GA and AA genotypes (odds ratio, 2.632;95% confidence interval, 1.481-4.678;P <0.001). In addition, GG genotype of CNR1 was significantly correlated with elevated levels of body mass index, systolic blood pressure, homeostasis model assessment of insulin resistance, and C-reactive protein, as well as decreased levels of high-density lipoprotein cholesterol in patients with T2DM. Conclusions: G1359A polymorphism of CNR1 may be not associated with T2DM but may contribute to the genetic risk for the presence of CAD in patients with T2DM of Chinese Han population. Copyright © 2012 by The American Federation for Medical Research.

Wang H.,Tianjin Medical University | Wan N.,Tianjin Medical University | Hu Y.,Tianjin Hospital
International Orthopaedics | Year: 2012

Giant cell tumour (GCT) of bone is still one of the most obscure and intensively studied tumours of bone. The histogenesis of GCT remains unclear. The recommended therapy of GCT evolved during the 20th century. The best treatment should ensure local control and maintain function. Curettage has been the preferred treatment for most GCTs. Good results have also been published on the use of high-speed burr and local adjuvants. Local tumour control can be satisfactorily achieved by wide excision. However, treatment options for GCT have remained fairly static over the past 30 years and there is no widely held consensus regarding the standard treatment selection for all patients. This challenge may result from the fact that there are no single clinical, radiographic, histological or morphological aspects that allow surgeons to accurately predict the trend of a single lesion to recur. In this research, a comprehensive review of the previously described radiographic staging systems by Enneking and Campanacci et al. and the shortfalls associated with them are provided, and then the possible risk factors of predicting local recurrence or evaluating functional outcome of GCT are also discussed. A new preoperative evaluating system of GCT may be necessary and feasible, so that surgeons may accurately assess the aggressiveness or severity of GCT in order to reliably guide treatment decisions and predict outcomes. © 2012 Springer-Verlag Berlin Heidelberg.

Ma X.-L.,Tianjin Medical University | Ma X.-L.,Tianjin Hospital | Xing D.,Tianjin Medical University | Xing D.,Tianjin Gongan Hospital | And 4 more authors.
European Spine Journal | Year: 2012

Objective To assess the safety and efficacy of balloon kyphoplasty (KP) compared with percutaneous vertebroplasty (VP) and provide recommendations for using these procedures to treat osteoporotic vertebral compression fractures (OVCF). Methods A systematic search of all studies published through March 2012 was conducted using the MEDLINE, EMBASE, OVID, ScienceDirect and Cochrane CENTRAL databases. The randomized controlled trials (RCTs) and non-randomized controlled trials that compared KP to VP and provided data on safety and clinical effects were identified. Demographic characteristics, adverse events and clinical outcomes were manually extracted from all of the selected studies. The evidence quality levels and recommendations were assessed using the GRADE system. Results Twelve studies encompassing 1,081 patients met the inclusion criteria. Subgroup meta-analyses were performed according to the study design. In the RCT subgroup, there were significant differences between the two procedures in short-term visual analog scale (VAS), long-term kyphosis angles, operative times and anterior vertebrae heights. In the cohort study subgroup, there were significant differences between the two procedures in short- and longterm VAS, short- and long-term Oswestry Disability Index (ODI), cement leakage rates, short- and long-term kyphosis angles, operative times and anterior vertebrae heights. However, there were no significant differences in long-term VAS or adjacent vertebral fracture rates in the RCT subgroup. There were no significant differences in short- or long-term VAS, short- or long-term ODI, cement leakage rates, adjacent vertebral fracture rates, short- or long-term kyphosis angles or anterior vertebrae heights in the CCT subgroup, and the adjacent vertebral fracture rates did not differ significantly in the cohort study subgroup. The overall GRADE system evidence quality was very low, which lowers our confidence in their recommendations. Conclusions KP and VP are both safe and effective surgical procedures for treating OVCF. KP may be superior to VP in patients with large kyphosis angles, vertebral fissures, fractures in the posterior edge of the vertebral body or significant height loss in the fractured vertebrae. Due to the poor quality of the evidence currently available, highquality RCTs are required. © Springer-Verlag 2012.

Li S.,Tianjin Medical University | Wei M.,Tianjin Medical University | Zhou Z.,Tianjin Medical University | Wang B.,Tianjin Medical University | And 2 more authors.
Brain Research | Year: 2012

This study aimed to investigate the effects of SDF-1α on brain angiogenesis and neurological functional recovery in rats after traumatic brain injury (TBI) and the potentially involved mechanisms. Youth male Wistar rats were injured via lateral fluid percussion injury and then randomly divided into one of 3 groups: I. vehicle treated group; II. SDF-1α neutralizing antibody treated group and III. rhSDF-1α treated group. rhSDF-1α and its neutralizing antibody or normal saline were administered to the brain penumbra via stereotactic injection 30 min after TBI. Modified neurological severity score (mNSS) and Morris water maze (MWM) test were used to assess the neurologic functional recovery (n = 6/group). 14 days after injury, animals were euthanized and brain tissues were collected for quantitative real time polymerase chain reaction (qRT-PCR) (n = 6/group) and immunohistochemistry (n = 6/group) analysis. mNSS and MWM test indicated distinct amelioration of neurological disability in rhSDF-1α group(P < 0.05). Microvessel density (MVD) of rhSDF-1α treated animals was remarkably increased around the injured area. On the contrary, MVD of the SDF-1α antibody administrated group was significantly decreased compared to that of vehicle treated animals (P < 0.05). The mNSS and MVD had significant negative correlation as tested by Spearman rank correlation coefficient. Immunofluorescence staining showed that CD34 and CXCR4 co-expressed on microvessels. The rhSDF-1α treated animals had greater, contrarily, the SDF-1α antibody treated animals had lesser number of double positive microvessels compared to that of vehicle treated animals. The mRNA expression of CD34 and CXCR4 was obviously elevated in the rhSDF-1α administration group, conversely, declined in SDF-1α antibody treated animals around the injured area compared with that of the vehicle treatment group (P < 0.05). These data indicated that SDF-1α could induce angiogenesis after TBI, potentially via SDF-1/CXCR4 axis. © 2012 Elsevier B.V. All rights reserved.

Wang J.,Tianjin Medical University | Qin W.,Tianjin Medical University | Liu B.,CAS Institute of Automation | Wang D.,Tianjin Medical University | And 3 more authors.
NeuroImage | Year: 2013

The oxytocin receptor gene (OXTR) rs53576A has been associated with autism spectrum disorders (ASDs). A smaller hypothalamic volume has been reported in healthy male A-allele carriers than in male GG homozygotes and in patients with ASDs than in healthy controls. These findings prompt the hypothesis that male AA homozygotes may have weaker hypothalamic functional connectivity when compared to male G-allele carriers. We calculated local functional connectivity density (FCD) using a voxel-wise data-driven approach based on resting-state functional MRI data in 270 young healthy subjects. Both the main effect of genotype and the gender-by-genotype interaction were considered. Of the whole brain, only the local FCD of the hypothalamus exhibited the main effect of genotype. Post-hoc testing revealed significantly lower local FCD in male AA homozygotes compared to male G-allele carriers although there was only a trend of significance in the gender-by-genotype interaction. We further analyzed the resting-state functional connectivity (rsFC) of the hypothalamic region that demonstrating significant genotype differences in local FCD. We found a significant gender-by-genotype interaction in rsFC between the hypothalamic region and the left dorsolateral prefrontal cortex, but no significant main effect of genotype was found. Post-hoc testing revealed that this rsFC was significantly weaker in male AA homozygotes compared to male G-allele carriers. Our findings identify gender-dependent mechanisms of OXTR rs53576 gene variation impacting the functional connectivity of the hypothalamus in healthy individuals and suggest that these mechanisms are important for understanding ASDs. © 2013 Elsevier Inc.

Meng L.,Tianjin TEDA Hospital | Meng L.,Tianjin Medical University | Zhang Y.,Tianjin Hospital | Lu Y.,Tianjin TEDA Hospital | Lu Y.,Tianjin Hospital
Orthopaedics and Traumatology: Surgery and Research | Year: 2013

Objective: To analyze the mini-external fixation and percutaneous K-wire internal fixation for the treatment of Bennett fracture by using finite element analysis and to compare the biomechanical stability and postoperative impact of the two fixations on the fracture. Methods: Three-dimensional digital models of the first metacarpal bone, second metacarpal bone, and the trapezium were established using Mimics 10.01 software. A solid model and finite element models were created and analyzed using ANSYS 10.0. The same load of 100. N was exerted on both the mini-external fixator and the Kirschner (K)-wire internal fixator for the treatment of Bennett fracture. Finally, the none-line solution was analyzed, and displacement nephograms were obtained. Results: The displacement nephograms of the distal and proximal fragments of the fracture obtained using the mini-external and K-wire models were established. The X/Y/Z (SUM)-component displacements of 15 nodes aligned with the articular surface fracture were obtained. The relative displacement of the distal and the proximal fragments of the fracture were calculated, and all digits of relative displacement were entered into SPSS 13.0 software. The difference between the X-component relative displacements was statistically significant. Moreover, the comparison of the Y-component, Z-component, and SUM-component relative displacements yielded statistical significance. The average relative displacement in the X-direction was 0.3214. mm in the K-wire model. Conclusion: Mini-external fixation is more effective than K-wire internal fixation for secure Bennett fracture stability. Both fixations have similar effects on postoperative traumatic arthritis and postoperative hand functions. Level of evidence: 1 Biomechanical studies. © 2012 Elsevier Masson SAS.

Zheng Y.-W.,Tianjin Medical University | Li H.,Tianjin Medical University | Yu J.-P.,Tianjin Medical University | Zhao H.,Tianjin Medical University | And 2 more authors.
Journal of Innate Immunity | Year: 2013

Interferon (IFN)-λs are a new addition to the old IFN family and share many similarities, such as antiviral and antiproliferative characteristics, with type I IFNs. IFN-λs also exhibit unique characteristics in immunomodulation. Accumulating studies have indicated the interactions between IFN-λs and immune cells, which lead to the regulation of the latter. IFN-λs can influence dendritic cells (DCs) and their product, IFN-λs-DCs, can then regulate the function of T cells. On the other hand, IFN-λs can also directly affect T cells through inhibition of the T helper 2 cell (Th2) responses. IFN-λs have varying immunomodulatory functions under different physiological conditions or in different organs and can inhibit tumor growth via regulation of the immune system. Diseases associated with IFN-λs include asthma, allergy, and systemic lupus erythematosus. In this review, we summarize the current knowledge of the biology of IFN-λs and their immunomodulatory function in relevant human diseases. Copyright © 2012 S. Karger AG, Basel.

Liu R.,Tianjin Medical University | Li J.,Zhengzhou University | Teng Z.,Kaifeng Peoples Hospital | Zhang Z.,Tianjin Medical University | Xu Y.,Tianjin Medical University
PLoS ONE | Year: 2013

MicroRNAs, non-coding 20-22 nucleotide single-stranded RNAs, result in translational repression or degradation and gene silencing of their target genes, and significantly contribute to the regulation of gene expression. In the current study, we report that miR-182 expression was significantly upregulated in prostate cancer tissues and four cell lines, compared to benign prostatic hyperplasia tissues and normal prostatic epithelial (RWPE-1) cells. Ectopic overexpression of miR-182 significantly promotes the proliferation, increases the invasion, promotes the G1/S cell cycle transition and reduces early apotosis of PC-3 cells, while suppression of miR-182 decreased the proliferation and invasion, inhibits the G1/S cell cycle transition and increase early apotosis of PC-3 cells. Additionally, we demonstrated that miR-182 could downregulate expression of NDRG1 by directly targeting the NDRG1 3′-untranslated region. In conclusion, our results suggest that miR-182 plays an important role in the proliferation of human prostate cancer cells by directly suppressing the tumor supressor gene NDRG1. We uncovered a new epigenetic regulation of NDRG1. © 2013 Liu et al.

Li Y.,Tianjin Medical University | Qin W.,Tianjin Medical University | Jiang T.,CAS Institute of Automation | Zhang Y.,Tianjin Medical University | Yu C.,Tianjin Medical University
PLoS ONE | Year: 2012

Harm avoidance (HA) is a personality dimension involving the tendency to respond intensely to signals of aversive stimuli. Many previous neuroimaging studies have associated HA scores with the structural and functional organization of the amygdala, but none of these studies have evaluated the correlation between HA score and amygdala resting-state functional connectivity (rsFC). Moreover, the amygdala is not a homogeneous structure, and it has been divided into several structurally and functionally distinct subregions. Investigating the associations between HA score and properties of subregions of the amygdala could greatly improve our understanding of HA. In the present study, using a large sample of 291 healthy young adults, we aimed to uncover correlations between HA scores and the rsFCs of each amygdala subregion and to uncover possible sex-based differences in these correlations. We found that subregions of the amygdala showed different rsFC patterns, which contributed differently to individual HA scores. More specifically, HA scores were correlated with rsFCs between the laterobasal amygdala subregion and temporal and occipital cortices related to emotional information input, between the centromedial subregion and the frontal cortices associated with emotional output control, and between the superficial subregion and the frontal and temporal areas involved in both functions. Moreover, significant gender-based differences were uncovered in these correlations. Our findings provide a more detailed model of association between HA scores and amygdala rsFC, extend our understanding of the connectivity of subregions of the amygdala, and confirm sex-based differences in HA associations. © 2012 Li et al.

Xing D.,Tianjin Hospital | Ma X.L.,Tianjin Hospital | Ma X.L.,Tianjin Medical University | Ma J.X.,Tianjin Medical University | And 3 more authors.
Osteoporosis International | Year: 2014

Benzodiazepines (BZDs) are some of the most commonly prescribed drugs in the world. It has been shown that BZD use could be associated with increased fracture risk. However, studies on the use of BZDs and fracture risk have yielded inconsistent results. Results from the present meta-analysis show that BZD use is associated with a moderate and clinically significant increase in the risk of fractures. Introduction: The relationship between the use of BZDs and fracture risk has been neither well identified nor summarized. This meta-analysis reports on the use of BZDs, especially short-acting BZDs, and their correlation with a moderate and clinically significant increase in fracture risk. This analysis will provide evidence for clinicians to consider fracture risk when prescribing BZDs among the elderly population. This study was conducted to determine whether people who take BZDs are at an increased fracture risk. Methods: A systematic search of studies published through January 2013 was conducted using MEDLINE, EMBASE, OVID, and ScienceDirect. Case-control and cohort studies that assessed the relationship between BZD use and the risk of fractures were identified. Literature searches, study selections, methodological assessments, and data mining were independently conducted by two reviewers. Disagreements were resolved by consensus. STATA 12.0 software was used for the meta-analysis. Random effects models were used for pooled analysis due to heterogeneity among the studies. Results: There were 25 studies, including 19 case-control studies and 6 cohort studies, that met the inclusion criteria. Overall, the results of the meta-analysis indicated that BZD use was associated with a significantly increased fracture risk (relative risk (RR) = 1.25; 95 % confidence intervals (CI), 1.17-1.34; p < 0.001). Increased fracture risk associated with BZD use was observed in participants aged ≥65 years old (RR = 1.26; 95 % CI, 1.15-1.38; p < 0.001). When only hip fractures were included as the outcome measure, the RR increased to 1.35. However, subgroup meta-analyses showed that there was no significant association between BZD use and fracture risk in Eastern countries (RR = 1.27; 95 % CI, 0.76-2.14; p = 0.362) as well as between long-acting BZD use and risk of fractures (RR = 1.21; 95 % CI, 0.95-1.54; p = 0.12). After accounting for publication bias, we observed that the overall association between BZD use and fracture risk to be slightly weaker (RR = 1.21; 95 % CI, 1.13-1.30) but still significant. Conclusion: The results of this meta-analysis demonstrate that the use of BZD, especially short-acting BZD, is associated with a moderate and clinically significant increase in fracture risk. However, large prospective studies that minimize selection bias are necessary to determine a more accurate fracture risk associated with BZD use. © 2013 International Osteoporosis Foundation and National Osteoporosis Foundation.

Li R.,Tianjin Medical University | Qin W.,Tianjin Medical University | Zhang Y.,Tianjin Medical University | Jiang T.,CAS Institute of Automation | Yu C.,Tianjin Medical University
PLoS ONE | Year: 2012

Digits backward (DB) is a widely used neuropsychological measure that is believed to be a simple and effective index of the capacity of the verbal working memory. However, its neural correlates remain elusive. The aim of this study is to investigate the neural correlates of DB in 299 healthy young adults by combining voxel-based morphometry (VBM) and resting-state functional connectivity (rsFC) analyses. The VBM analysis showed positive correlations between the DB scores and the gray matter volumes in the right anterior superior temporal gyrus (STG), the right posterior STG, the left inferior frontal gyrus and the left Rolandic operculum, which are four critical areas in the auditory phonological loop of the verbal working memory. Voxel-based correlation analysis was then performed between the positive rsFCs of these four clusters and the DB scores. We found that the DB scores were positively correlated with the rsFCs within the salience network (SN), that is, between the right anterior STG, the dorsal anterior cingulate cortex and the right fronto-insular cortex. We also found that the DB scores were negatively correlated with the rsFC within an anti-correlation network of the SN, between the right posterior STG and the left posterior insula. Our findings suggest that DB performance is related to the structural and functional organizations of the brain areas that are involved in the auditory phonological loop and the SN. © 2012 Li et al.

Fang L.,Nanchang Hangkong University | Wang Y.,Tianjin Medical University | He X.,Nanchang Hangkong University
Optics Express | Year: 2013

The analysis of the change in residual wavefront aberrations after laser refractive surgery is important for the development of visual correction technology. Based on the ablation profile for wavefront-guided refractive surgery including optical zone and transition zone, the effect of pupil size on residual wavefront aberrations was studied. The research revealed that the optical zone to pupil ratio had a significant influence on the residual wavefront aberrations. The residual spherical aberration and coma were obviously larger than other individual Zernike higher-order terms when pupil diameter was larger than the optical zone size, and they increased rapidly as the pupil size increased. In addition, when the ablation zone diameter was kept constant, the residual higher-order aberrations increased rapidly as the blend coefficient increased for a 6mm or 7mm pupil. Furthermore, the residual higher-order aberrations with treatment decentration were distinctly larger than those without decentration. In the achievement of the best postoperative visual performance, the design of ablation profile played a crucial role in decrease of the residual wavefront aberrations after refractive surgery, especially optical zone size and the ablation pattern of transition zone. © 2013 Optical Society of America.

Fang L.,Nanchang Hangkong University | Wang Y.,Tianjin Medical University | He X.,Nanchang Hangkong University
Journal of Cataract and Refractive Surgery | Year: 2013

Purpose: To analyze the induced wavefront aberrations caused by treatment decentration and transition zone after custom myopic laser refractive surgery. Setting: Refractive Surgery Center, Tianjin Eye Hospital & Eye Institute, Tianjin Medical University, Tianjin, China. Design: Cohort study. Methods: Wavefront aberration data from potential refractive surgery candidates were used. Based on the preoperative wavefront aberrations, the custom ablation profile was computed. Then, the influence of treatment decentration and especially that of the transition zone on induced wavefront aberrations was studied. The impact of angle mismatch on induced aberrations was analyzed. Results: Data from 117 eyes (77 patients) were analyzed. The transition zone played a significant role in the influence of decentration on the induced aberrations in refractive surgery. Induced coma and spherical aberration increased rapidly as the lateral translation increased, and coma was significantly larger than other Zernike aberration terms. The induced aberrations from decentration with oblique incidence in the laser ablation profile were less than in the actual laser ablation process for slight subclinical decentration. The induced aberrations were not closely related to the subclinical unmatched angle from eye cyclotorsion. The induced aberrations from lateral translation were correlated with the position vector. The transition zone was designed to smooth the transition from the optical zone to the untreated cornea, and it mainly dominated induced coma and spherical aberration. Conclusion: To achieve the best postoperative visual performance, the effect of the transition zone in refractive surgery should be taken into account, especially for scotopic pupils. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2013 ASCRS and ESCRS Published by Elsevier Inc.

Sun Y.,Tianjin Medical University | Sun Y.,University of Houston | Hu L.,University of Houston | Zheng H.,Tianjin Medical University | And 12 more authors.
Journal of Pathology | Year: 2015

Extensive investigations have shown that miRNAs are important regulators of epithelial-to-mesenchymal transition (EMT), mainly targeting the transcriptional repressors of E-cadherin (E-cad). Less is known about the post-transcriptional regulation of vimentin or N-cadherin (N-cad) in EMT. Our previous study identified miR-506 as a key EMT inhibitor through directly targeting the E-cad transcriptional repressor SNAI2. In this study, we provide evidence that miR-506 simultaneously suppresses vimentin and N-cad. The knockdown of vimentin using siRNA reversed EMT, suppressed cell migration and invasion, and increased E-cad expression on the cell membrane in epithelial ovarian cancer (EOC) cells. In a set of tissue microarrays that included 204 EOCs of all major subtypes (eg serous, endometrioid, clear cell, and mucinous), miR-506 was positively correlated with E-cad and negatively correlated with vimentin and N-cad in all subtypes of EOC. A high level of miR-506 was positively associated with early FIGO stage and longer survival in EOC. Introduction of miR-506, mediated by nanoparticle delivery, in EOC orthotopic mouse models resulted in decreased vimentin, N-cad, and SNAI2 expression and increased E-cad expression; it also suppressed the dissemination of EOC cells. Thus, miR-506 represents a new class of miRNA that regulates both E-cad and vimentin/N-cad in the suppression of EMT and metastasis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chang X.-Z.,Tianjin Medical University | Yu J.,Weifang University | Liu H.-Y.,Weifang Peoples Hospital | Dong R.-H.,Weifang Peoples Hospital | Cao X.-C.,Tianjin Medical University
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose To investigate the eVects of Akt/ARK5 pathways on the metastatic potential of human breast cancer cells. Materials and methods The human ARK5 gene was transfected into MDA-MB-231 cells. EVects of ARK5 on MDA-MB-231 cells were investigated in vitro. The tumorigenicity and spontaneously metastatic capability regulated by ARK5 were determined using an orthotopic xenograft tumor model. Results ARK5 enhanced the invasive and metastatic potential of MDA-MB-231 cells under regulation by Akt. The enhancement was associated with increasing MMP-2, MMP-9, and MT1-MMP expression. The results were further demonstrated by RNA interference experiment. In an in vivo study, we also demonstrated that ARK5-transfected breast cancer cells grew faster and had more pulmonary metastases than its parental counterparts. Conclusion ARK5 led to a more invasive phenotype and metastatic potential in human breast cancer dependent on Akt. © 2011 Springer-Verlag.

Riising E.M.,Copenhagen University | Riising E.M.,CR UK London Research Institute | Comet I.,Copenhagen University | Leblanc B.,Copenhagen University | And 6 more authors.
Molecular Cell | Year: 2014

Polycomb group (PcG) proteins are required for normal differentiation and development and are frequently deregulated in cancer. PcG proteins are involved in gene silencing; however, their role in initiation and maintenance of transcriptional repression is not well defined. Here, we show that knockout of the Polycomb repressive complex 2 (PRC2) does not lead to significant gene expression changes in mouse embryonic stem cells (mESCs) and that it is dispensable for initiating silencing of target genes during differentiation. Transcriptional inhibition in mESCs is sufficient to induce genome-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of untranscribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds by default to nontranscribed CGI genes to maintain their silenced state and to protect cell identity. © 2014 Elsevier Inc.

Chen W.,Tianjin Medical University | Chen W.,National Research Council Canada | Song X.,National Research Council Canada | Song X.,Dalhousie University | Zhang Y.,Tianjin Medical University
American Journal of Neuroradiology | Year: 2011

BACKGROUND AND PURPOSE: VRSs are the perivascular spaces surrounding the deep perforating arteries in the brain. Although VRS variations with age and disease pathologies have been reported previously, the radiologic characteristics of the VRS in relation to AD are poorly understood. This study investigated the prevalence, spatial distribution, and severity of the VRS in AD, MCI, and older adults who were CN. It also investigated the relationship of the VRS to white matter changes. MATERIALS AND METHODS: Structural MR imaging data were acquired from 158 participants (AD = 37, MCI = 71, CN = 50, mean age = 74.97 ± 7.20 years) who had undergone T1WI at 3T. The severity of VRS in the white matter, basal ganglia, hippocampus, and brain stem structures was evaluated by using a semiquantitative scale, adapted from existing rating scales. A VRS total score summarizing the subscales was calculated to assess the whole-brain VRSs. RESULTS: VRSs were observed in multiple brain regions of all participants, typically presented as <2-mm well-margined symmetric round-, oval- and linear-shaped hypointensities on T1WI. The VRS total score increased with leukoaraiosis, atrophy, and advanced age (P < .001). Individuals with AD and MCI showed greater levels of VRS than control subjects. The VRS total score discriminated individuals with AD and those who were CN with an accuracy of 0.79 (95% CI, 0.69-0.89). CONCLUSIONS: VRSs are common in older adults and are more severe in AD and MCI than in CN. Whether increased VRSs can be reliably used to aid in AD diagnosis warrants further investigation.

Maegawa R.O.B.,University of Colorado at Denver | Tang S.-C.,University of Colorado at Denver | Tang S.-C.,Tianjin Medical University
Cancer Investigation | Year: 2010

Triple-negative breast cancer is defined by the lack of expression of estrogen-receptor, progesterone-receptor, and HER-2/neu. It primarily, but not exclusively, carries the basal-like molecular profile on gene expression arrays and is associated with BRCA-1 and p53 mutations. It has an aggressive behavior and predilection for visceral metastasis, therefore accounting for its poor prognosis. Despite lacking targeted therapies, it is sensitive to anthracyclines and taxanes. Increasing knowledge has generated a better understanding of its pathophysiology, therefore leading to the development of directed therapies, although their validation still needs further investigation. This review focuses on its biology, management, evolving concepts, and future directions. © 2010 Informa Healthcare USA, Inc.

Zhang Y.,Inner Mongolia Peoples Hospital | Zhang Y.,Tianjin Medical University | Ju W.,Inner Mongolia Peoples Hospital | Ju W.,Tianjin Medical University | And 6 more authors.
Obesity Surgery | Year: 2015

Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are two most common weight loss procedures; our meta-analysis aims to compare these two in the treatment of morbid obesity and its related comorbidities. An electronic literature research of published studies concerning LRYGB and LSG was performed from inception to October 2013. Percentage of excess weight loss (%EWL), resolution or improvement rate of comorbidities, and adverse events were all pooled and compared by the software Review Manager 5.1. As a result, a total of 21 studies involving 18,766 morbidly obese patients were eventually selected according to the inclusion criteria. No significant difference was found in %EWL during 0.5- to 1.5-year follow-up (P > 0.05), but after that, LRYGB achieved higher %EWL than LSG (P < 0.05). Except for type 2 diabetes mellitus (T2DM) (P < 0.001), the difference between these two procedures in the resolution or improvement rate of other comorbidities did not reach a statistical significance (P > 0.05). There were more adverse events in LRYGB compared with LSG (P < 0.01). In conclusion, LRYGB is superior to LSG in efficacy but inferior to LSG in safety. © 2014, Springer Science+Business Media New York.

Zhang N.,National Research Council Canada | Zhang N.,Tianjin Medical University | Song X.,National Research Council Canada | Song X.,Dalhousie University | Zhang Y.,Tianjin Medical University
Dementia and Geriatric Cognitive Disorders | Year: 2012

Background: Several structural brain changes have been associated with Alzheimer's disease (AD). This study investigated the prediction of AD by combining multiple brain changes with the hallmark medial temporal lobe atrophy (MTA). Methods: High-resolution magnetic resonance imaging (MRI) data of people with mild AD (n = 39), mild cognitive impairment (MCI; n = 82), and of healthy controls (HC; n = 58) were obtained at baseline. Among these people, 26 AD, 53 MCI, and 46 HC subjects had 24-month follow-up MRI scans. Bilateral MTA was evaluated using a medial temporal lobe atrophy scale (MTAS). Common changes in the aging brain were summarized using a brain atrophy and lesion index (BALI). The performance of the MTAS, BALI, and a score combining both, using a logistic regression model, were assessed. Results: The MTAS and BALI scores were closely correlated (r2 > 0.56); each differed between the diagnostic groups. Having an unfavorable MTAS score was associated with an increased risk of MCI-AD conversion (OR = 3.71, p = 0.039), adjusted for age, sex, and education; having an unfavorable BALI score marginally contributed to such risks (OR = 4.08, p = 0.080). Combining MTAS and BALI components resulted in a greater OR (8.99, p = 0.007) and an improved predictive accuracy (75.9%, p = 0.002). Conclusion: Multiple structural changes have an additive effect on AD. The data support potential future roles of combining multiple coexisting structural changes to benefit AD diagnosis, progression monitoring, and/or treatment effect evaluation. Copyright © 2012 S. Karger AG, Basel.

Chen J.,Tianjin Medical University | Sun F.,Tianjin Medical University | Fu J.,Wuhan Medical Care Center for Women and Children | Zhang H.,Teda International Cardiovascular Hospital
Pediatric Cardiology | Year: 2015

As a transcription factor mainly expressed in cardiovascular system, T-box 20 (TBX20) plays an important role in embryonic cardiovascular system development and adult heart function. Previous studies have identified associations of two SNPs in the T-box DNA-binding domain of TBX20 with congenital heart disease (CHD) in two Caucasian families, but the associations of TBX20 mutations underlying the more common populations with CHD remain to be uncovered. In this study, 25 unrelated Chinese Han neonates with CHD and 25 healthy children as controls were investigated for TBX20 mutations. SNP genotyping was performed by PCR-DNA sequencing. The selected SNPs were well genotyped and SNP rs3999941 was found to be strongly associated with CHD (p = 0.007). The minor allele of rs3999941 showed a high-risk factor for CHD (OR 4.24; 95 % CI 1.41–12.71). Besides, we found a new SNP site located at the 657th nucleotide of the exon 5 of TBX20 gene which may also be associated with CHD, c.657A>C. The frequency was significantly different between two groups (p = 0.011), the minor allele of SNP c.657A>C also showed a risk factor for CHD (OR 2.56; 95 % CI 1.02–6.46). These findings suggested that the TC genotype of SNP rs3999941 and AC genotype of the new SNP c.657A>C in the TBX20 gene may be risk factors for CHD and thus screening of these SNPs may have some implications in the prevention and treatment of CHD in Han Chinese children. © 2014, Springer Science+Business Media New York.

Song X.,National Research Council Canada | Song X.,Dalhousie University | Mitnitski A.,Dalhousie University | Zhang N.,National Research Council Canada | And 5 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2013

Background: On average, cognition declines as people age, but improvement can also occur. Objective: To evaluate the dynamics of age-related changes in brain structure and cognitive function in patients with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) and in healthy control (HC) older adults. Methods: High-resolution 3-Tesla MRI and clinical data were obtained from the Alzheimer's Disease Neuroimaging Initiative in 187 subjects (a cohort aged 55-91 years; AD=43, MCI=84, HC=60). At 24 months, 151 people had clinical and 128 had MRI follow-up. Brain structure was assessed using the Medial Temporal Atrophy Scale (MTAS) and the Brain Atrophy and Lesion Index (BALI). Cognition was assessed using the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Responsiveness was tested. Changes were analysed using a multistate dynamic model, adjusted for age, gender, ApoE4 genotype and vascular risk factors. Results: Over 2 years, decline in brain structure and cognition predominated, each showing detectable effect sizes (Cohen's d=0.33 for MTAS, 0.32 for BALI, 0.41 for MMSE, 0.38 for ADAS-cog; standard response mean=0.71, 0.69, 0.50 and 0.47, respectively). Structural improvement was observed (10.2% in BALI and 0.8% in MTAS), as was cognitive improvement (23.2% MMSE, 27.2% ADAS-cog). Most people (66.7%) whose BALI score improved also improved in either the MMSE or ADAS-cog. No patient with MCI whose MTAS or BALI improved converted to AD. Conclusions: Despite average decline in brain structure, improvement was observed and related to cognition and MCI-AD conversion. Ageing-related brain changes reflect a dynamic process.

Chen H.-G.,Tianjin Medical University | Xie K.-L.,Tianjin Medical University | Han H.-Z.,Tianjin Medical University | Wang W.-N.,Tianjin Medical University | And 3 more authors.
International Journal of Surgery | Year: 2013

Background: Molecular hydrogen (H2) as a new medical gas has an anti-inflammatory effect. In the present study, we investigated whether heme oxygenase-1 (HO-1) contributes to the anti-inflammatory effect of H2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Methods: RAW 264.7 macrophages were stimulated by LPS (1μg/mL) with presence or absence of different concentrations of H2. Cell viability and injury were tested by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and lactate dehydrogenase (LDH) release, respectively. The cell culture supernatants were collected to measure inflammatory cytokines [TNF-α, IL-1β, HMGB1 (high mobility group box-1) and IL-10] at different time points. Moreover, HO-1 protein expression and activity were tested at different time points. In addition, to further identify the role of HO-1 in this process, zinc protoporphyrin (ZnPP)-IX, an HO-1 inhibitor, was used. Results: H2 treatment had no significant influence on cell viability and injury in normally cultured RAW 264.7 macrophages. Moreover, H2 treatment dose-dependently attenuated the increased levels of pro-inflammatory cytokines (TNF-α, IL-1β, HMGB1), but further increased the level of anti-inflammatory cytokine IL-10 at 3h, 6h, 12h and 24h after LPS stimulation. Furthermore, H2 treatment could also dose-dependently increase the HO-1 protein expression and activity at 3h, 6h, 12h and 24h in LPS-activated macrophages. In addition, blockade of HO-1 activity with ZnPP-IX partly reversed the anti-inflammatory effect of H2 in LPS-stimulated macrophages. Conclusions: Molecular hydrogen exerts a regulating role in the release of pro- and anti-inflammatory cytokines in LPS-stimulated macrophages, and this effect is at least partly mediated by HO-1 expression and activation. © 2013 Surgical Associates Ltd.

Dong N.,Capital Medical University | Xu B.,Capital Medical University | Benya S.R.,University of Texas Medical Branch | Tang X.,Tianjin Medical University
Molecular and Cellular Biochemistry | Year: 2014

MicroRNAs (miRNAs) are a class of small endogenous gene regulators that play important roles in various developmental and pathological processes. However, little is known about the precise identity and functions of miR-26b in posterior capsule opacification (PCO). In this study, we report that the expression of miR-26b is decreased in human PCO-attached lens epithelial cells (LECs) and SRA01/04 cells in the presence of TGF-β2. Overexpression of miR-26b inhibited the proliferation of LECs based on MTT assays and BrdU incorporation assays. In addition, the overexpression of miR-26b inhibited the migration ability of LECs, as shown by wound-healing and transwell migration assays. The overexpression of miR-26b increased the level of the lens epithelial marker E-cadherin and reduced the levels of mesenchymal-related proteins, such as fibronectin, a-SMA, and type I collagen, in SRA01/04 cells in the presence of TGF-β2. Furthermore, the upregulation of E-cadherin and downregulation of mesenchymal-related proteins were induced in human PCO-attached LECs transfected with miR-26b mimics. We further demonstrated that Smad4 and COX-2 are targets of miR-26b in LECs using luciferase reporter assays. These data reveal that miR-26b can inhibit the proliferation, migration, and EMT of lens epithelial cells, and restoration of miRNA-26b may be a potential, novel therapeutic target for the prevention and treatment of posterior capsule opacification. © 2014 Springer Science+Business Media New York.

Wang T.,Tianjin Medical University | Zhang L.,Tianjin Medical University | Zhang L.,Breast Oncology of Cancer Institute and Hospital | Li H.,Tianjin Medical University | And 2 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Many studies have reported that prostate stem cell antigen (PSCA) polymorphisms (rs2294008 and/or 2976392) are significantly associated with gastric cancer (GC) risk, although the published results are inconsistent. We conducted a systematic review and meta-analysis for relevant literatures to quantitatively evaluate the relationship between PSCA polymorphisms and GC susceptibility. Methods: Extensive searches were conducted in three databases up to November 1, 2011. ORs and 95% CIs were used to assess the strength of the associations. The data were further stratified by ethnicity, histopathology, subsite, and study design. All of the associations were evaluated with dominant model and recessive model, respectively. Heterogeneity and publication bias were also assessed by Q test, I 2, and funnel plot accordingly. Results: Nine articles including 11 case-control data sets were included, with 10,746 GC cases and 9,158 controls for rs2294008 and 6,060 cases and 4,824 controls for rs2976392. The results showed that risk allele carriers were significantly associated with GCrisk compared with nonrisk allele homozygotes. In stratification analyses, these associations remained significant for majority of subgroups except for Caucasians and noncardia tumor in dominant model, and cardia tumor in both dominant and recessive model. Random model was used when heterogeneity among studies was detected. No publication bias was observed. Conclusions: The two loci of PSCA (rs2294008 and rs2976392) were both significantly associated with GC susceptibility and in linkage disequilibrium. Impact: More prospective studies on PSCA polymorphisms at multicenters with sufficient sample size and less heterogeneity will be needed for further validations. ©2012 AACR.

Fang L.,Nanchang Hangkong University | Wang Y.,Tianjin Medical University | Chen F.,Nanchang Hangkong University
Journal of the Optical Society of America A: Optics and Image Science, and Vision | Year: 2012

We evaluated the impact of the Stiles-Crawford effect (SCE) on visual performance following laser in situ keratomileusis procedures. This prospective study included 71 eyes of 36 consecutive myopic patients (mean age, 20.94 ± 3.69 years). Ocular aberrations and contrast sensitivity were measured one month after surgery. The SCE was modeled optically as a filter placed in front of the eye, and then the modulation transfer functions (MTFs) and the predicted log contrast sensitivity were calculated from the measured wavefront aberration data. Then the visual Strehl ratio for MTF (VSMTF) was calculated. The results indicated that the computed MTF with SCE were superior to that without SCE. The predicted contrast sensitivity functions were underestimated about 20% when the SCE was not taken into account for the scotopic pupil. Moreover, the measured contrast sensitivity was not significantly different from that with SCE at 6, 12, and 18 cycles / deg spatial frequencies. According to the obtained VSMTF ratio, optical qualities of all eyes were underestimated with the range from 5% (0.02 log unit) to 65% (0.22 log unit) without SCE, and the average value is 41% (0.15 log unit). When only taking higher-order aberrations into account, the predicted postoperative visual performance would be different from the real values. The evaluation of postoperative visual performance from wavefront aberrations should consider not only the compensation relationship between defocus and spherical aberration but also the SCE. © 2012 Optical Society of America.

Hao Y.-B.,Xi'an Jiaotong University | Hao Y.-B.,Zhengzhou University | Yi S.-Y.,Zhengzhou University | Ruan J.,Tianjin Medical University | And 2 more authors.
Cancer Letters | Year: 2014

Chemotherapy is the mainstay of treatment in mid-advanced tumors. Considering their toxicity on hematopoietic cells, chemotherapeutics are often considered as immunosuppressive inducers. However, recently accumulating data indicate that some chemotherapeutic agents with specific administration schedules also display some positive immunological effect to contribute to tumor elimination. For instance, metronomic chemotherapy could promote tumor eradication not only by inhibiting tumor angiogenesis but also by selectively eliminating immunosuppressive cells and improving anti-tumor immune responses. In this review, we summarize what is currently known regarding metronomic chemotherapy-induced immunoregulation. Understanding of the molecular mechanisms of metronomic chemotherapy-induced immunoregulation may yield invaluable information for the optimal design of immunochemotherapies. © 2014 Elsevier Ireland Ltd. All rights reserved.

Jing L.,Tianjin Medical University | Qiu Y.,State University of New York at Buffalo | Zhang Y.,Research Triangle Institute | Li J.-X.,State University of New York at Buffalo
Drug and Alcohol Dependence | Year: 2014

Background: Cannabinoid CB1 receptors play an essential role in drug addiction. Given the side effect profiles of orthosteric CB1 antagonism, new strategies have been attempted to modulate this target, such as CB1 receptor allosteric modulation. However, the effect of CB1 allosteric modulation in drug addiction is unknown. The present study examined the effects of the CB1 receptor allosteric modulator ORG27569 on the reinstatement of cocaine- and methamphetamine-seeking behavior in rats. Methods: Rats were trained to self-administer 0.75 mg/kg cocaine or 0.05 mg/kg methamphetamine in 2-h daily sessions for 14 days which was followed by 7 days of extinction sessions in which rats responded on the levers with no programmed consequences. On reinstatement test sessions, rats were administered ORG27569 (1.0, 3.2, 5.6 mg/kg, i.p.) or SR141716A (3.2 mg/kg, i.p.) 10 min prior to re-exposure to cocaine- or methamphetamine-paired cues or a priming injection of cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.). Results: Both cues and a priming injection of cocaine or methamphetamine significantly reinstated the extinguished active lever responding. Pretreatment with ORG27569 resulted in a dose-related attenuation of both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior. SR141716A also exhibited similar inhibitory action on reinstatement of drug-seeking behavior. Conclusion: Negative allosteric modulation of CB1 receptors can produce similar functional antagonism as orthosteric CB1 receptor antagonists on reinstatement of drug-seeking behavior. Thus, ORG27569 or other negative allosteric modulators deserve further study as potentially effective pharmacotherapy for drug addiction. © 2014 Elsevier Ireland Ltd. All rights reserved.

Cui Y.,Johns Hopkins University | Cui Y.,Tianjin Medical University | Andersen D.K.,Johns Hopkins University | Andersen D.K.,Tianjin Medical University
Endocrine-Related Cancer | Year: 2012

Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage. © 2012 Society for Endocrinology.

Yang X.L.,Chinese University of Hong Kong | Yang X.L.,Tianjin Medical University | Ma R.C.W.,Chinese University of Hong Kong | So W.-Y.,Chinese University of Hong Kong | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Motivated by recent reports on associations between diabetes and cancer, many researchers have used administrative databases to examine risk association of cancer with drug use in patients with diabetes. Many of these studies suffered from major biases in study design and data analysis, which can lead to erroneous conclusions if these biases are not adjusted. This article discusses the sources and impacts of these biases and methods for correction of these biases. To avoid erroneous results, this article suggests performing sensitivity and specificity analysis as well as using a drug with a known effect on an outcome to ascertain the validity of the proposed methods. Using the Hong Kong Diabetes Registry, we illustrated the impacts of biases of drug use indication and prevalent user by examining the effects of statins on cardiovascular disease. We further showed that 'immortal time bias' may have a neutral impact on the estimated drug effect if the hazard is assumed to be constant over time. On the contrary, adjustment for 'immortal time bias' using time-dependent models may lead to misleading results biased towards against the treatment. However, artificial inclusion of immortal time in non-drug users to correct for immortal time bias may bias the result in favour of the therapy. In conclusion, drug use indication bias and prevalent user bias but not immortal time bias are major biases in the design and analysis of drug use effects among patients with diabetes in non-clinical trial settings. © 2011 Blackwell Publishing Ltd.

Yang D.,Wuhan University | Yang D.,Tianjin Medical University | Jia R.,Wuhan University | Ding G.,Wuhan University
American Journal of Nephrology | Year: 2013

Background: The precise mechanisms underlying radiocontrast nephropathy (RCN) are not well understood. Intracellular Ca2+ overload is considered to be a key factor in RCN. The Na+ /Ca2+ exchanger (NCX) system is one of the main pathways of intracellular Ca 2+ overload. We investigated whether intracellular Ca2+ overload via the NCX system was involved in contrast-induced renal tubular cytotoxicity. Methods: NRK-52E cells were exposed to ioversol (100 mg iodine/ml) for 4 h. KB-R7943 (inhibitor of reverse mode of NCX, 4 × 10-5, 4 × 10-6 M ) was added 1 h before incubation with ioversol. Cell viability and permeability were determined by 3-(4,5-dimethyldiazol-2-yl)- 2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assay. Apoptosis was determined by flow cytometry. Intracellular Ca2+ concentration ([Ca2+]i ) and reactive oxygen species (ROS) were detected by confocal microscopy. The expression of NCX1 mRNA and caspase-3 protein was evaluated by reverse transcription-polymerase chain reaction and Western blot, re-spectively. Results: Ioversol exposure induced significantly increased lactate dehydrogenase release and decreased 3-(4,5-dimethyldiazol-2-yl)-2,5- diphenyl tetrazolium bromide conversion in NRK-52E cells. Significantly increased apoptosis and caspase-3 protein expression were observed in the NRK-52E cells exposed to ioversol for 4 h. Ioversol treatment induced a significant increase in [Ca2+]i and intracellular ROS. KB-R7943 dose-dependently and significantly suppressed the increase in [Ca 2+]i, intracellular ROS and caspase-3 overexpression induced by ioversol and attenuated the contrast-induced NRK-52E cell apoptosis. No significant changes in NCX1 mRNA expression were observed following contrast exposure. Conclusion: Intracellular Ca2+ overload via the reverse mode of NCX, followed by ROS overproduction and caspase-3 overexpression played an important role in the contrast-induced renal tubular cytotoxicity. The reverse mode of the NCX inhibitor KB-R7943 attenuated contrast-induced renal tubular cytotoxicity. Copyright © 2013 S. Karger AG, Basel.

Yang D.,Tianjin Medical University | Lin S.,Tianjin Medical University | Yang D.,Wuhan University | Wei L.,Tianjin Medical University | Shang W.,Tianjin Medical University
American Journal of Nephrology | Year: 2012

Background: Whether hypercholesterolemia is a risk factor for contrast-induced acute kidney injury (CI-AKI) remains unclear. In the present study, the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity were evaluated. Methods: Rats were fed either a normal rodent diet (N) or high-cholesterol diet (H). At the end of 2 and 8 weeks, 8 rats from each diet group were given a tail vein injection of either iohexol (group NC and group HC) or vehicle (group N and group H). Blood lipids, renal function and renal hemodynamics were evaluated 1 day after contrast media administration. Renal and urinary prostaglandin E 2 (PGE 2) and thromboxane B 2 (TXB 2) were detected by radioimmunoassay. Renal nitric oxide and malondialdehyde (MDA) were measured by the Griess reaction and thiobarbituric acid method, respectively. Results: Contrast media administration increased serum creatinine levels and induced severe renal tubular necrosis in rats fed the high-cholesterol diet for 8 weeks but not in rats fed the normal diet or high-cholesterol diet for 2 weeks. The renal and urinary PGE 2 and TXB 2 levels increased significantly in rats in group H and group HC at the end of 8 weeks. Renal nitric oxide production decreased, and MDA levels increased markedly in group HC and group H at the end of 8 weeks. Conclusions: We conclude that long-term hypercholesterolemia appeared to be a risk factor for CI-AKI, which might be associated with disorders in intrarenal prostaglandins and abnormalities in renal nitric oxide system induced by lipid peroxidation. Copyright © 2011 S. Karger AG, Basel.

Cai J.,University of Louisville | Cai J.,Tianjin Medical University | Tuong C.M.,University of Louisville | Zhang Y.,Norton Neuroscience Institute | And 4 more authors.
Journal of Pathology | Year: 2012

Premature babies are at high risk for both infantile apnoea and long-term neurobehavioural deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development, and synapse formation mainly occur in the third trimester of gestation and first postnatal year, infantile apnoea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 and 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix, and cerebellum, but not in the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG, and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultrastructural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin, and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of synapsin I, synaptophysin, and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioural sequelae. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Zhang P.-P.,Tianjin Medical University | Zhang P.-P.,Hubei Cancer Hospital | Sun J.-W.,Hubei Cancer Hospital | Wang X.-Y.,Tianjin Medical University | And 2 more authors.
European Journal of Surgical Oncology | Year: 2013

Background and aims D-dimer is a stable end product of fibrin degradation that is associated with advanced tumor stage and poor prognosis in lung cancer patients. Venous thromboembolism (VTE) is a frequent complication of cancer and is associated with a poor prognosis in cancer patients. The purpose of the study is to elucidate whether the increased mortality in non-small cell lung (NSCLC) patients with elevated D-dimer levels is independent of VTE. Patients and methods A retrospective review was conducted of 232 patients with operable NSCLC from January 2007 to June 2008. All the patients underwent a pneumonectomy, lobectomy or wedge resection. We assessed the ability of preoperative plasma D-dimer levels to predict 1-year mortality and overall survival among them, and a multivariable Cox proportional-hazard regression analysis was performed after controlling for the following potential confounding factors: age, gender, TNM stage, histology, tumor size, VTE and surgical interventions. Results The overall 1-year survival rate was 91.4% (95% confidence interval (CI), 82.7-94.8%), with a 76.5% survival (95% CI, 71.4-81.6%) in the high D-dimer group and a 93.9% survival (95% CI, 86.4-97.9%) in the normal D-dimer group. Comparing the high D-dimer group with the normal D-dimer group, the adjusted hazard ratio for 1-year mortality and overall survival was 3.19 (95% CI, 1.18-7.12) and 1.54 (95% CI, 1.11-2.78) respectively. Conclusion Our study concluded that the preoperative plasma D-dimer level is an important prognostic biomarker in patients with operable NSCLC that is independent of VTE. © 2013 Elsevier Ltd. All rights reserved.

Chertok B.,University of Michigan | David A.E.,University of Michigan | David A.E.,ISTN Inc. | Yang V.C.,University of Michigan | Yang V.C.,Tianjin Medical University
Biomaterials | Year: 2011

The delivery of bioactive proteins to tumors is associated with many difficulties that have impeded clinical translation of these promising therapeutics. Herein we present an approach, including (1) use of magnetically-responsive and MRI-visible nanoparticles as drug carriers, (2) topography-optimized intra-arterial magnetic targeting, (3) MRI-guided subject alignment within the magnetic field, and (4) surface modification of the protein drug with membrane-permeable polyethyleneimine (PEI), to prevail over the obstacles in protein delivery. Applying these methodologies, we demonstrated the delivery of a significant quantity of β-Galactosidase selectively into brain tumors of glioma-bearing rats, while limiting the exposure of normal brain regions. Clinical viability of the technologies utilized, and the ability to deliver proteins at high nanomolar-range tumor concentrations, sufficient to completely eradicate a tumor lesion with existing picomolar-potency protein toxins, renders the prospect of enabling protein-based cancer therapy extremely promising. © 2011 Elsevier Ltd.

Jing L.,State University of New York at Buffalo | Jing L.,Tianjin Medical University | Zhang Y.,Research Triangle Institute | Li J.-X.,State University of New York at Buffalo
International Journal of Neuropsychopharmacology | Year: 2014

Background: Methamphetamine is a major drug of abuse with no effective pharmacotherapy available. Trace amine associated receptor 1 is implicated in cocaine addiction and represents a potential therapeutic target. However, the effects of trace amine associated receptor 1 agonists on addiction-related behavioral effects of methamphetamine are unknown. Methods: This study examined the effects of a trace amine associated receptor 1 agonist RO5263397 on methamphetamineinduced behavioral sensitization, methamphetamine self-administration, cue- and methamphetamine-induced reinstatement of drug seeking, and cue-induced reinstatement of sucrose-seeking behaviors in rats. Male Sprague-Dawley rats were used to examine the effects of methamphetamine alone and in combination with the trace amine associated receptor 1 agonist RO5263397 (3.2-10 mg/kg). Results: RO5263397 dose-dependently attenuated the expression of behavioral sensitization to methamphetamine, reduced methamphetamine self-administration, and decreased both cue- and a priming dose of methamphetamine-induced reinstatement of drug-seeking behaviors. However, RO5263397 did not alter cue-induced reinstatement of sucrose-seeking behavior. Conclusions: Taken together, trace amine associated receptor 1 agonists attenuate some abuse-related behavioral effects of methamphetamine, strongly suggesting that drugs activating trace amine associated receptor 1 may be potentially useful for the treatment of methamphetamine addiction and warrant further studies. © The Author 2015.

Xu Z.,Tianjin Medical University | Zhou J.,Xi'an Jiaotong University
BioMetals | Year: 2013

As an important trace element, zinc is required for the normal cellular structure and function, and impairment of zinc homeostasis is associated with a variety of health problems including cardiovascular disease. Zinc homeostasis is regulated through zinc transporters, zinc binding molecules, and zinc sensors. Zinc also plays a critical role in cellular signaling. Studies have documented that zinc homeostasis is impaired by ischemia/reperfusion in the heart and zinc dyshomeostasis may play a role in the pathogenesis of myocardial ischemia/reperfusion injury. Both exogenous and endogenously released zinc may play an important role in cardioprotection against ischemia/reperfusion injury. The goal of this review is to summarize the current understanding of the roles of zinc homeostasis and zinc signaling in myocardial ischemia/reperfusion injury. © 2013 Springer Science+Business Media New York.

Guo X.,Tianjin Medical University | Guo X.,Southern Research Institute | Yang C.,Southern Research Institute | Qian X.,Tianjin Medical University | And 5 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear. Experimental Design: We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. Onthe basis of the clinical data, we conducted siRNA knockdown to study the role of ERα on ATM expression in breast cancer cell lines. Furthermore, we used antisense oligonucleotides against micro RNAs (miRNA) or miRNA overexpression plasmids to study the role of miR-18a and -106a on ATM expression. Finally we used in situ hybridization to assess miR-18a and -106a expression in breast cancer tissues. Results: We found that in ER-negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage-response protein, is aberrantly upregulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we showed that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miR-18a and -106a to downregulate ATM expression. We also showed that miR-18a and -106a were significantly underexpressed in ER-negative breast cancer tissues. Conclusions: We reveal a novel mechanism involving ERα and miR-18a and -106a regulation of ATM in breast cancer. © 2013 American Association for Cancer Research.

Liu M.,University of Michigan | Liu M.,Tianjin Medical University | Lara-Lemus R.,University of Michigan | Shan S.-O.,California Institute of Technology | And 6 more authors.
Diabetes | Year: 2012

Recently, missense mutations upstream of preproinsulin's signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin- A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER-oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY. © 2012 by the American Diabetes Association.

Song F.,Tianjin Medical University | Song F.,Harvard University | Qureshi A.A.,Harvard University | Giovannucci E.L.,Harvard University | And 8 more authors.
PLoS Medicine | Year: 2013

Background: Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC. Methods and Findings: In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05-1.18), and in women (RR = 1.20; 95% CI 1.15-1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years). Conclusion: This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women. Please see later in the article for the Editors' Summary. © 2013 Song et al.

Li W.-Q.,Harvard University | Li W.-Q.,University of Rhode Island | Qureshi A.A.,Harvard University | Qureshi A.A.,University of Rhode Island | And 5 more authors.
JAMA Internal Medicine | Year: 2014

IMPORTANCE The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk. OBJECTIVE To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States. DESIGN, SETTING, AND PARTICIPANTS Our study is a prospective cohort study. In 2000, participants in the Health Professionals' Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25 848 men remained in the analysis. MAIN OUTCOMES AND MEASURES The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed. RESULTS We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95%CI, 1.04-3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95%CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95%CI, 1.14-3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95%CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use. CONCLUSIONS AND RELEVANCE Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association. Copyright 2014 American Medical Association. All rights reserved.

Su Y.,Tianjin Medical University | Fan W.,Tianjin Huanhu Hospital | Ma Z.,Baoding No 1 Hospital | Wen X.,Tianjin Medical University | And 3 more authors.
Neuroscience | Year: 2014

We investigated the effect of taurine on inflammatory cytokine expression, on astrocyte activity and cerebral edema and functional outcomes, following traumatic brain injury (TBI) in rats. 72 rats were randomly divided into sham, TBI and Taurine groups. Rats subjected to moderate lateral fluid percussion injury were injected intravenously with taurine (200. mg/kg) or saline immediately after injury or daily for 7. days. Functional outcome was evaluated using Modified Neurological Severity Score (mNSS). Glial fibrillary acidic protein (GFAP) of the brain was measured using immunofluorescence. Concentration of 23 cytokines and chemokines in the injured cortex at 1 and 7. days after TBI was assessed by Luminex xMAP technology. The results showed that taurine significantly improved functional recovery except 1. day, reduced accumulation of GFAP and water content in the penumbral region at 7. days after TBI. Compared with the TBI group, taurine significantly suppressed growth-related oncogene (GRO/KC) and interleukin (IL)-1β levels while elevating the levels of regulated on activation, normal T cell expressed and secreted (RANTES) at 1. day. And taurine markedly decreased the level of 17 cytokine: eotaxin, Granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17, leptin, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and only increased the level of MIP-1α in a week. The results suggest that taurine effectively mitigates the severity of brain damage in TBI by attenuating the increase of astrocyte activity and edema as well as pro-inflammatory cytokines. © 2014 IBRO.

Yang D.,Tianjin Medical University | Yang D.,Wuhan University | Jia R.,Wuhan University | Tan J.,Tianjin Medical University
Journal of Nephrology | Year: 2013

Background: Intracellular Ca2+ overload is considered to be a key factor in contrast-induced acute kidney injury (CI-AKI). The Na+/Ca2+ exchanger (NCX) system is one of the main pathways of intracellular Ca2+ overload. We investigated the effects of KB-R7943, an inhibitor of the reverse mode of NCX, on CI-AKI in a rat model. Method: Rats were divided into control group, CI-AKI group and pretreatment groups (with KB-R7943 dose of 5 or 10 mg/kg). CI-AKI was induced by diatrizoate administration in rats with cholesterol-supplemented diet for 8 weeks. Renal function and renal hemodynamics were determined 1 day following contrast medium administration. Renal histopathology was observed by light microscope. Renal tubular apoptosis was examined by TUNEL. Renal endothelin-1 (ET-1) was measured by radioimmunoassay. Renal malondialdehyde (MDA) and catalase (CAT) were measured as oxidative markers. Results: Levels of serum creatinine (Scr), renal ET-1, MDA and CAT, and resistance index (RI) of renal blood vessels increased significantly in CI-AKI rats. The increases in Scr and RI of renal blood vessels induced by diatrizoate were suppressed significantly and dose-dependently by pretreatment with KB-R7943. Histopathological and TUNEL results showed that the contrast medium-induced severe renal tubular necrosis and apoptosis were significantly and dosedependently attenuated by KB-R7943. KB-R7943 significantly suppressed the increment of renal ET-1 content and MDA and CAT level induced by contrast medium administration. Conclusion: Activation of the reverse mode of NCX, followed by ET-1 overproduction and increased oxidative stress, seems to play an important role in the pathogenesis of CI-AKI. The inhibitor of the reverse mode of NCX, KB-R7943, has renoprotective effects on CI-AKI. © 2013 Società Italiana di Nefrologia.

Yang D.,University of Houston | Khan S.,University of Houston | Khan S.,University of Helsinki | Sun Y.,University of Houston | And 5 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results. Objective: To determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer. Design, Setting, and Patients: Observational study of multidimensional genomics and clinical data on 316 high-grade serous ovarian cancer cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project. Main Outcome Measures: OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome). Results: BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P=.003 and 5-year OS, 61% for BRCA2-mutated vs 25% for BRCA wild-type cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22-0.74; P=.004 and 3-year PFS, 44% for BRCA2-mutated vs 16% for BRCA wild-type cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2-mutated vs 82% [P=.02] and 80% [P=.05] for BRCA wild-type and BRCA1-mutated cases, respectively) and longer platinum-free duration (median platinum-free duration, 18.0 months for BRCA2-mutated vs 11.7 [P=.02] and 12.5 [P=.04] months for BRCA wild-type and BRCA1-mutated cases, respectively). BRCA2-mutated, but not BRCA1-mutated cases, exhibited a "mutator phenotype" by containing significantly more mutations than BRCA wild-type cases across the whole exome (median mutation number per sample, 84 for BRCA2-mutated vs 52 for BRCA wildtype cases, false discovery rate <0.1). Conclusion: Among women with high-grade serous ovarian cancer, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type. ©2011 American Medical Association. All rights reserved.

Yang C.,Methodist Hospital Research Institute | Tang X.,Southern Research Institute | Guo X.,Methodist Hospital Research Institute | Guo X.,Tianjin Medical University | And 7 more authors.
Molecular Cell | Year: 2011

The ATM kinase plays a critical role in the maintenance of genetic stability. ATM is activated in response to DNA damage and is essential for cell-cycle checkpoints. Here, we report that ATM is activated in mitosis in the absence of DNA damage. We demonstrate that mitotic ATM activation is dependent on the Aurora-B kinase and that Aurora-B phosphorylates ATM on serine 1403. This phosphorylation event is required for mitotic ATM activation. Further, we show that loss of ATM function results in shortened mitotic timing and a defective spindle checkpoint, and that abrogation of ATM Ser1403 phosphorylation leads to this spindle checkpoint defect. We also demonstrate that mitotically activated ATM phosphorylates Bub1, a critical kinetochore protein, on Ser314. ATM-mediated Bub1 Ser314 phosphorylation is required for Bub1 activity and is essential for the activation of the spindle checkpoint. Collectively, our data highlight mechanisms of a critical function of ATM in mitosis. © 2011 Elsevier Inc.

Leavenworth J.W.,Dana-Farber Cancer Institute | Leavenworth J.W.,Harvard University | Verbinnen B.,Dana-Farber Cancer Institute | Verbinnen B.,Harvard University | And 6 more authors.
Nature Immunology | Year: 2015

Follicular helper T cells (T FH cells) and follicular regulatory T cells (T FR cells) regulate the quantity and quality of humoral immunity. Although both cell types express the costimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that activation of ICOS in CD4+ T cells promoted interaction of the p85α regulatory subunit of the signaling kinase PI(3)K and intracellular osteopontin (OPN-i), followed by translocation of OPN-i to the nucleus, its interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 by OPN-i was essential for sustained responses of T FH cells and T FR cells and regulation of the germinal center B cell response to antigen. Thus, the p85α-OPN-i axis represents a molecular bridge that couples activation of ICOS to Bcl-6-dependent functional differentiation of T FH cells and T FR cells; this suggests new therapeutic avenues to manipulate the responses of these cells. © 2015 Nature America, Inc.

Yan W.,Chinese PLA General Hospital | Wu K.,Huazhong University of Science and Technology | Herman J.G.,Johns Hopkins University | Brock M.V.,Johns Hopkins University | And 6 more authors.
Epigenetics | Year: 2013

Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC. © 2013 Landes Bioscience.

Deng J.,Tianjin Medical University | Liang H.,Tianjin Medical University | Ying G.,Tianjin Medical University | Zhang R.,Tianjin Medical University | And 4 more authors.
Oncotarget | Year: 2014

RNF 180, a novel tumor suppressor, has been implicated in the carcinogenesis and progress of gastric cancer. At present study, we found that lower expression of RNA180 was specific in gastric cancer tissues, and the inconsistently methylated levels of RNF180 promoter were identified in the gastric cancer tissues. Importantly, we demonstrated that the methylated CpG site count and four hypermethylated CpG sites (-116, -80, +97, and +102) were significantly associated with the survival of 400 gastric cancer patients, respectively. With multivariate survival analyses, we demonstrated that both the methylation of combined CpG (-116, -80, +97, and +102) sites and N stage were the independent indictor of prognosis of gastric cancer patients. Eventually, the methylation of combined CpG (-116, -80, +97, and +102) sites was identified to have smaller AIC value than N stage by mean of AIC calculation with the Cox proportional hazards model. These findings indicated that the quantitative detection of RNF180 promoter methylation had the intensive feasibility for evaluation the prognosis of gastric cancer patients in clinic. © 2008-2014 Impact Journals, LLC.

Xiong S.,University of Texas M. D. Anderson Cancer Center | Mu T.,Dalian Medical University | Wang G.,Tianjin Medical University | Jiang X.,Sloan Kettering Cancer Center
Protein and Cell | Year: 2014

The mitochondria-mediated caspase activation pathway is a major apoptotic pathway characterized by mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c into the cytoplasm to activate caspases. MOMP is regulated by the Bcl-2 family of proteins. This pathway plays important roles not only in normal development, maintenance of tissue homeostasis and the regulation of immune system, but also in human diseases such as immune disorders, neurodegeneration and cancer. In the past decades the molecular basis of this pathway and the regulatory mechanism have been comprehensively studied, yet a great deal of new evidence indicates that cytochrome c release from mitochondria does not always lead to irreversible cell death, and that caspase activation can also have non-death functions. Thus, many unsolved questions and new challenges are still remaining. Furthermore, the dysfunction of this pathway involved in cancer development is obvious, and targeting the pathway as a therapeutic strategy has been extensively explored, but the efficacy of the targeted therapies is still under development. In this review we will discuss the mitochondria-mediated apoptosis pathway and its physiological roles and therapeutic implications. © 2014, The Author(s).

Xu W.L.,University of Stockholm | Xu W.L.,Tianjin Medical University | Xu W.L.,Karolinska Institutet | Atti A.R.,University of Stockholm | And 8 more authors.
Neurology | Year: 2011

Objective: The relation of overweight to dementia is controversial. We aimed to examine the association of midlife overweight and obesity with dementia, Alzheimer disease (AD), and vascular dementia (VaD) in late life, and to verify the hypothesis that genetic and early-life environmental factors contribute to the observed association. Methods: From the Swedish Twin Registry, 8,534 twin individuals aged ≥65 (mean age 74.4) were assessed to detect dementia cases (DSM-IV criteria). Height and weight at midlife (mean age 43.4) were available in the Registry. Data were analyzed as follows: 1) unmatched case-control analysis for all twins using generalized estimating equation (GEE) models and 2) cotwin matched case-control approach for dementia-discordant twin pairs by conditional logistic regression taking into account lifespan vascular disorders and diabetes. Results: Among all participants, dementia was diagnosed in 350 subjects, and 114 persons had questionable dementia. Overweight (body mass index [BMI] >25-30) and obesity (BMI >30) at midlife were present in 2,541 (29.8%) individuals. In fully adjusted GEE models, compared with normal BMI (20-25), overweight and obesity at midlife were related to dementia with odds ratios (ORs) (95% CIs) of 1.71 (1.30-2.25) and 3.88 (2.12-7.11), respectively. Conditional logistic regression analysis in 137 dementia-discordant twin pairs led to an attenuated midlife BMI-dementia association. The difference in ORs from the GEE and the matched case-control analysis was statistically significant (p = 0.019). Conclusions: Both overweight and obesity at midlife independently increase the risk of dementia, AD, and VaD. Genetic and early-life environmental factors may contribute to the midlife high adiposity-dementia association. © 2011 by AAN Enterprises, Inc. All rights reserved.

Chalyan D.A.,University of California at Irvine | Chalyan D.A.,University of Iowa | Zhang Z.,University of California at Irvine | Zhang Z.,Tianjin Medical University | And 2 more authors.
Circulation: Cardiovascular Interventions | Year: 2014

Background-Diastolic fractional flow reserve (dFFR) has been shown to be highly sensitive for detection of inducible myocardial ischemia. However, its reliance on measurement of left-ventricular pressure for zero-flow pressure correction, as well as manual extraction of the diastolic interval, has been its major limitation. Given previous reports of minimal zero-flow pressure at end-diastole, we compared instantaneous ECG-gated end-diastolic FFR with conventional fullcardiac cycle FFR and other diastolic indices in the porcine model. Methods and Results-Measurements of FFR in the left anterior descending and left circumflex arteries were performed in an open-chest swine model with an external occluder device on the coronary artery used to produce varying degrees of epicardial stenosis. An ultrasound flow-probe that was placed proximal to the occluder measured absolute blood flow in ml/min, and it was used as a gold standard for FFR measurement. A total of 17 measurements at maximal hyperemia were acquired in 5 animals. Correlation coefficient between conventional mean hyperemic FFR with pressure-wire and directly measured FFR with flow-probe was 0.876 (standard error estimate=0.069; P<0.0001). The hyperemic enddiastolic FFR with pressure-wire correlated better with FFR measured directly with flow-probe (r=0.941, standard error estimate=0.050; P<0.0001). Conclusions-Instantaneous hyperemic ECG-gated FFR acquired at end-diastole, as compared with conventional full-cardiac cycle FFR, has an improved correlation with FFR measured directly with ultrasound flow-probe. © 2014 American Heart Association, Inc.

Xu W.,Karolinska Institutet | Xu W.,Tianjin Medical University | Caracciolo B.,Karolinska Institutet | Wang H.-X.,Karolinska Institutet | And 5 more authors.
Diabetes | Year: 2010

OBJECTIVE - The effect of diabetes on mild cognitive impairment (MCI) and its conversion to dementia remains controversial. We sought to examine whether diabetes and pre-diabetes are associated with MCI and accelerate the progression from MCI to dementia. RESEARCH DESIGN AND METHODS - In the Kungsholmen Project, 963 cognitively intact participants and 302 subjects with MCI (120 with amnestic MCI [aMCI ] and 182 with other cognitive impairment no dementia [oCIND]) age ≥75 years were identified at baseline. The two cohorts were followed for 9 years to detect the incident MCI and dementia following international criteria. Diabetes was ascertained based on a medical examination, hypoglycemic medication use, and random blood glucose level ≥11.0 mmol/l. Pre-diabetes was defined as random blood glucose level of 7.8 -11.0 mmol/l in diabetes-free participants. Data were analyzed using standard and time-dependent Cox proportional-hazards models. RESULTS - During the follow-up period, in the cognitively intact cohort, 182 people developed MCI (42 aMCI and 140 oCIND), and 212 developed dementia. In the MCI cohort, 155 subjects progressed to dementia, the multi-adjusted hazard ratio (95% CI) of dementia was 2.87 (1.30-6.34) for diabetes, and 4.96 (2.27-10.84) for pre-diabetes. In a Kaplan-Meier survival analysis, diabetes and pre-diabetes accelerated the progression from MCI to dementia by 3.18 years. Diabetes and pre-diabetes were neither cross-sectionally nor longitudinally associated with MCI. CONCLUSIONS - Diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia, and anticipate dementia occurrence by more than 3 years in people with MCI. The association of diabetes with the development of MCI is less evident in old people. © 2010 by the American Diabetes Association.

Pan J.G.,Guangzhou University | Zhou X.,Guangzhou University | Zeng G.W.,Guangzhou University | Han R.F.,Tianjin Medical University
Tumor Biology | Year: 2011

Novel treatment strategies such as gene therapy are warranted in view of the failure of current treatment approaches to cure a high percentage of patients with advanced bladder cancers. Testing of the hypothesis that blocking the angiogenic switch may keep tumour growth in check has been facilitated by the discovery of endogenous inhibitors of angiogenesis and has also added another research dimension to the field of cancer gene therapy. Consequently, the concept of targeting the tumour vasculature with anti-angiogenic agents has emerged as an attractive new strategy in the treatment of cancer. Targeted biological therapies that selectively interfere with tumour angiogenesis could improve survival among patients with bladder cancer. Endostatin is a tumour-derived angiogenesis inhibitor and is the first endogenous inhibitor of angiogenesis to be indentified in a matrix protein. Gene therapy represents an attractive approach to treat cancers and other chronic diseases. The development of an effective delivery system is absolutely critical to the usefulness and safety of gene therapy. At present, the adeno-associated virus (AAV) vector has the most promising potential in view of its non-pathogenicity, wide tropisms and long-term transgene expression in vivo. Gene therapy studies using different serotypes of recombinant AAV (rAAV) as delivery vehicles have proved rAAVs to be an effective modality of cancer gene therapy. In the present study, an IgG fragment was inserted at the start of the sequence coding for endostatin with the aim of enabling continuous secretion of endostatin the serum. We also investigated the suppression effect of AAV-mediated endostatin expression on endothelial cells and in mice xenograft models of bladder cancer. Our data demonstrates that rAAV-endostatin controlled tumour cell growth and achieves strong anti-tumour efficacy in vivo. © International Society of Oncology and BioMarkers (ISOBM) 2010.

Wu Y.,Florida College | Zhao Y.,Florida College | Ma X.,Florida College | Zhu Y.,Tianjin Medical University | And 2 more authors.
Biochemical Journal | Year: 2013

AGAP2 [Arf (ADP-ribosylation factor) GAP (GTPase-activating protein) with GTP-binding-protein-like, ankyrin repeat and PH (pleckstrin homology) domains] is a multidomain Arf GAP that was shown to promote the fast recycling of transferrin receptors. In the present study we tested the hypothesis that AGAP2 regulates the trafficking of β2-adrenergic receptors. We found that AGAP2 formed a complex with β-arrestin1 and β-arrestin2, proteins that are known to regulate β2-adrenergic receptor signalling and trafficking. AGAP2 co-localized with β-arrestin2 on the plasma membrane, and knockdown of AGAP2 expression reduced plasma membrane association of β-arrestin2 upon β2-adrenergic receptor activation. AGAP2 also co-localized with internalized β2-adrenergic receptors on endosomes, and overexpression of AGAP2 slowed accumulation of β2-adrenergic receptor in the perinuclear recycling endosomes. In contrast, knockdown of AGAP2 expression prevented the recycling of the β2-adrenergic receptor back to the plasma membrane. In addition, AGAP2 formed a complex with endogenous ERK (extracellular-signal-regulated kinase) and overexpression of AGAP2 potentiated ERK phosphorylation induced by β2-adrenergic receptors. Taken together, these results support the hypothesis that AGAP2 plays a role in the signalling and recycling of β2-adrenergic receptors. © The Authors Journal compilation © 2013 Biochemical Society.

Zhang J.,Tianjin Medical University | Wang Y.,Tianjin Huanhu Hospital | Yin Q.,WuQing Hospital | Zhang W.,Tianjin Medical University | And 2 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2013

Background: Triple negative breast cancer (TNBC) is heterogeneous and considered as an aggressive tumor. This study was to evaluate the associated classification and its correlations with prognosis and the response to chemotherapy in Chinese women. Methods: Four hundred and twenty-eight cases of invasive TNBC were involved in this study. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6), Ki67 and p53 were analyzed by immunohistochemistry and compared with patient outcome, and its implications and chemotherapy response were evaluated in four subgroups: typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), non-specific invasive ductal carcinoma (IDC) and other types. Results: The factors of tumor grade, tumor stage, lymph node status, EGFR/CK5/6 status and p53 labeling index were different among the groups. TMC tumors had the lowest rate of relapse (5.8%), while AMC, IDC and other types were associated with an increased risk of relapse (19.1%, 26.7% and 38.2% respectively). Many factors were risk predictors of relapse for TNBC and IDC, while only positive lymph node was for AMC. For MC tumors, adjunctive chemotherapy decreased the risk of relapse in lymph node positive subgroup (36.8% and 66.7%), while not significant in lymph node negative one (8.1% and 10.0%). Conclusion: The classification based on histologic and IHC findings may be a significant improvement in predicting outcome in TNBC. The different chemotherapy response in subgroups may contribute to guiding the treatment of TNBC.

Wang C.,Tianjin Medical University | Zheng X.,Tianjin Medical University | Shen C.,Chinese Armed Police Medical Institute Affiliated Hospital | Shi Y.,Tianjin Cancer Institute
Journal of Experimental and Clinical Cancer Research | Year: 2012

Background: This study was performed to investigate the effect of microRNA-203 (miR-203) on cell proliferation and migration in triple-negative breast cancer (TNBC). Methods: Real-time PCR was performed to detect the expression of miR-203 in TNBC cell lines. miR-203 precursor and control microRNA (miRNA) were transfected into triple-negative breast cancer (TNBC) cell lines and the effects of miR-203 up-regulation on the proliferation and migration of cells were investigated. Meanwhile, the mRNA and protein levels of baculoviral IAP repeat-containing protein 5 (BIRC5) and Lim and SH3 domain protein 1 (LASP1) were measured. Luciferase assays were also performed to validate BIRC5 and LASP1 as miR-203 targets. Results: Both miR-203 and BIRC5 siRNA signicantly inhibited cell proliferation in TNBC cells. Both miR-203 and LASP1 siRNA signicantly inhibited cell migration in TNBC cells, also. Moreover, up-regulated of BIRC5 and LASP1 was able to abrogate the effects induced by transfection with the miR-203 precursor. Conclusions: These data suggest that miR-203 may function as a tumor suppressor in TNBC cells. Thus, miR-203 could be a potential therapeutic target for this disease. © 2012 Wang et al.; licensee BioMed Central Ltd.

Huang B.,Tianjin Medical University | Cheng X.,Tianjin Medical University | Wang D.,Tianjin Medical University | Peng M.,Tianjin Medical University | And 7 more authors.
Oncotarget | Year: 2014

Adiponectin is an adipocyte-secreted adipokine with pleiotropic actions. Clinical evidence has shown that serum adiponectin levels are increased and that adiponectin can protect pancreatic beta cells against apoptosis, which suggests that adiponectin may play an anti-apoptotic role in pancreatic cancer (PC). Here, we investigated the effects of adiponectin on PC development and elucidated the underlying molecular mechanisms. Adiponectin deficiency markedly attenuated pancreatic tumorigenesis in vivo. We found that adiponectin significantly inhibited the apoptosis of both human and mouse pancreatic cancer cells via adipoR1, but not adipoR2. Furthermore, adiponectin can increase AMP-activated protein kinase (AMPK) phosphorylation and NAD-dependent deacetylase sirtuin-1 (Sirt1) of PC cells. Knockdown of AMPK or Sirt1 can increase the apoptosis in PC cells. AMPK up-regulated Sirt1, and Sirt1 can inversely phosphorylate AMPK. Further studies have shown that Sirt1 can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a), which can increase the expression levels of mitochondrial genes. Thus, adiponectin exerts potent anti-apoptotic effects on PC cells via the activation of AMPK/Sirt1/PGC1a signaling. Finally, adiponectin can elevate ß-catenin levels. Taken together, these novel findings reveal an unconventional role of adiponectin in promoting pancreatic cancers, and suggest that the effects of adiponectin on tumorigenesis are highly tissue-dependent.

Goudis C.A.,General Hospital of Grevena | Korantzopoulos P.,University of Ioannina | Ntalas I.V.,University of Ioannina | Kallergis E.M.,University of Crete | And 2 more authors.
International Journal of Cardiology | Year: 2015

Diabetes mellitus (DM) represents one of the most important risk factors for atrial fibrillation (AF) while AF is a strong and independent marker of overallmortality and cardiovascularmorbidity in diabetic patients. Autonomic, electrical, electromechanical, and structural remodeling, including oxidative stress, connexin remodeling and glycemic fluctuations seemto be implicated in AF pathophysiology in the setting of DM. The present reviewhighlights the association between DMand AF, provides a comprehensive overview of the responsible pathophysiological mechanisms and briefly discusses potential upstream therapies for DM-related atrial remodeling. © 2015 Elsevier Ireland Ltd. All rights reserved.

Zheng X.,Tianjin Medical University | Wei S.,Tianjin Medical University | Han Y.,Tianjin Medical University | Li Y.,Southern Medical University | And 4 more authors.
Annals of Surgical Oncology | Year: 2013

Background: Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies. It is estimated that papillary thyroid microcarcinoma (PTMC) accounts for up to 30 % of all PTCs. The clinical significance of PTMC is still unclear, although it may be related to recurrence, distant metastasis, and mortality. The purpose of this study was to analyze the clinical characteristics and BRAFV600E mutational status of PTMCs in a Chinese population and to determine risk factors for poor prognosis. Methods: We performed a retrospective review of 977 PTMC cases that underwent surgical resection from January 2001 to January 2010 at Tianjin Medical University Cancer Institute and Hospital. Results: The mean size of 977 PTMCs was 5.2 (range, 2-10) mm. Multifocal tumors were seen in 323 patients. The majority of patients (692) had a T1 lesion, whereas 279 had T3 and 6 had T4a; 40.1 % patients had BRAFV600E mutation. The frequencies of extrathyroidal extension and lymph node metastasis were 29.2 and 23.4 %, respectively. Distant metastasis was present in 15 patients. Half of the patients (50.8 %) received a total thyroidectomy and others had a lobectomy. Conclusions: The present study suggests that highly aggressive PTMCs may arise in a subset of patients with BRAFV600E mutation and tumors greater than 5 mm. Extrathyroidal invasion, lymph node metastases, and the type of surgical procedures were significantly associated with tumor recurrence. Although multivariate analysis showed that tumor recurrence was not associated with BRAFV600E mutation, it has not been shown that treating these patients more aggressively changes outcomes. © 2013 Society of Surgical Oncology.

Zhao A.,Tianjin Medical University | Qin H.,Tianjin Medical University | Fu X.,Chinese PLA General Hospital
BioScience | Year: 2016

The regenerative phenomenon is widespread, but regenerative capacity varies greatly across animals. Invertebrates and phylogenetically primitive vertebrates, such as salamanders and zebrafish, often possess a higher regenerative capacity than mammals have. Even in the same individual, different tissues or organs exhibit distinct regenerative capacity; for example, livers regenerate more readily than hearts in mammals. In addition, the younger animal is usually easier to regenerate than the older. Decades of research are beginning to yield explanations about why regenerative capacity differs markedly, based on cellular and molecular components and evolutionary ideas. Here, we discuss several reasons for differences in regenerative capacity, including the properties of stem cells, dedifferentiation and transdifferentiation potentials, expression of regeneration-associated genes, epigenetic regulators, and immune responses. Comprehensive analyses of these perspectives would provide new insights into how to promote regeneration in mammals. © The Author(s) 2016. Published by Oxford University Press on behalf of the American Institute of Biological Sciences.

Xie K.,Tianjin Medical University | Yu Y.,Tianjin Medical University | Pei Y.,PLA Fourth Military Medical University | Hou L.,PLA Fourth Military Medical University | And 3 more authors.
Shock | Year: 2010

Despite recent advances in antibiotic therapy and intensive care, sepsis is still considered to be the most common cause of death in intensive care units. Excessive production of reactive oxygen species plays an important role in the pathogenesis of sepsis. Recently, it has been suggested that molecular hydrogen (H2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radicals (•OH, the most cytotoxic reactive oxygen species) and effectively protects against organ damage induced by I/R. Therefore, we hypothesized that H2 treatment had a beneficial effect on sepsis. In the present study, we found that H2 inhalation starting at 1 and 6 h after cecal ligation and puncture (CLP) or sham operation significantly improved the survival rate of septic mice with moderate or severe CLP in a concentration-and time-dependent manner. Furthermore, moderate or severe CLP mice showed significant multiple organ damage characterized by the increases of lung myeloperoxidase activity, wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters, and organ histopathologic scores at 24 h after CLP operation, which was significantly attenuated by 2% H2 treatment. In addition, we found that the beneficial effects of H2 treatment on sepsis and sepsis-associated organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzymes, and reduced levels of high-mobility group box 1 in serum and tissue. Thus, H2 inhalation may be an effective therapeutic strategy for patients with sepsis. Copyright © 2010 by the Shock Society.

Wang Z.,Nanjing Medical University | Fu Y.,Nanjing Medical University | Tang C.,Nanjing Medical University | Lu S.,Tianjin Medical University | Chu W.-M.,Brown University
Breast Cancer Research and Treatment | Year: 2010

The SULT1A1 R213H polymorphism is suggested to be implicated in the development and progression of breast cancer. However, the published findings are inconsistent. We therefore performed a meta-analysis of 8,454 breast cancer cases and 11,800 controls from 14 published case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association of the R213H polymorphism with breast cancer risk. Overall, our results suggested that there is no significant relationship between SULT1A1 R213H polymorphism and the risk of breast cancer. However, further ethnic population analysis revealed a significantly increased risk of breast cancer for HH allele carriers among Asians (for HH vs. RR: OR = 2.27, 95% CI = 1.11-4.63, P heterogeneity = 0.63; for the recessive model: OR = 2.03, 95% CI = 1.00-4.41, P heterogeneity = 0.62). Taken together, this meta-analysis suggests that the SULT1A1 R213H may be a low-penetrant risk factor for developing breast cancer in Asian population. © 2009 Springer Science+Business Media, LLC.

Liu Y.-C.,Tianjin Medical University | Zou X.-B.,Chinese PLA General Hospital | Chai Y.-F.,Tianjin Medical University | Yao Y.-M.,Chinese PLA General Hospital
International Journal of Biological Sciences | Year: 2014

Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases. © Ivyspring International Publisher.

Liu G.,University of Houston | Liu G.,Tianjin Medical University | Sun Y.,University of Houston | Sun Y.,Tianjin Medical University | And 11 more authors.
Journal of Pathology | Year: 2014

Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has anti-tumour activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over-expression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that CDK4 and CDK6 are direct targets of miR-506, and that miR-506 can inhibit CDK4/6-FOXM1 signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506-CDK4/6-FOXM1 axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Yang J.,Columbia University | Yang J.,Tianjin Medical University | Li Y.,Columbia University | Chan L.,Columbia University | And 9 more authors.
Human Molecular Genetics | Year: 2014

While the past decade has seen great progress in mapping loci for common diseases, studying how these risk alleles lead to pathology remains a challenge. Age-related macular degeneration (AMD) affects 9 million older Americans, and is characterized by the loss of the retinal pigment epithelium (RPE). Although the closely linked genome-wide association studies ARMS2/HTRA1 genes, located at the chromosome 10q26 locus, are strongly associated with the risk of AMD, their downstream targets are unknown.Low population frequencies of risk alleles in tissue banks make it impractical to study their function in cells derived from autopsied tissue. Moreover, autopsy eyes from end-stage AMD patients, where age-related RPE atrophy and fibrosis are already present, cannot be used to determine how abnormal ARMS2/HTRA1 expression can initiate RPE pathology. Instead, induced pluripotent stem(iPS) cell-derived RPE from patients provides us with earlier stage AMD patient-specific cells and allowsus toanalyze the underlying mechanisms at this critical time point.An unbiased proteome screen of A2E-aged patient-specific iPS-derived RPE cell lines identified superoxide dismutase 2 (SOD2)-mediated antioxidative defense in the genetic allele's susceptibility of AMD. The AMD-associated risk haplotype (T-in/del-A) impairs the ability of the RPE to defend against aging-related oxidative stress. SOD2 defense is impaired in RPE homozygous for the risk haplotype (T-in/del-A; T-in/del-A), while the effect was less pronounced in RPE homozygous for the protective haplotype (G-Wt-G; G-Wt-G). ARMS2/HTRA1 risk alleles decrease SOD2 defense, making RPE more susceptible to oxidative damage and thereby contributing to AMD pathogenesis. © The Author 2014.Published by Oxford University Press. All rights reserved.

Wang Y.Q.,Tianjin University | Guo J.,Tianjin University | Chen W.,Southern Medical University | Zhang W.,Tianjin Medical University
Signal Processing | Year: 2013

The Perona-Malik (PM) model, or the anisotropic diffusion, shows good performance for image restoration. However, it suffers from the so-called staircasing effect if the contrast parameter is small and otherwise cannot preserve edges. This paper proposes a modified Perona-Malik (MPM) model based on directional Laplacian, which diffuses image along the edge direction of the original image. A slightly weighted Laplacian is also integrated to suppress noise. The proposed model can alleviate the staircasing effect, preserve sharp discontinuities, and remove noise simultaneously. Experimental results compared with several relevant methods demonstrate the good performance of the proposed algorithm. © 2013 Elsevier B.V. All rights reserved.

Tian R.,Tianjin Medical University | Chen J.,Tianjin University | Niu R.,Tianjin Medical University
Nanoscale | Year: 2014

To improve the anti-cancer efficacy and to counteract the side effects of chemotherapy, a variety of drug delivery systems have been invented in past decades, but few of these systems have succeeded in clinical trials due to their respective inherent shortcomings. Recently, low-molecular weight hydrogels of peptides that self-assemble via non-covalent interactions have attracted considerable attention due to their good biocompatibility, low toxicity, inherent biodegradability as well as their convenience of design. Low-molecular weight hydrogels have already shown promise in biomedical applications as diverse as 3D-cell culture, enzyme immobilization, controllable MSC differentiation, wound healing, drug delivery etc. Here we review the recent development in the use of low-molecular weight hydrogels for cancer therapy, which may be helpful in the design of soft materials for drug delivery. This journal is © the Partner Organisations 2014.

Zhao H.,Tianjin Medical University | Zhang Y.,Tianjin Medical University | Xue F.,Chinese Academy of Sciences | Xu J.,Ningbo University | Fang Z.,Ningbo University
Autoimmunity | Year: 2013

The aim of the present study was to investigate the association of single nucleotide polymorphisms (SNP) of the interleukin-27 (IL-27) genes with the risk for immune thrombocytopenia (ITP). In this case-control study, the genotyping of IL-27 rs153109 polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In ITP patients, the frequencies of GG, GA and AA genotypes, and G and A alleles were 9.7%, 58.5%, 31.8%, 38.9% and 61.1%, respectively. There was no significant difference in genotype and alleles distribution between the ITP patient and the healthy controls (p=0.68 and 0.80, respectively). Similar results were found between the two groups when stratified by the age and disease course including non-chronic adult, chronic adult, non-chronic childhood, and chronic childhood. In conclusion, the IL-27 polymorphism may not be involved in susceptibility to ITP in a Chinese population. © 2013 Informa UK Ltd.

Pu Y.,City University of New York | Chen J.,Tianjin Medical University | Wang W.,City University of New York
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2014

The scattering coefficient, μs, the anisotropy factor, g, the scattering phase function, p(θ), and the angular dependence of scattering intensity distributions of human cancerous and normal prostate tissues were systematically investigated as a function of wavelength, scattering angle and scattering particle size using Mie theory and experimental parameters. The Matlab-based codes using Mie theory for both spherical and cylindrical models were developed and applied for studying the light propagation and the key scattering properties of the prostate tissues. The optical and structural parameters of tissue such as the index of refraction of cytoplasm, size of nuclei, and the diameter of the nucleoli for cancerous and normal human prostate tissues obtained from the previous biological, biomedical and bio-optic studies were used for Mie theory simulation and calculation. The wavelength dependence of scattering coefficient and anisotropy factor were investigated in the wide spectral range from 300 nm to 1200 nm. The scattering particle size dependence of μs, g, and scattering angular distributions were studied for cancerous and normal prostate tissues. The results show that cancerous prostate tissue containing larger size scattering particles has more contribution to the forward scattering in comparison with the normal prostate tissue. In addition to the conventional simulation model that approximately considers the scattering particle as sphere, the cylinder model which is more suitable for fiber-like tissue frame components such as collagen and elastin was used for developing a computation code to study angular dependence of scattering in prostate tissues. To the best of our knowledge, this is the first study to deal with both spherical and cylindrical scattering particles in prostate tissues. © 2014 SPIE.

Chen S.,Tianjin Medical University | Yan H.,Tianjin Medical University | Sun B.,Tianjin Medical University | Zuo A.,Doheny Eye Institute | Liang D.,Doheny Eye Institute
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

The local interaction between retinal pigment epithelium (RPE) and immigrated effector T cells is crucial for the pathogenesis of autoimmune uveitis. After being activated by the pattern recognition receptors (PRRs) signaling pathway, RPE can present the antigen reactivated invading autoreactive T cells, resulting in uveitis. In the present study, we showed that the transfection of chitosan-loaded TLR3-siRNA toward RPE could effectively remit experimental autoimmune uveitis (EAU) in B10RIII mice. Initially, we verified the constitutive expression of Tlr3 in RPE at high levels, which was not altered in response to TNFα, IFNγ and IL-17A treatments. Compared with other TLRs, the activation of TLR3 signaling following polyIC treatment resulted in increased IL-6 and IFNγ secretion from and MHCII expression on RPE. It is polyIC-, but not other TLR ligands, treated RPE showed significant synergetic effect with IL-17 on stimulating RPE secreting CXCL8 and CCl2, which might be resulted from elevated Il17ra expression in RPE following polyIC treatment. Furthermore, polyIC-treated RPE caused a robust stimulation of differentiation of CD4 cell toward Th1 or Th17 cells, in addition to the secretion of the cytokines IFNγ and IL-17. The in vitro knockdown of TLR3 expression in RPE by chitosan/TLR3-siRNA transfection could effectively block polyIC-induced MHCII expression, pro-inflammatory cytokine secretion and autoreactive CD4 cell activation. Studies conducted in firefly luciferase gene transgenic mice demonstrated that the subretinal CS/Luci-siRNA transfection specifically reduced the luciferase activity in RPE but not in the liver and spleen. Finally, the CS/TLR3-siRNA was locally administered in the EAU induced B10RIII mice. The results revealed that chitosan-mediated TLR3-siRNA transfection had a significant therapeutic effect on either delaying the outbreak or remitting the severity of uveitis.

Zhu H.-J.,Tianjin University | Liu J.-H.,Tianjin University | Sun L.-F.,Tianjin Medical University | Hu Z.-F.,Tianjin University | Qiao J.-J.,Tianjin University
Bioresource Technology | Year: 2013

Spent mushroom substrate (SMS) was pretreated with alkaline reagents including potassium hydroxide, lime and ammonia to enhance enzymatic saccharification. Under the best pretreatment conditions (1M KOH, 80°C, 90min; 1M lime, 80°C, 120min; 10M ammonia, 70°C, 120min), the total reducing sugar (TRS) yield reached 258.6, 204.2 and 251.2mg/g raw SMS, which were respectively 6.15, 4.86, and 5.98times of untreated SMS. The effects of pretreatment by above alkaline reagents and sulfuric acid on the composition and structure of SMS were evaluated to provide comparative performance data. A new process, combined alkali and acid (CAA) pretreatment followed by enzymatic hydrolysis, was innovatively proposed to improve the cost-effectiveness and avoid environmental problems. The SMS residue after CAA pretreatment-enzymatic hydrolysis process was converted to biofertilizer with Pichia farinose FL7 and a cell density of 3.0×108cfu/g in biomass was attained. © 2013 Elsevier Ltd.

Li M.,University of Electronic Science and Technology of China | Chen H.,University of Electronic Science and Technology of China | Wang J.,Tianjin Medical University | Liu F.,University of Electronic Science and Technology of China | And 3 more authors.
Neuropsychologia | Year: 2015

Altered structure in the temporal cortex has been implicated in the variable language laterality of left-handers (LH). The neuroanatomy of language lateralization and the corresponding synchronous functional connectivity (FC) in handedness cohorts are not, however, fully understood. We used structural and resting-state functional magnetic resonance imaging (fMRI) data to investigate the effect of altered cortical thickness on FC in LH and right-handers (RH). Whole-brain cortical thickness was calculated and compared between the LH and RH. We observed increased cortical thickness in the right superior temporal gyrus (STG) in the LH. A further FC analysis was conducted between the right STG and the remaining voxels in the brain. Compared with RH, the LH showed significantly higher FC in the left STG, right occipital cortex, and lower FC in the left inferior frontal gyrus and supramarginal gyrus. Our findings suggest that LH have atypical connectivity in the language network, with an enhanced role of the STG, findings which provide novel insights into the structural and functional substrates underlying the atypical language development of left-handed individuals. © 2014 Elsevier Ltd.

Nie W.,Tianjin University | Yuan X.,Tianjin University | Zhao J.,Tianjin University | Zhou Y.,Tianjin University | Bao H.,Tianjin Medical University
Carbohydrate Polymers | Year: 2013

A novel in situ forming polysaccharides/polypeptide hydrogel composed of naturally derived materials for applications as adhesive sealant and hemostatic material was developed via Michael addition crosslinking, taking advantage of its mild condition. Thiol-modified chitosan (CSS) was fast in situ crosslinked by an efficient polypeptide crosslinker (EPLM) which was prepared by introducing maleimide groups onto ε-polylysine. Gelation can happen swiftly within 15-215 s depending on the CSS concentration, the degree of substitution (DS) of maleimide groups, and the molar ratio of maleimide group to thiol group. Results indicated that storage modulus of the hydrogel increased dramatically with the increase of CSS concentration and DS of maleimide. The obtained adhesive hydrogel had an adhesion strength 4 times higher than that of the commercial fibrin glue. Notably, it is non-toxic to L929 cells and exhibits excellent prompt hemostatic property. Polysaccharides/polypeptide structure designed here facilitates to improve both the biocompatibility and the adhesive property. © 2013 Elsevier Ltd. All rights reserved.

Zhang X.,Nihon University | Zhang X.,Japan National Institute of Infectious Diseases | Zhang X.,Tianjin Medical University | Senpuku H.,Tianjin Medical University
Japanese Journal of Infectious Diseases | Year: 2013

Actinomyces naeslundii and Streptococcus gordonii are the predominant bacteria and initial colonizers of oral microflora. The binding of A. naeslundii and S. gordonii and the interaction between them on the salivary pellicle-coated tooth surface play an important role in the biofilm development. Recently, we reported that NOD/SCID.e2f1- mice are a useful model for studying oral biofilm formation by Streptococcus mutans on the tooth surface. In this study, we aimed to determine whether NOD/SCID.e2f1- mice can be used for studying oral colonization of A. naeslundii and S. gordonii. Colonization of A. naeslundii in mice fed with 1z sucrose water for 24 h before inoculation was higher than that among mice fed with sucrose water for 1 h. A. naeslundii colonization using mixed species-inoculation was lower than that using single-species inoculation 30-90 min after inoculation; however, the colonization was higher 120-180 min after inoculation. The mixed inoculation induced better colonization of S. gordonii than single-species inoculation 60-180 min after inoculation. Polyclonal and fluorescein isothiocyanate-labeled antibody stained bacteria showed better colonization of S. gordonii when a mixed culture is used in vivo. NOD/SCID.e2f1- mice were useful for studying the initial colonization of A. naeslundii and S. gordonii. Long-term supply of sucrose water creates a favorable environment for the initial colonization of A. naeslundii that, in turn, supports the colonization of S. gordonii.

Wang H.,Tianjin University | Zhao P.,Tianjin Medical University | Su W.,Tianjin University | Wang S.,Tianjin University | And 3 more authors.
Biomaterials | Year: 2010

Chemotherapy is one of the most effective approaches to treat cancers in the clinic, but the problems, such as multidrug resistance (MDR), low bioavailability and toxicity, severely constrain the further application of chemotherapy. Our group recently reported that cationic PLGA/folate coated PEGlated polymeric liposome core-shell nanoparticles (PLGA/FPL NPs). It was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell for targeting co-delivery of drug and gene. Hydrophobic drugs can be incorporated into the core and the cationic shell of the drug-loaded nanoparticles can be used to bind DNA. The drug-loaded PLGA/FPL NPs/DNA complexes offer advantages to overcome these problems mentioned above, such as co-delivery of drugs and DNA to improving the chemosensitivity of cancer cells at a gene level, and targeting delivery of drug to the cancer tissue that enhance the bioavailability and reduce the toxicity. The experiment showed that nanoparticles have core-shell structure with nanosize, sustained drug release profile and good DNA-binding ability. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and genes to the same cells with high gene transfection and drug delivery efficiency. Our data suggest that the PLGA/FPL NPs may be a useful drug and gene co-delivery system. © 2010 Elsevier Ltd.

Liu Z.,Tianjin University | Dong C.,Tianjin University | Wang X.,Tianjin University | Wang H.,Tianjin University | And 3 more authors.
ACS Applied Materials and Interfaces | Year: 2014

Self-assembled nanostructures based on amphiphilic protein-polymer conjugates have shown great advantages in the field of nanomedicine such as inherent biocompatibility with biosystems because of their excellent performance. Herein, a novel biodegradable protein-polymer conjugate was prepared by covalently linking the tailor-made hydrophobic maleimide- functionalized poly(ε-caprolactone) (PCL) to hydrophilic bovine serum albumin (BSA) via the maleimide-sulfhydryl coupling reaction. This protein-based conjugate with a biodegradable polyester was reported for the first time, and the obtained biohybrid displayed well-defined structure, excellent biocompatibility and low cytotoxicity, and self-assembly behaviors similar to those of the traditional amphiphilic small molecules and block copolymers. The amphiphilic BSA-PCL conjugate can self-assemble into a nanosized vesicle with a negative surface charge. Furthermore, the self-assembled vesicle based on the BSA-PCL conjugate was functionalized via linking targeting ligand cetuximab to its surface to enhance cell uptake, and the doxorubicin (DOX)-encapsulated cetuximab-functionalized vesicle exhibited enhanced antitumor activity compared with that of free DOX in vitro. These results indicate that the biodegradable protein-polymer conjugate based on BSA and PCL had great potential as a drug delivery vehicle for cancer therapy. © 2014 American Chemical Society.

Wang H.,Tianjin University | Zhao P.,Tianjin Medical University | Liang X.,Tianjin University | Gong X.,Tianjin University | And 3 more authors.
Biomaterials | Year: 2010

In this paper, a folate-PEG coated polymeric liposome (FPL) formed from octadecyl-quaternized lysine modified chitosan (OQLCS) and cholesterol has been prepared successfully. The OQLCS and its derivatives were characterized using 1H NMR and infrared spectrum analysis. The FPLs properties were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). Due to the amphiphilic property and positive zeta potential of OQLCS, the OQLCS and cholesterol can form stable core-shell FPLs with small size (effective diameter: 163.5 nm) and narrow distribution (polydispersity: 0.108) in aqueous solutions. The PLs could form multi-lamellar structure similar to that of traditional liposomes prepared from phosphatidylcholine/cholesterol (PC/Chol). Compared with traditional liposome, calcein-loaded Polymeric Liposome exhibited high encapsulation efficiency in aqueous solution and slow, controlled release under different pH conditions. Most important, in cellular uptake experiment, folate coated FPLs showed significant higher uptake by MCF-7 cells as compared to FPLs without folate and traditional liposomes, because of the folate-receptor mediated endocytosis. The data suggest that the folate-PEG coated polymeric liposomes (FPLs) may be a useful drug delivery system. © 2010 Elsevier Ltd. All rights reserved.

Ge P.,Tianjin Medical University | Xiao G.,Ningbo University
OncoTargets and Therapy | Year: 2016

Non-small-cell lung cancer (NSCLC) has a multifactorial pathogenesis, and the genetic background may be one of the critical etiologic factors. Interleukin (IL)-27, a novel member of the IL-12 family, plays a vital role in antitumor immunity. The aim of the current study was to determine the association of a single nucleotide polymorphism of the IL-27 gene with the risk of NSCLC. The genotype of the IL-27 rs153109 polymorphism was analyzed in 388 patients with NSCLC and 390 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. In the patients with NSCLC, the frequencies of the GG, GA, and AA genotypes and the G and A alleles were 14.0%, 56.4%, 29.6%, 42.1%, and 57.9%, respectively. There were no significant differences in the genotype and allele distributions of the IL-27 rs153109 polymorphism between the patients with NSCLC and healthy controls (P.0.05). Furthermore, no association was determined between this polymorphism and different clinical characteristics in patients with NSCLC. Taken together, these findings suggest that the IL-27 gene may not be involved in the development of NSCLC in the Chinese population. © 2016 Ge and Xiao.

Likun Z.,Tianjin Medical University | Xiang J.,Tianjin Medical University | Yi B.,Tianjin Medical University | Xin D.,University of Sichuan | Tao Z.L.,Shuangliu Hospital of Traditional Chinese Medicine
Oncologist | Year: 2011

Objectives. We performed a systematic review and meta-analysis to compare treatment effectiveness and adverse effects in cancer patients receiving chemotherapy with palonosetron to prevent chemotherapy-induced nausea and vomiting (CINV). Methods. We identified randomized controlled clinical trials (RCT) comparing palonosetron with first generation 5-HT3RA in the prevention of CINV in cancer patients. Meta-analyses were performed on homogeneous studies. Fixed or random-effects models were used to combine data. Results. Eight eligible trials were identified, reporting outcomes on 3,592 patients. Meta-analyses showed statistically significant differences in favor of palonosetron compared with first-generation 5-HT3RA in prevention of acute CINV (p=0003), delayed CINV (p<00001), and overall phase of CINV (p<.00001). Subgroup analyses showed statistically significant differences in favor of both 0.25 mg and 0.75mgof palonosetron in prevention of all phases of CINV. There were no statistically significant differences between 0.25 and 0.75mgof palonosetron. Compared with the first-generation 5-HT3RA, 0.75 mg of palonosetron showed a statistically significant difference in the occurrence of constipation (p =04). Interpretation. The use of palonosetron should be considered an integral part of adjuvant therapy for prevention of the acute, delayed, and overall phases of CINV. The 0.25 mg intravenous palonosetron dose is as effective as the 0.75 mg intravenous palonosetron dose. However, 0.75 mg intravenous palonosetron causes constipationmore frequently than the first-generation 5-HT3RA. © AlphaMed Press.

Yang J.,Tianjin University | Zhang P.,Tianjin University | Tang L.,Tianjin University | Sun P.,Tianjin University | And 4 more authors.
Biomaterials | Year: 2010

In this work, thermoresponsive diblock copolymers, poly[2-(2-methoxyethoxy) ethyl methacrylate]-b-poly(2-hydroxyethyl methacrylate) (PMEO2MA-b-PHEMA) with low polydispersity were synthesized by atomic transfer radical polymerization(ATRP). Low molecular weight (LWM) polyethylenimine (PEI, 1200Da) was then grafted to 1,1′-carbonyldiimidazole (CDI)-activated PMEO2MA-b-PHEMA to fabricate PEI-g-(PMEO2MA-b-PHEMA) (PEIMH) copolymer vectors. The LCSTs of PEIMHs with 3 and 8 grafted PEI side chains, separately termed as PEIMH-1 and PEIMH-2, were 32.5 and 38.7 °C in PBS solution. Variable temperature agarose retardation, Zeta potential and time-resolved fluorescence assays were performed to elucidate the temperature sensitive DNA condensation. It showed that DNA was condensed more efficiently by PEIMH, and the collapse of PMEO2MA chains led to more exposure of surface positive charges of PEIMH-1/pDNA complexes while temperature was above LCST. Variable temperature time-resolved fluorescence measurement of lifetimes of bound and free ethidium bromide (EB) unveiled that the population of EB at different states was dependent on temperature. At a temperature above LCST, the collapsed PMEO2MA polymer chains squeezed the loosely bound EB out of complex to become free species; thereby DNA was more tightly packaged by PEIMH-1. Temporary cooling was shown to improve the transfection efficiency of PEIMH-1 in COS-7 and HEK293 cell lines. The variable temperature protocol is more efficient in improving gene expression level in HEK293 cells. The transfection efficiency was equivalent or superior to that of PEI25K at an optimal weight ratio of vector/DNA. Furthermore, the cytotoxicity of PEIMH-1 was considerably lower than that of control PEI25K. © 2009 Elsevier Ltd. All rights reserved.

Zhang Q.,Tianjin Medical University | Liu T.,Tianjin Medical University | Ng C.Y.,Loma Linda University | Li G.,Tianjin Medical University
Cardiovascular Therapeutics | Year: 2014

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, and its prevalence has increasing substantially over the last decades. Recent data suggest that there is an increased risk of AF among the patients with diabetes mellitus (DM). However, the potential molecular mechanisms regarding DM-related AF and diabetic atrial remodeling are not fully understood. In this comprehensive review, we would like to summarize the potential relationship between diabetes and atrial remodeling, including structural, electrical, and autonomic remodeling. Also, some upstream therapies, such as thiazolidinediones, probucol, ACEI/ARBs, may play an important role in the prevention and treatment of AF. Therefore, large prospective randomized, controlled trials and further experimental studies should be challengingly continued. © 2014 John Wiley & Sons Ltd.

Liu X.,Tianjin Medical University | Chen L.,Tianjin Medical University | Feng B.,Tianjin Medical University | Liu G.,Tianjin Huanhu Hospital
Anatomical Record | Year: 2014

Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx, and chemoresistance is an essential aspect of NPC chemotherapy failure. Sorcin has been implicated in multidrug resistance (MDR) of many types of human tumor. However, the effect and mechanism of Sorcin in MDR of human NPC is not fully clear. In this report, we silenced Sorcin in human NPC CNE2/DDP cells, and explored the role of Sorcin in MDR reversal. The results showed an increased cytotoxicity of cisplatin and intracellular accumulation of Rhodamine-123 and glutathione depletion in Sorcin silencing CNE2/DDP cells. We also found a decreased messenger RNA and protein expression of multidrug resistance gene (MDR1), multidrug resistance-associated protein (MRP1), excision repair cross-complementing gene 1 (ERCC1), glutathione S-transferase-π (GST-n), RhoE, Bcl-2, and Survivin in Sorcin silencing CNE2/DDP cells. The increased expression of PTEN and decreased expression of p-Akt and NF-κB suggested that the key cellular signaling pathways were triggered by Sorcin silencing. We concluded that Sorcin silencing would contribute to establish a potent target point for MDR reversal. © 2013 Wiley Periodicals, Inc.

Zhao X.,Tianjin Medical University | Gao S.,Tianjin Medical University | Ren H.,Tianjin Medical University | Huang H.,Tianjin University | And 2 more authors.
Current Molecular Medicine | Year: 2014

Objectives: Celastrol, a quinone methide triterpenoid, could induce apoptosis in pancreatic cancer cells. The purpose of this study is to determine whether there is protective autophagy after celastrol treatment in pancreatic cancer cells and the synergistic effects of celastrol and 3-MA in vitro and in vivo. Methods: The cells viability was measured using MTT assays. Degree of apoptosis and amount of autophagic vacuoles were measured by flow cytometry. Immunofluorescence was adapted to monitor the localization of autophagic protein LC3-II. Expression of LC3-II, cleaved caspase-3, Bax and bcl-2 was detected by immunoblot. Autophagosomes were observed by electron microscopy. The synergistic effect of celastrol and 3-MA in vivo was studied in the MiaPaCa-2 xenograft tumor model. Results: Celastrol increased the level of autophagy in pancreatic cancer cells. Furthermore in vitro, when inhibiting the autophagy with 3-MA, the level of celastrol-induced apoptosis elevated; after upgrading autophagy by starvation, the level of celastrol-induced apoptosis descended. 3-MA enhanced celastrol-induced apoptosis and inhibitory effect on tumor growth in vivo. Conclusions: In pancreatic cancer, celastrol treatment increased the level of autophagy to protect cancer cells against apoptosis. Autophagy inhibitor 3-MA could improve the therapeutic effect of celastrol in vitro and in vivo. © 2014 Bentham Science Publishers.

Zhu Z.,Tianjin Medical University | Zhu Z.,Tianjin HuanHu Hospital | Fu Y.,Tianjin Medical University | Tian D.,Tianjin Medical University | And 11 more authors.
Circulation | Year: 2015

Background-Inflammatory and immune responses triggered by brain ischemia worsen clinical outcomes of stroke and contribute to hemorrhagic transformation, massive edema, and reperfusion injury associated with intravenous alteplase. We assessed whether a combination of the immune-modulator fingolimod and alteplase is safe and effective in attenuating reperfusion injury in patients with acute ischemic stroke treated within the first 4.5 hours of symptom onset. Methods and Results-In this multicenter trial, we randomly assigned 25 eligible patients with hemispheric ischemic stroke stemming from anterior or middle cerebral arterial occlusion to receive alteplase alone and 22 patients to receive alteplase plus oral fingolimod 0.5 mg daily for 3 consecutive days within 4.5 hours of the onset of ischemic stroke. Compared with patients who received alteplase alone, patients who received the combination of fingolimod with alteplase exhibited lower circulating lymphocytes, smaller lesion volumes (10.1 versus 34.3 mL; P=0.04), less hemorrhage (1.2 versus 4.4 mL; P=0.01), and attenuated neurological deficits in National Institute of Health Stroke Scales (4 versus 2; P=0.02) at day 1. Furthermore, restrained lesion growth from day 1 to 7 (-2.3 versus 12.1 mL; P<0.01) with a better recovery at day 90 (modified Rankin Scale score 0-1, 73% versus 32%; P<0.01) was evident in patients given fingolimod and alteplase. No serious adverse events were recorded in all patients. Conclusions-In this pilot study, combination therapy of fingolimod and alteplase was well tolerated, attenuated reperfusion injury, and improved clinical outcomes in patients with acute ischemic stroke. These findings need to be tested in further clinical trials. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02002390. © 2015 American Heart Association, Inc.

Li W.,Tianjin Huanhu Hospital | Guo F.,Tianjin Medical University | Wang P.,Tianjin Huanhu Hospital | Hong S.,Tianjin Huanhu Hospital | Zhang C.,Tianjin Huanhu Hospital
Current Molecular Medicine | Year: 2014

Glioblastoma is highly resistant to radiation therapy. The underlying molecular mechanism is not completely understood. The DNA damage response (DDR) pathway plays a crucial role in radioresistance of glioablastoma cells. Growing evidence has demonstrated that radiation induces alterations in microRNA (miR) profiles. However, how radiation induces specific miRs and how they might regulate the DDR remain elusive. In our study, we found that radiation induced c-jun transcription of miR-221 and miR-222. miR-221 and miR-222 modulated DNA-PKcs expression to affect DNA damage repair by activating Akt independent of PTEN status. Knocking down of miR-221/222 significantly increased radiosensitivity of glioblastoma cells. Inhibition of Akt by RNAi or LY294002 treatment may overcome miR-221/222 induced radioresistance. Notably, combined anti-miR-221/222 and radiotherapy has remarkably inhibited tumor growth compared with anti-miR-221/222 or radiotherapy alone in a subcutaneous mouse model. Our results suggest that radio-induced c-jun promotes transcription of miR-221/222, which mediates DNA damage repair of glioblastoma cells independent of PTEN. These data indicate for the first time that miR-221/222 play an important role in mediating radio-induced DNA damage repair and that miR-221/222 could serve as potential therapeutic targets for increasing radiosensitivity of glioblastoma cells. © 2014 Bentham Science Publishers.

Qian X.,Tianjin University | Long L.,Tianjin University | Shi Z.,Tianjin Medical University | Liu C.,Tianjin University | And 6 more authors.
Biomaterials | Year: 2014

The combined treatment of chemotherapeutant and microRNA (miR) has been proven to be a viable strategy for enhancing chemosensitivity due to its synergistic effect for tumor therapy. However, the co-delivery of drugs and genes remains a major challenge as they lack efficient co-delivery carriers. In this study, three amphiphilic star-branched copolymers comprising polylactic acid (PLA) and polydimethylaminoethyl methacrylate (PDMAEMA) with AB3, (AB3)2,and (AB3)3 molecular architectures were synthesized respectively by a combination of ring-opening polymerization, atom transfer radical polymerization, and click chemistry via an "arm-first" approach. The star copolymers possessed a low critical micelle concentration (CMC) and formed nano-sized micelles with positive surface charges in water as well as exhibiting a much lower cytotoxicity than PEI 25kDa. Nevertheless, their gene transfection efficiency and tumor inhibition ability showed a remarkable dependence on their molecular architecture. The (AB3)3 architecture micelle copolymer exhibited the highest transfection efficiency, about 2.5 times higher than PEI. In addition, after co-delivering DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells, the micelles could mediate escaping miR-21i from lysosome degradation and the release of DOX to the nucleus, which significantly decreased the miR-21 expression. Moreover, co-delivery of DOX and miR-21i surprisingly exhibited an anti-proliferative efficiency compared with DOX or the miR-21i treatment alone. These results demonstrated that amphiphilic star-branched copolymers are highly promising for their combinatorial delivery of genes and hydrophobic therapeutants. © 2013 Elsevier Ltd.

Ye J.,Tianjin University | Ye J.,Tianjin Medical University | Shin M.C.,University of Michigan | Liang Q.,Tianjin Medical University | And 3 more authors.
Journal of Controlled Release | Year: 2015

Traditionally, any drug intended for combating the tumor would distribute profoundly to other organs and tissues as lack of targeting specificity, thus resulting in limited therapeutic effects toward the tumor but severe drug-induced toxic side effects. To prevail over this obstacle of drug-induced systemic toxicity, a novel approach termed "ATTEMPTS" (antibody targeted triggered electrically modified prodrug type strategy) was designed, which directly introduces both of the targeting and prodrug features onto the protein drugs. The ATTEMPTS system is composed of the antibody targeting component consisting of antibodies linked with heparin, and the cell penetrating peptide (CPP) modified drug component. The two components mentioned above self-assembled into a tight complex via the charge to charge interaction between the anionic heparin and cationic CPP. Once accumulated at the targeting site, the CPP modified drug is released from the blockage by a second triggering agent, while remaining inactive in the circulation during tumor targeting thus aborting its effect on normal tissues. We utilized the heparin-induced inhibition on the cell-penetrating activity of CPP to create the prodrug feature, and subsequently the protamine-induced reversal of heparin inhibition to resume cell transduction of the protein drug via the CPP function. Our approach is the first known system to overcome this selectivity issue, enabling CPP-mediated cellular drug delivery to be practically applicable clinically. In this review, we thoroughly discussed the historical and novel progress of the "ATTEMPTS" system. © 2014 Elsevier B.V. All rights reserved.

Zhang L.,Tianjin Medical University | Yang H.,Tianjin Medical University | Zhang X.,Tianjin Huanhu Hospital
World Journal of Surgical Oncology | Year: 2014

Renal cell carcinoma (RCC) is one of the most frequent urological malignancies in adults. RCC often metastasizes to other organs, but rarely to the oromaxillofacial region. Metastatic tumors to the jaws are also unusual. In this report, we present two cases of RCC metastasis to the jaws. Metastatic RCC is resistant to radiotherapy and chemotherapy, so surgery is the primary therapeutic choice. This report describes the diagnostic procedures utilized and the therapeutic process in the two cases. The differential diagnosis and treatment methods are discussed. © 2014 Zhang et al.; licensee BioMed Central Ltd.

Li J.,University of Pittsburgh | Li J.,Tianjin Medical University | Ezzelarab M.B.,University of Pittsburgh | Ayares D.,Revivicor Inc. | Cooper D.K.C.,University of Pittsburgh
Stem Cell Reviews and Reports | Year: 2014

Mesenchymal stromal cells (MSCs) are known to have regenerative, anti-inflammatory, and immunodulatory effects. There are extensive indications that pig MSCs function satisfactorily across species barriers. Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation, where they have several potential advantages. (i) pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig. (ii) They are easy to obtain in large numbers, negating the need for prolonged ex vivo expansion. (iii) They can be obtained from genetically-engineered pigs, and the genetic modification can be related to the therapeutic goal of the MSCs. We have reviewed our own studies on MSCs from genetically-engineered pigs, and summarize them here. We have successfully harvested and cultured MSCs from wild-type and genetically-engineered pig bone marrow and adipose tissue. We have identified several pig (p)MSC surface markers (positive for CD29, CD44, CD73, CD105, CD166, and negative for CD31, CD45), have demonstrated their proliferation and differentiation (into adipocytes, osteoblasts, and chondroblasts), and evaluated their antigenicity and immune suppressive effects on human peripheral blood mononuclear cells and CD4+T cells. They have identical or very similar characteristics to MSCs from other mammals. Genetically-modified pMSCs are significantly less immunogenic than wild-type pMSCs, and downregulate the human T cell response to pig antigens as efficiently as do human MSCs. We hypothesized that pMSCs can immunomodulate human T cells through induction of apoptosis or anergy, or cause T cell phenotype switching with induction of regulatory T cells, but we could find no evidence for these mechanisms. However, pMSCs upregulated the expression of CD69 on human CD4+ and CD8+ T cells, the relevance of which is currently under investigation. We conclude that MSCs from genetically-engineered pigs should continue to be investigated for their immunomodulatory (and regenerative and anti-inflammatory) effects in pig-to-nonhuman primate organ and cell transplantation models. © 2013 Springer Science+Business Media New York.

Wang Q.,Tianjin Huanhu Hospital | Li P.,Tianjin Medical University | Li A.,Tianjin Huanhu Hospital | Jiang W.,Tianjin Huanhu Hospital | And 3 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2012

Objective. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with a poor prognosis. MicroRNAs (miRNAs) are a class of small non-coding RNAs, approximately 21-25 nucleotides in length. Recently, some researchers have demonstrated that plasma miRNAs are sensitive and specific biomarkers of various cancers. The primary aim of the study is to investigate whether miRNAs present in the plasma of GBM patients can be used as diagnostic biomarkers and are associated with glioma classification and clinical treatment. Materials and Methods. Plasma samples were attained by venipuncture from 50 patients and 10 healthy donors. Plasma levels of miRNAs were determined by real-time quantitative polymerase chain reaction. Results: The plasma levels of miR-21, miR-128 and miR-342-3p were significantly altered in GBM patients compared to normal controls and could discriminate glioma from healthy controls with high specificity and sensitivity. However, these three miRNAs were not significantly changed in patients with other brain tumors such as meningioma or pituitary adenoma. Furthermore, the plasma levels of these three miRNAs in GBM patients treated by operation and chemo-radiation almost revived to normal levels. Finally, we also demonstrated that miR-128 and miR-342-3p were positively correlated with histopathological grades of glioma. Conclusions: These findings suggest that plasma specific miRNAs have potential use as novel biomarkers of glioma and may be useful in clinical management for glioma patients. © 2012 Wang et al.; licensee BioMed Central Ltd.

Sun W.,Tianjin Chest Hospital | Ma Y.,Tianjin Huanhu Hospital | Chen P.,Tianjin Medical University | Wang D.,Tianjin Medical University
Molecular Medicine Reports | Year: 2015

Lung cancer is one of the primary causes of mortality worldwide and drug resistance is the key contributing factor which results in the failure of lung cancer chemotherapy. Previous studies have shown that microRNA (miR)-10a was involved in the reversal of cisplatin (DDP) resistance in numerous types of tumors; however, the underlying mechanism of action of this remains to be fully elucidated. In the present study, miR-10a silencing in human DDP-resistant lung cancer A549/DDP cells was demonstrated to improve DDP sensitivity, apoptosis, intracellular rhodamine-123 content as well as the expression and activity of caspase-3/8. In addition, miR-10a suppressed the cellular expression of P-glycoprotein, multi-drug resistance protein (MDR) 1, MDR-associated protein 1, RhoE, B cell lymphoma-2 and survivin in A549/DDP cells. Furthermore, miR-10a silencing inhibited the secretion of transforming growth factor (TGF)-β, phosphorylation of Sma-and Mad-related protein (Smad)2, signal transducer and activator of transcription (STAT)3 and STAT5, the transcriptional activity of hypoxia-inducible factor and eukaryotic translation initiation factor 4E in human lung cancer A549/DDP cell line. These results therefore indicated that miR-10a may be a potential target for improving the effectiveness of lung cancer chemotherapy via regulation of the TGF-β/Smad2/STAT3/STAT5 pathway.

Wang C.-Y.,Tianjin Second Peoples Hospital | Lu W.,Tianjin Second Peoples Hospital | Hu D.-S.,Tianjin Second Peoples Hospital | Wang G.-D.,Rizhao Peoples Hospital | Cheng X.-J.,Tianjin Medical University
World Journal of Gastroenterology | Year: 2014

AIM: To study the diagnostic value of controlled attenuation parameter (CAP), evaluated by transient elastography, for liver steatosis in patients with chronic hepatitis B (CHB).METHODS: Eighty-eight patients with CHB were enrolled in this study. All of the patients were subjected to transient elastography to determine CAP. These patients also underwent liver biopsy in the same period. Using liver biopsy as a reference, we determined receiver operating characteristic (ROC) curves for different endpoints. Areas under the ROC curves (AUCs) were used to evaluate the diagnostic importance of CAP for liver steatosis in patients with CHB.RESULTS: A positive correlation was observed between the AUCs of CAP and liver pathological stage (r = 0.582, P < 0.05). CAP was not correlated with inflammation degree and fibrosis degree (r = -0.025, P < 0.05; r = 0. 068, P < 0.05). The mean CAP value at S0 was 209.59 ± 41.25 dB/m, 223.84 ± 35.28 dB/m at S1, 274.17 ± 43.69 dB/m at S2, and 312.50 ± 25.44 dB/m at S3. CAP values among S0, S1, S2, and S3 were significantly different (F = 17.79, P < 0.01). The AUC values for CAP were 0.711 (0.592-0.870), 0.868 (0.748-0.989), and 0.974 (0.922-1.026) for S1, S2, and S3, respectively. The optimal cut-off values were 219.5, 230.0, and 283.5 dB/m.CONCLUSION: CAP is a novel tool that can be used to assess the degree of steatosis. © 2014 Baishideng Publishing Group Inc. All rights reserved.

Liu X.,Tianjin University | Zhi X.,Tianjin University | Liu Y.,Tianjin University | Wu B.,Tianjin University | And 2 more authors.
Journal of Agricultural and Food Chemistry | Year: 2012

Two water-soluble chitosan derivatives, O-carboxymethyl chitosan (O-CM-chitosan) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride (N-CQ-chitosan), were prepared, and the therapeutic effects of chitosan, O-CM-chitosan, and N-CQ-chitosan on insulin resistance were simultaneously evaluated by rats fed on a high-fat diet. The parameters of high-fat diet-induced rats indicated that chitosan and its two derivatives not only have low cytotoxicity but can control overnutrition by fat and achieve insulin resistance therapy. However, the results in experiment in vivo showed that the therapeutic degree varied by the molecular weight and surface charge of chitosan, O-CM-chitosan, and N-CQ-chitosan. N-CQ-chitosan with a MW of 5 × 10 4 decreased body weight, the ratio of fat to body weight, triglyceride, fasting plasma glucose, fasting plasma insulin, free fatty acid, and leptin by 11, 17, 44, 46, 44, 87, and 64% and increased fecal lipid by 95%, respectively. © 2012 American Chemical Society.

Lin Y.-L.,Peoples Hospital of Jiangsu Province | He Z.-K.,Tianjin Medical University | Li Z.-G.,China National Petroleum Corporation | Guan T.-Y.,Peoples Hospital of Jiangsu Province
Urologia Internationalis | Year: 2013

Objective: To investigate the association of downregulated CDH13 expression with invasiveness of bladder transitional cell carcinoma (TCC). Materials and Methods: CDH13 and matrix metalloproteinase-2 (MMP2) expression was detected in 23 normal bladder epithelial tissues and 71 bladder TCC tissues. RNA interference was used to inhibit CDH13 expression in bladder TCC 5637 cells and then analyzed its effects on migration, invasion, adhesion, and proliferation of 5637 cells, as well as MMP2 expression in 5637 cells. Results: The CDH13 expression in bladder TCC tissues was significantly lower than that in normal bladder epithelial tissues. Moreover, the expression of CDH13 from the muscle-invasive group was significantly lower than that from the non-muscle-invasive group. In addition, the MMP2 expression was increased in bladder TCC, especially in muscle-invasive tumors. After the transfection of CDH13 siRNA into 5637 cells, CDH13 expression was significantly decreased, and the migration, invasion, adhesion of 5637 cells, as well as MMP2 expression in 5637 cells was significantly promoted compared with blank and negative controls. Conclusions: Downregulated expression of CDH13 is associated with increased invasion of bladder TCC, and may be due to the enhancement of cell-extracellular matrix adhesion and increased MMP2 expression. Copyright © 2012 S. Karger AG, Basel.

Du J.,Tianjin Medical University | Du J.,Tianjin Central Hospital for Gynaecology and Obstetrics | Zhao X.,Tianjin Medical University | Guo D.,Tianjin Central Hospital for Gynaecology and Obstetrics | And 2 more authors.
Human Pathology | Year: 2011

Intravenous leiomyomatosis is a rare variant of leiomyoma that could result in death. Early and accurate diagnosis and appropriate treatment strategies play a dominant role in good prognosis. Eighteen cases of Intravenous leiomyomatosis, along with clinicopathologic data, were retrieved from our database. Most of the patients who ranged in age from 33 to 54 years (median, 44 years) presented with a pelvic mass or abnormal uterine bleeding. The diagnosis was confirmed by a immunohistochemical staining for smooth muscle actin, CD34, and Ki67. Surgical exploration confirmed the presence of a uterine mass (mean size, 5.08 cm). Wormlike plugs were identified within the broad ligament in 5 cases. The tumor penetrated to the inferior vena cava in 1 case. Histologic variants were noted in 33.33% (6/18) of our cases, which were classified as cellular intravenous leiomyomatosis (3 cases) and intravenous leiomyomatosis with papillary-like contour (1 case) and with fat metaplasia (2 cases). The 18 cases are made up 0.097% of all genital smooth muscle tumor cases of the hospital. The ratios of intravenous leiomyomatosis with uterine leiomyoma, with adenomyosis, with uterine leiomyoma and adenomyosis were 38.89% (7/18), 11.11% (2/18), and 27.78% (5/18), respectively. Follow-up information was available for 16 patients, with a follow-up duration of 26 to 104 months (mean, 55 months). Three cases (16.67%) recurred in patients younger than 40 years (33, 34, and 37 years). We propose that young patients undertake hysterectomy and unilateral salpingo-oophorectomy if they do not have any birthing requests. The cases of intravenous leiomyomatosis were underestimated because early diagnosis was easily missed. It is important to adequately sample all uterine leiomyomas and carefully examine the soft tissue on either side of the lower uterine segment below the peritoneal reflection to identify early-stage intravenous leiomyomatosis. © 2011 Elsevier Inc. All rights reserved.

Bizet A.A.,McGill University | Tran-Khanh N.,Ecole Polytechnique de Montréal | Saksena A.,McGill University | Liu K.,McGill University | And 3 more authors.
Journal of Cellular Biochemistry | Year: 2012

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates a wide variety of cellular processes including proliferation, differentiation, and extracellular matrix deposition. Dysregulation of TGF-β signaling is associated with several diseases such as cancer and tissue fibrosis. TGF-β signals through two transmembrane proteins known as the type I (TGFBR1) and type II (TGFBR2) receptors. The levels of these receptors at the cell surface are tightly regulated by several mechanisms, including degradation following recruitment of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor (Smurf) 2 by SMAD7. In addition, TGF-β co-receptors can modulate TGF-β signaling receptor activity in a cell-specific manner. We have previously identified a novel TGF-β co-receptor, CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein that negatively regulates TGF-β signaling. Despite CD109's potential relevance as a regulator of TGF-β action in vivo, the mechanisms by which CD109 regulates TGF-β signaling are still incompletely understood. Previously, we have shown that CD109 downregulates TGF-β signaling by promoting TGF-β receptor localization into the lipid raft/caveolae compartment and by enhancing TGF-β receptor degradation. Here, we demonstrate that CD109 enhances SMAD7/Smurf2-mediated degradation of TGFBR1 in a ligand-dependent manner. Moreover, we show that CD109 regulates the localization and the association of SMAD7/Smurf2 with TGFBR1. Finally, we demonstrate that CD109's inhibitory effect on TGF-β signaling and responses require SMAD7 expression and Smurf2 ubiquitin ligase activity. Taken together, these results suggest that CD109 is an important regulator of SMAD7/Smurf2-mediated degradation of TGFBR1. Copyright © 2011 Wiley Periodicals, Inc.

Kong A.P.S.,Chinese University of Hong Kong | Yang X.,Chinese University of Hong Kong | Yang X.,Tianjin Medical University | Luk A.,Chinese University of Hong Kong | And 9 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: We examined the associations of clinical profiles in type 2 diabetic patients who developed severe hypoglycemia and their clinical outcomes, including death and all-site cancer. RESEARCH DESIGN AND METHODS: A consecutive cohort of 8,767 type 2 diabetic patients with and without severe hypoglycemia in the 12 months before enrollment were recruited between 1995 and 2007, with follow-up until 2009. Severe hypoglycemia was defined by ICD-9 codes as hospitalizations resulting from hypoglycemia. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% CIs of clinical factors collected at enrollment for severe hypoglycemia. RESULTS: In this cohort, mean age was 57.4 (SD 13.2) years and median disease duration of diabetes was 5 (interquartile range [IQR] 1-11) years. During a median follow-up of 6.71 (IQR 3.47-10.38) years, 235 patients had severe hypoglycemia (incidence 3.96 [95% CI 3.45-4.46] per 1,000 patient-years). At enrollment, patients with and without severe hypoglycemia had similar cancer rates. During follow-up, patients with severe hypoglycemia had a higher incidence of all-site cancer (13.4 vs. 6.4%, P < 0.0001) and mortality (32.8 vs. 11.2%, P < 0.0001) than those without severe hypoglycemia. After adjusting for confounders, old age, low BMI, high glycated hemoglobin, low triglyceride (TG), low LDL cholesterol (LDL-C), albuminuria, and chronic kidney disease were independent predictors for severe hypoglycemia. CONCLUSIONS: In type 2 diabetes, severe hypoglycemia is associated with advanced age, renal dysfunction, poor glycemic control, and cancer subphenotypes (low BMI, low LDL-C, and low TG). © 2014 by the American Diabetes Association.

Tutino G.E.,Chinese University of Hong Kong | Tam W.H.,Chinese University of Hong Kong | Yang X.,Tianjin Medical University | Chan J.C.N.,Chinese University of Hong Kong | And 2 more authors.
Diabetic Medicine | Year: 2014

There has been a marked increase in the prevalence of diabetes in Asia over recent years. Diabetes complicating pregnancy, in particular gestational diabetes, has also increased markedly in the region. Multi-ethnic studies have highlighted the increased risk of gestational diabetes mellitus among the different Asian populations. Prevalence of gestational diabetes in Asian countries varies substantially according to the screening strategy and diagnostic criteria applied, and ranges from 1% to 20%, with evidence of an increasing trend over recent years. The International Association for Diabetes in Pregnancy Study group criteria have been adopted by some Asian countries, although they present significant challenges in implementation, especially in low-resource settings. Studies on offspring of mothers with gestational diabetes have reported adverse cardiometabolic profiles and increased risk of diabetes and obesity. Gestational diabetes is likely to be a significant factor contributing to the epidemic of diabetes and other non-communicable diseases in the Asian region. In recognition of this, several large-scale prevention and intervention programmes are currently being implemented in different Asian countries in order to improve glucose control during pregnancy, as well as overall maternal health. Lessons emerging from gestational diabetes studies in Asia may help inform and provide insights on the overall burden and treatment strategies to target gestational diabetes, with the ultimate aim to reduce its adverse short- and long-term consequences. © 2014 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Chen Z.-P.,National IDD Advisory Committee to Ministry of Health | Chen Z.-P.,Tianjin Medical University | Hetzel B.S.,Womens and Childrens Hospital
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Endemic cretinism includes two syndromes: a more common neurological disorder with brain damage, deaf mutism, squint and spastic paresis of the legs and a less common syndrome of severe hypothyroidism, growth retardation and less severe mental defect. Both conditions are due to dietary iodine deficiency and can be prevented by correction of iodine deficiency before pregnancy. Endemic cretinism is now included in the spectrum of the effects of iodine deficiency in a population termed the 'iodine deficiency disorders (IDDs)', which also includes a wide range of lesser degrees of cognitive defect that can be prevented by the correction of iodine deficiency. Iodine deficiency is now recognised by the World Health Organization (WHO) as the most common preventable cause of brain damage with in excess of 2 billion at risk from 130 countries. A global United Nations (UN) programme of prevention has achieved 68% household usage of iodised salt by the year 2000 compared with less than 20% prior to 1990. © 2009 Elsevier Ltd.

Choi S.Y.C.,BC Cancer Agency | Choi S.Y.C.,Vancouver Prostate Center | Lin D.,BC Cancer Agency | Lin D.,Vancouver Prostate Center | And 7 more authors.
Advanced Drug Delivery Reviews | Year: 2014

The development of novel cancer therapeutics is often plagued by discrepancies between drug efficacies obtained in preclinical studies and outcomes of clinical trials. The inconsistencies can be attributed to a lack of clinical relevance of the cancer models used for drug testing. While commonly used in vitro culture systems are advantageous for addressing specific experimental questions, they are often gross, fidelity-lacking simplifications that largely ignore the heterogeneity of cancers as well as the complexity of the tumor microenvironment. Factors such as tumor architecture, interactions among cancer cells and between cancer and stromal cells, and an acidic tumor microenvironment are critical characteristics observed in patient-derived cancer xenograft models and in the clinic. By mimicking these crucial in vivo characteristics through use of 3D cultures, co-culture systems and acidic culture conditions, an in vitro cancer model/microenvironment that is more physiologically relevant may be engineered to produce results more readily applicable to the clinic. © 2014 The Authors.

Wu X.-Z.,Tianjin Medical University | Chen D.,Tianjin Medical University | Han X.-Q.,Chinese University of Hong Kong
Molecules | Year: 2011

Gekko swinhonis Guenther has been used as an anti-cancer drug in traditional Chinese medicine for hundreds of years. Previous studies showed that the Gekko sulfated polysaccharide-protein complex suppressed the proliferation and migration of hepatoma cells. Gekko sulfated glycopeptide α was obtained from Gekko sulfated polysaccharide-protein complex using papain hydrolysis. Gekko sulfated glycopeptide α inhibited the proliferation and migration of SMMC-7721 cells. The secretion of IL-8 and the concentration of intracellular calcium were decreased after Gekko sulfated glycopeptide α exposure. SMMC-7721 cells in the control group showed abnormal features, with a polygonal shape, whereas this changed to a spindle shape after the treatment with Gekko sulfated glycopeptide a. Actin filaments were distributed diffusely along the cell membrane in control cells, whereas those were polymerized and preferentially accumulated in the cytoplasm of treated cells. Microtubules distributed in the cytoplasm of untreated cells were located diffusely whereas those in treated cells were polymerized. Therefore, Gekko sulfated glycopeptide α inhibit the migration of hepatoma cells via reducing the secretion of IL-8 and the concentration of intracellular calcium, as well as regulating the reorganization of cytoskeleton. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Yue X.,Shandong Academy of Sciences | Wang P.,Tianjin Medical University | Xu J.,Shandong Academy of Sciences | Zhu Y.,Shandong Academy of Sciences | And 3 more authors.
Oncology Reports | Year: 2012

MicroRNAs (miRNAs) are endogenously small non-coding RNAs which are key post-transcriptional regulators of gene expression. Deregulation of miRNAs is common in human tumorigenesis. We report that miRNA-205 is significantly down-regulated in glioma cell lines and tissue specimens. Ectopic expression of miRNA-205 induces apoptosis, cell cycle arrest, impairs cell viability, clonability and invasive properties of glioma cells. We further demonstrate that miRNA-205 can specifically suppress expression of VEGF-A by directly interacting with the putative miRNA-205 binding site at the 3′-UTR. Identification of VEGF-A as a direct target for miRNA-205 may imply that miRNA-205 is a novel target for glioma therapy. Taken together, the present study for the first time provides evidence that miRNA-205 is a glioma-specific tumor suppressor by targeting VEGF-A.

Wang Y.,Tianjin Medical University | Chen H.,Xinxiang Medical University | Liu Y.,Tianjin Medical University | Wu J.,Tianjin Medical University | And 4 more authors.
Biomaterials | Year: 2013

This study designs a pH-sensitive nanoparticle carrier of methotrexate (MTX) and combretastatin A4 (CA4) based on pullulan for the combination therapy against hepatocellular carcinoma (HCC). Briefly, N-urocanyl pullulan (URPA) with the degree of substitution (DS) of 5.2% was synthesized and then conjugated with MTX to form MTX-URPA, in which MTX content was 17.8%. MTX-URPA nanoparticles prepared by the dialysis method had spherical shape and the mean size of 187.1nm, and showed high affinity for HepG2 cells. CA4 was successfully loaded into MTX-URPA nanoparticles and exhibited pH-sensitive invitro release property. After intravenous injection to PLC/PRF/5-bearing nude mice, CA4 loaded MTX-URPA (CA4/MTX-URPA) nanoparticles achieved the enhanced antitumor and anti-angiogenic effects, the prolonged circulation time in blood, and the increased distributions both in the liver and the tumor. In conclusion, this drug carrier system has significant liver-targeting property and exhibits advantages for the combination therapy against hepatocellular carcinoma. © 2013 Elsevier Ltd.

Yang X.,Tianjin Medical University | Lee H.M.,Tianjin Medical University | Chan J.C.N.,Chinese University of Hong Kong
Nature Reviews Endocrinology | Year: 2015

On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug-cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co-occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin-angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5′-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1-cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug-subphenotype interactions. © 2015 Macmillan Publishers Limited. All rights reserved.

Du Q.-S.,Guangxi Academy of science | Du Q.-S.,Guangxi University | Du Q.-S.,Gordon Life Science Institute | Huang R.-B.,Guangxi Academy of science | And 3 more authors.
PLoS ONE | Year: 2010

Background: M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591-595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus. Methodology: Docking calculation is performed to build the complex structure between receptor M2 proton channel and ligands, including existing drugs amantadine and rimantadine, and two newly designed inhibitors. The computer-aided drug design methods are used to calculate the binding free energies, with the computational biology techniques to analyze the interactions between M2 proton channel and adamantine-based inhibitors. Conclusions: 1) The NMR structure of M2 proton channel provides a reliable structural basis for rational drug design against influenza virus. 2) The channel gating mechanism and the inhibiting mechanism of M2 proton channel, revealed by the NMR structure of M2 proton channel, provides the new ideas for channel inhibitor design. 3) The newly designed adamantane-based inhibitors based on the modeled structure of H1N1-M2 proton channel have two pharmacophore groups, which act like a "barrel hoop", holding two adjacent helices of the H1N1-M2 tetramer through the two pharmacophore groups outside the channel. 4) The inhibitors with such binding mechanism may overcome the drug resistance problem of influenza A virus to the adamantane-based drugs. © 2010 Du et al.

Zhang Y.,Tianjin Medical University | Sun C.-M.,Yuhuangding Hospital | Hu X.-Q.,Tianjin Central Hospital of Gynecology and Obstetrics | Zhao Y.,Tianjin Medical University
Scientific Reports | Year: 2014

Studies have investigated the relationship between genetic variants and risk of gestational diabetes mellitus (GDM). However, the results remain inconclusive. The aim of this study was to investigate the association of rs10830963 and rs1387153 variants in melatonin receptor 1B (MTNR1B) and rs1801278 variant in insulin receptor substrate 1 (IRS1) with GDM susceptibility. Electronic database of PubMed, Medline, Embase, and CNKI (China National Knowledge Infrastructure) were searched for relevant studies between 2005 and 2014. The odds ratio (OR) with its 95% confidence interval (CI) were employed to estimate the association. Total ten case-control studies, including 3428 GDM cases and 4637 healthy controls, met the inclusion criteria. Our results showed a significant association between the three genetic variants and GDM risk, rs10830963 with a P-value less than 0.0001, rs1387153 with a P-value of 0.0002, and rs1801278 with a P-value of 0.001. Furthermore, all the genetic models in these three polymorphisms were associated with increased risks of GDM as well (P< = 0.009). In conclusion, our study found that the genetic polymorphisms rs10830963 and rs1387153 in MTNR1B and rs1801278 in IRS1 were associated with an increased risk of developing GDM. However, further studies with gene-gene and gene-environmental interactions should be considered.

Choi H.H.,University of Houston | Choi H.H.,Texas A&M University | Su C.-H.,University of Houston | Fang L.,University of Houston | And 4 more authors.
Oncotarget | Year: 2015

Understanding genome integrity and DNA damage response are critical to cancer treatment. In this study, we identify CSN6's biological function in regulating genome integrity. Constitutive photomorphogenic 1 (COP1), an E3 ubiquitin ligase regulated by CSN6, is downregulated by DNA damage, but the biological consequences of this phenomenon are poorly understood. p27Kip1 is a critical CDK inhibitor involved in cell cycle regulation, but its response to DNA damage remains unclear. Here, we report that p27Kip1 levels are elevated after DNA damage, with concurrent reduction of COP1 levels. Mechanistic studies showed that during DNA damage response COP1's function as an E3 ligase of p27 is compromised, thereby reducing the ubiquitin-mediated degradation of p27Kip1. Also, COP1 overexpression leads to downregulation of p27Kip1, thereby promoting the expression of mitotic kinase Aurora A. Overexpression of Aurora A correlates with poor survival. These findings provide new insight into CSN6- COP1-p27Kip1-Aurora A axis in DNA damage repair and tumorigenesis.

Chen X.,Nanjing Medical University | Liu Y.,Nanjing Medical University | Sheng X.,Ningxia Eye Hospital | Tam P.O.S.,Chinese University of Hong Kong | And 10 more authors.
Human Molecular Genetics | Year: 2014

Retinitis pigmentosa (RP), a disease characterized by progressive loss of photoreceptors, exhibits significant genetic heterogeneity. Several genes associated with U4/U6-U5 triple small nuclear ribonucleoprotein (trisnRNP) complex of the spliceosome have been implicated in autosomal dominant RP (adRP). HPrp4, encoded by PRPF4, regulates the stability of U4/U6 di-snRNP, which is essential for continuous splicing. Here, we identified two heterozygous variants in PRPF4, including c.-114_-97del in a simplex RP patient and c.C944T (p.Pro315Leu), which co-segregates with disease phenotype in a family with adRP. Both variants were absent in 400 unrelated controls. The c.-114_-97del, predicted to affect two transcription factor binding sites, was shown to down-regulate the promoter activity of PRPF4 by a luciferase assay, and was associated with a significant reduction of PRPF4 expression in the blood cells of the patient. In fibroblasts from an affected individual with the p.Pro315Leu variant, the expression levels of several tri-snRNP components, including PRPF4 itself, were up-regulated, with altered expression pattern of SC35, a spliceosome marker. The same alterations were also observed in cells over expressing hPrp4Pro315Leu, suggesting that they arose as a compensatory response toacompromised splicingmechanismcausedbyhPrp4dysfunction. Further, over expression ofhPrp4Pro315Leu, but nothPrp4WT, triggered systemic deformities in wild-type zebrafishembryoswith the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced.Weconclude that mutations ofPRPF4 causeRPvia haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP. © The Author 2014. Published by Oxford University Press. All rights reserved. Published by Oxford University Press. All rights reserved.

Lou Z.,Wenzhou Medical College | Wang Y.,Wenzhou Medical College | Yu G.,Tianjin Medical University
Growth Factors | Year: 2014

Objective: To compare the healing outcomes of higher and lower doses of basic fibroblast growth factor (bFGF) on human traumatic tympanic membrane perforation (TMP). Study design: Prospective clinical study. Methods: All patients with traumatic TMP were treated by direct application of bFGF, and were sequentially allocated into one of two groups: lower-dose group (2-3 drops of bFGF solution daily, approximately 0.1-0.15 mL) and higher-dose group (5-6 drops of bFGF solution daily, approximately 0.25-0.3 mL). The results of closure rate, closure time, and rate of otorrhea between the higher- and lower-dose groups were compared at 3 months. Results: In total, 126 patients were included in this study. The higher-dose group showed significantly improved purulent otorrhea rate compared with the lower-dose group (p<0.01) for perforations of the same size, although the closure rate of the middle-sized perforations did not differ significantly between higher- and lower-dose groups (p>0.05). However, the lower-dose group had a significantly shorter closure time of 5 d compared with the higher-dose group (p<0.05). In addition, although the lower-dose group showed shorter healing times (about 3 d) compared to the higher-dose group for large-sized perforations, the dosage of bFGF did not significantly affect the large-sized perforation closure rate (p>0.05) or closure time (p>0.05). Nine large-sized perforations with secondary purulent otorrhea achieved complete closure, with closure times of 7-25 (14.2 ± 5.8) d. Conclusion: This study suggested that continued daily application of a lower dose of bFGF not only shortens the closure time of human traumatic TMP but also avoids secondary purulent otorrhea. © 2014 Informa UK Ltd. All rights reserved.

Li M.,Temple University | Yu D.,Tianjin Medical University | Jon Williams K.,Temple University | Liu M.-L.,Temple University
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective: To investigate whether exposure of human monocytes/macrophages to tobacco smoke induces their release of membrane microvesicles (MVs) that carry tissue factor (TF) released from cells, whether smoke-induced MVs are procoagulant, and what cellular processes might be responsible for their production. Methods and Results: We found that exposure of human THP-1 monocytes and primary human monocyte-derived macrophages to 3.75% tobacco smoke extract (TSE) significantly increased their total and TF-positive MV generation. More importantly, MVs released from TSE-treated human monocytes/macrophages exhibited 3 to 4 times the procoagulant activity of control MVs, as assessed by TF-dependent generation of factor Xa. Exposure to TSE increased TF mRNA and protein expression and cell surface TF display by both THP-1 monocytes and primary human monocyte-derived macrophages. In addition, TSE exposure caused activation of C-Jun-N-terminal kinase (JNK), p38, extracellular signal regulated kinase (ERK) mitogen-activated protein kinases (MAPK), and apoptosis (a major mechanism for MV generation). Treatment of THP-1 cells with inhibitors of ERK, MAP kinase kinase (MEK), Ras, or caspase 3, but not p38 or JNK, significantly blunted TSE-induced apoptosis and MV generation. Surprisingly, neither ERK nor caspase 3 inhibition altered the induction of cell surface TF display by TSE, indicating an effect solely on MV release. Inhibition of ERK or caspase 3 essentially abolished TSE-induced generation of procoagulant MVs from THP-1 monocytes. Conclusion: Tobacco smoke exposure of human monocytes/macrophages induces cell surface TF display, apoptosis, and ERK-and caspase 3-dependent generation of biologically active procoagulant MVs. These processes may be novel contributors to the pathological hypercoagulability of active and secondhand smokers. © 2010 American Heart Association, Inc.

Du J.,Tianjin Medical University | Du J.,Tianjin Central Hospital of Gynecology Obstetrics | Sun B.,Tianjin Medical University | Zhao X.,Tianjin Medical University | And 7 more authors.
Gynecologic Oncology | Year: 2014

Objectives The functions of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in vasculogenic mimicry (VM) are currently unclear. This study aimed to investigate the effects of hypoxia on VM formation in ovarian cancer, and explore the possible mechanism involved. Methods The expression levels of HIF-1α, E-cadherin, vimentin, Twist1, Slug, and VE-cadherin proteins were analyzed by immunohistochemistry in 71 specimens of epithelial ovarian cancer. The results were correlated with VM and survival analysis. We used a well-established in vitro model of a three-dimensional culture to compare VM formation under hypoxia and normoxia in ovarian cancer cell lines SKOV3 and OVCAR3. To explore the potential mechanism, we examined the effects of hypoxia on the mRNA and protein expression levels of both E-cadherin and vimentin. Results HIF-1α expression was correlated with loss of E-cadherin expression and up-regulated vimentin expression in 11 of the 18 VM-positive patients. Ovarian cancer with evidence of VM was significantly more likely to have high Twist1, Slug, and VE-cadherin expression levels. VM was observed in vitro under hypoxia. The ovarian cancer cells presented morphological epithelial-mesenchymal transition (EMT)-like changes (more fibroblastoid morphology and loss of cellular cohesiveness) under hypoxic conditions. The mRNA and protein levels demonstrated the induction of EMT after hypoxia. Clinicopathological analysis revealed that both VM and HIF-1α expression levels presented shorter survival durations. Conclusions Hypoxia contributed to VM formation by inducing EMT. These results may offer new insights for consideration in ovarian cancer treatment strategies. © 2014 Published by Elsevier Inc.

Pan J.G.,Dong - A University | Zhou X.,Dong - A University | Luo R.,Dong - A University | Han R.F.,Tianjin Medical University
Medical Oncology | Year: 2012

Novel treatment strategies such as gene therapy are warranted in view of the failure of current treatment approaches to cure a high percentage of patients with advanced bladder cancers. The emergence of cancer gene therapy potentially offers a number of exciting treatments. The majority of approaches involve strategies to suppress the function of activated oncogenes to restore the expression of functional tumour suppressor genes or to initiate tumour self-destruction. One gene therapy approach against tumours that holds great promise is suicide gene therapy. Herpes simplex virus thymidine kinase (HSV-TK) phosphorylates ganciclovir (GCV), which in turn interacts with cellular DNA polymerase and interferes with DNA synthesis to cause death of rapidly dividing cells. The development of an effective delivery system is absolutely critical to the usefulness and safety of gene therapy. At present, the adeno-associated virus (AAV) vector has the most promising potential in view of its non-pathogenicity, wide tropisms and long-term transgene expression in vivo. Gene therapy studies using different serotypes of recombinant AAV (rAAV) as delivery vehicles have proved rAAVs to be an effective modality of cancer gene therapy. In the present study, we investigated the suppression effect of AAV-mediated HSV-TK/GCV system on the bladder cancer cells and in mice xenograft models of bladder cancer. Our data demonstrate that rAAV-HSV-TK system controlled tumour cell growth and achieves strong antitumour efficacy in vivo. These findings provide a foundation for the development of potential targeted clinical therapies for bladder cancer in humans. © Springer Science+Business Media, LLC 2011.

Shi L.,U.S. National Institutes of Health | Shi L.,Tianjin Medical University | Oberdoerffer P.,U.S. National Institutes of Health
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2012

DNA double-strand breaks (DSBs) occur in the context of a highly organized chromatin environment and are, thus, a significant threat to the epigenomic integrity of eukaryotic cells. Changes in break-proximal chromatin structure are thought to be a prerequisite for efficient DNA repair and may help protect the structural integrity of the nucleus. Unlike most bona fide DNA repair factors, chromatin influences the repair process at several levels: the existing chromatin context at the site of damage directly affects the access and kinetics of the repair machinery; DSB induced chromatin modifications influence the choice of repair factors, thereby modulating repair outcome; lastly, DNA damage can have a significant impact on chromatin beyond the site of damage. We will discuss recent findings that highlight both the complexity and importance of dynamic and tightly orchestrated chromatin reorganization to ensure efficient DSB repair and nuclear integrity. This article is part of a Special Issue entitled: Chromatin in time and space. © 2012.

Zang F.,Tianjin Medical University | Wei X.,Tianjin Medical University | Leng X.,Tianjin Medical University | Yu M.,University of Toronto | Sun B.,Tianjin Medical University
Biochemical and Biophysical Research Communications | Year: 2014

Breast cancers with HER2 amplification have a poorer prognosis than the luminal phenotypes. TRAIL activates apoptosis upon binding its receptors in some but not all breast cancer cell lines. Herein, we investigated the expression pattern of c-FLIP(L) in a cohort of 251 invasive breast cancer tissues and explored its potential role in TRAIL resistance. C-FLIP(L) was relatively high-expressed in HER2-positive breast cancer in comparison with other molecular subtypes, co-expressed with TRAIL death receptors, and inversely correlated with the apoptosis index. Downregulation of c-FLIP(L) sensitized SKBR3 cells to TRAIL-induced apoptosis in a concentration- and time-dependent manner and enhanced the activities and cleavages of caspase-8 and caspase-3, without altering the surface expression of death receptors. Together, our results indicate that c-FLIP(L) promotes TRAIL resistance and inhibits caspase-3 and caspase-8 activation in HER2-positive breast cancer. © 2014 Elsevier Inc. All rights reserved.

Zhang H.,Tianjin Medical University | Qi C.,Tianjin Medical University | Wang A.,Tianjin Medical University | Yao B.,Tianjin Medical University | And 3 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2013

Background: Nucleobindin 2 (NUCB2) protein, a novel oncoprotein, is overexpressed in breast cancer. To date, there have been no published data regarding the role of NUCB2 protein expression in prostate cancer (PCa). Therefore, this study was performed to investigate the correlations between NUCB2 protein expression and prognosis in patients with PCa. Methods. Through immunohistochemistry, NUCB2 protein expression was evaluated in 60 benign prostatic hyperplasia (BPH) specimens and 180 PCa specimens. The correlation of NUCB2 protein expression with clinicopathological parameters was assessed using χ §ssup§2§esup§ analysis. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 protein expression and prognosis of PCa patients. Results: The immunohistochemistry results showed that the expression level of NUCB2 in PCa cases was significantly higher than that in BPH tissues (P < 0.001). Moreover, statistical analysis also showed that high NUCB2 protein expression was positively related to seminal vesicle invasion, lymph node metastasis, angiolymphatic invasion, higher Gleason score, biochemical recurrence (BCR), and higher preoperative prostate-specific antigen (PSA). Furthermore, it was also shown that patients with high NUCB2 protein expression had significantly poorer overall survival and BCR- free survival compared with patients with low expression of NUCB2 protein. Multivariate Cox regression analysis revealed that high NUCB2 protein expression level was an independent prognostic factor for overall survival and BCR-free survival of patients with PCa. Conclusions: NUCB2 protein expression showed a strong association with the potencies of BCR and progression of PCa, and that may be applied as a novel biomarker for the prediction of BCR, and helpful for improving the diagnosis, prognosis and treatment of PCa. © 2013 Zhang et al.; licensee BioMed Central Ltd.

Liu L.,University of Georgia | Wu S.,Tianjin Medical University | Yu L.,Georgia Southern University
Journal of Systematics and Evolution | Year: 2015

Genome-scale sequence data have become increasingly available in the phylogenetic studies for understanding the evolutionary histories of species. However, it is challenging to develop probabilistic models to account for heterogeneity of phylogenomic data. The multispecies coalescent model describes gene trees as independent random variables generated from a coalescence process occurring along the lineages of the species tree. Since the multispecies coalescent model allows gene trees to vary across genes, coalescent-based methods have been popularly used to account for heterogeneous gene trees in phylogenomic data analysis. In this paper, we summarize and evaluate the performance of coalescent-based methods for estimating species trees from genome-scale sequence data. We investigate the effects of deep coalescence and mutation on the performance of species tree estimation methods. We found that the coalescent-based methods perform well in estimating species trees for a large number of genes, regardless of the degree of deep coalescence and mutation. The performance of the coalescent methods is negatively correlated with the lengths of internal branches of the species tree. © 2015 Institute of Botany, Chinese Academy of Sciences.

Cole A.J.,University of Michigan | David A.E.,University of Michigan | David A.E.,Industrial Science and Technology Network Inc. | Wang J.,University of Michigan | And 4 more authors.
Biomaterials | Year: 2011

Magnetic iron oxide nanoparticles (MNPs) have been studied to circumvent the limitations of status-quo brain tumor therapy and can be targeted by applying an external magnetic field to lesions. To address the pharmacokinetic shortcomings of MNPs that can limit targeting efficiency, we recently reported a long-circulating polyethylene glycol modified, cross-linked starch MNP (PEG-MNP) suitable for magnetic targeting. Using a rat model, this work explores the biodistribution patterns of PEG-MNPs in organs of elimination (liver, spleen, lung, and kidney) and shows proof-of-concept that enhanced magnetic brain tumor targeting can be achieved due to the relatively long circulation lifetime of the nanoparticles. Reductions in liver (∼12-fold) and spleen (∼2.5-fold) PEG-MNP concentrations at 1. h compared to parent starch-coated MNPs (D) confirm plasma pharmacokinetics observed previously. While liver concentrations of PEG-MNPs remained considerably lower than those observed for D at 1. h through 60 h, spleen values continue to increase and are markedly higher at later time points - a trend also observed with histology. Limited to no distribution of PEG-MNPs was visualized in lung or kidney throughout the 60. h course evaluated. Enhanced, selective magnetic brain tumor targeting (t = 1 h) of PEG-MNPs (12 mg Fe/kg) was confirmed in 9L-glioma tumors, with up to 1.0% injected dose/g tissue nanoparticle delivery achieved - a 15-fold improvement over targeted D (0.07% injected dose/g tissue). MRI and histological analyses visually confirmed enhanced targeting and also suggest a limited contribution of passive mechanisms to tissue retention of nanoparticles. Our results are exciting and justify both further development of PEG-MNP as a drug delivery platform and concurrent optimization of the magnetic brain tumor targeting strategy utilized. © 2011 Elsevier Ltd.

Xu Y.,Institute of Cardiovascular | Sharma D.,Tianjin Medical University | Li G.,Institute of Cardiovascular | Liu Y.,Institute of Cardiovascular
Medical Hypotheses | Year: 2013

Atrial fibrillation (AF), the most common sustained arrhythmia associated with substantial cardiovascular morbidity and mortality with stroke being the most critical complication. Most frequently, AF occurs in conjunction with other cardiovascular disease, such as hypertension, ischemic heart disease, valve disease or cardiac failure. Role of atrial remodeling has emerged as the new pathophysiological mechanism of atrial fibrillation. Experimental and clinical studies point at two major mechanisms involved in the intrinsically progressive nature of AF. The first consists of a change in the electrical properties of the atrium, notably a shortening of the AERP and a loss of rate adaptation, and hence was named electrical remodeling. Furthermore, based on data from is experimental models, it has been considered that AF is also associated with elaborate adaptive and maladaptive changes in tissue and cellular architecture. By parallel, this type of change was denominated structural remodeling. Together, these mechanisms will increase the probability of generating multiple atrial wavelets by enabling rapid atrial activation and dispersion of refractoriness. © 2012 Elsevier Ltd.

Du X.,Tianjin Medical University | Soon J.L.,National Heart Center
Journal of Cardiology | Year: 2011

Background: Aortic stenosis (AS) is the most common valvular disease in adult cardiac surgery and its incidence continues to rise. Increasingly older patients are being referred for coronary artery bypass grafting (CABG) with mild to moderate AS. Concomitant aortic valve replacement (AVR) for patients with moderate or severe AS undergoing CABG is warranted regardless of symptoms. Concomitant AVR remains contentious in patients with less than moderate severity AS undergoing CABG. Materials and methods: We review the contemporary literature aiming to resolve this dilemma in clinical practice. The assessment of these patients is reviewed. Considerations include identifying the rapid progressors, and balancing the risks of concomitant valve surgery against the potential prognostic gains. Results: Pathophysiological links between degenerative calcific AS and coronary artery disease suggest that the disease is an active, progressive process with mutually shared risk factors. Statins, however, offer limited protection against AS, despite its established role in coronary artery disease. Age, atherosclerosis risk, valve morphology, motion, and hemodynamics identify the rapid progressors, whilst the patients' general comorbidities and life expectancy influence the risk-benefit profile of concomitant operations. Conclusion: A precise echocardiographic quantification of the stenotic grade is mandatory before adopting any therapeutic strategy. Concomitant AVR for moderate AS is recommended if surgical risk is not prohibitive. Concomitant AVR for mild AS in 'rapid progressors' (i.e. moderate-severe valve calcification) may be considered, but patients should have reasonable life expectancy exceeding 5 years. Moderately restricted leaflet motions, gradient increase of >10. mm. Hg per year, and aortic jet velocity increase >0.4. m/s per year further supports intervention. Comorbidities increasing atherosclerotic burden and renal dialysis accelerate AS progression and increase surgical risk. Procedural advances in interventional cardiology and minimally invasive cardiac surgery may further expand the options available for these patients. © 2011 Japanese College of Cardiology.

Zhang C.,CAS Research Center for Eco Environmental Sciences | Zhang C.,Tianjin Medical University | Zhang S.,CAS Research Center for Eco Environmental Sciences | Zhang Z.,Tianjin Medical University | And 3 more authors.
Oncogene | Year: 2013

Rho-associated kinase (ROCK) has an essential role in governing cell morphology and motility, and increased ROCK activity contributes to cancer cell invasion and metastasis. Burgeoning data suggest that ROCK is also involved in the growth regulation of tumor cells. However, thus far, the molecular mechanisms responsible for ROCK-governed tumor cell growth have not been clearly elucidated. Here we showed that inhibition of ROCK kinase activity, either by a selective ROCK inhibitor Y27632 or by specific ROCK small interfering RNA (siRNA) molecules, attenuated not only motility but also the proliferation of PC3 prostate cancer cells in vitro and in vivo. Importantly, mechanistic investigation revealed that ROCK endowed cancer cells with tumorigenic capability, mainly by targeting c-Myc. ROCK could increase the transcriptional activity of c-Myc by promoting c-Myc protein stability, and ROCK inhibition reduced c-Myc-mediated expression of mRNA targets (such as HSPC111) and microRNA targets (such as miR-17-92 cluster). We provided evidence demonstrating that ROCK1 directly interacted with and phosphorylated c-Myc, resulting in stabilization of the protein and activation of its transcriptional activity. Suppression of ROCK-c-Myc downstream molecules, such as c-Myc-regulated miR-17, also impaired tumor cell growth in vitro and in vivo. In addition, c-Myc was shown to exert a positive feedback regulation on ROCK by increasing RhoA mRNA expression. Therefore, inhibition of ROCK and its stimulated signaling might prove to be a promising strategy for restraining tumor progression in prostate cancer.Oncogene advance online publication, 9 December 2013; doi:10.1038/onc.2013.505.

Wang Y.,Tianjin Medical University | Chen L.-M.,Tianjin Medical University | Liu M.-L.,Temple University
Acta Pharmacologica Sinica | Year: 2014

Microvesicles (MVs), also known as microparticles, are small membrane vesicles released from different cell types under different conditions. MVs have been detected in the circulation and in organs/tissues in various diseases, including diabetes. Patients with different types of diabetes and complications have different cellular MV patterns. Studies have shown that MVs may mediate vascular thrombosis, vascular inflammation, angiogenesis, and other pathological processes of the disease through their procoagulant, pro-inflammatory, pro-angiogenic, proteolytic, and other properties. Therefore, MVs contribute to the development of diabetic macrovascular and microvascular complications. In addition, clinical studies have indicated that changes in MV number and composition may reflect the pathophysiological conditions of disease, and therefore, may serve as potential biomarkers for diagnostic and prognostic use. Understanding MVs' involvement in the pathophysiological conditions may provide insight into disease mechanisms and would also be helpful for the development of novel therapeutic strategies in the future. Here, we review the latest publications from our group and other groups and focus on the involvement of MVs in diabetic complications. © 2014 CPS and SIMM.

Guan Z.,Tianjin Medical University | Zhang J.,Tianjin Medical University | Song S.,Tianjin Medical University | Dai D.,China Medical University at Heping
Diagnostic Pathology | Year: 2013

Background: Gastric carcinoma development is a multi-stage process that involves more than one gene. Aberrant changes in DNA methylation are considered as the third mechanism that leads to anti-oncogene inactivation, which plays an essential role in tumor development. In this study, we assessed the relationship among the aberrant methylation of the promoter CpG islands of tissue inhibitor of metalloproteinase 3 (TIMP3) gene, its protein expression, and the clinicopathological features of gastric adenocarcinoma.Methods: The methylation status of the promoter CpG islands and the protein expression of TIMP3 gene in tumors and adjacent normal mucosal tissues of 78 patients with gastric adenocarcinoma were detected by methylation-specific PCR (MSP) and immunohistochemistry.Results: The CpG island methylation of TIMP3 was detected in tumor tissues, cancer-adjacent tissues, and lymph nodes with metastasis. In increasing order, the hypermethylation frequency of these tissues were 35.9% (28 of 78 non-neoplastic tissues), 85% (17 of 20 early-stage cases), 89.7% (52 of 58 progressive-stage cases), and 100% (78 of 78 metastatic lymph node). A marked difference was found between tumors and non-neoplastic tissues (P < 0.05), but no difference existed among the subgroups of tumors (P > 0.05). Immunohistochemistry analysis confirmed TIMP3 down-regulation in tumor tissues. The rate of TIMP3 gene expression was 100% in non-neoplastic tissues but apparently decreased to various extents at different stages, i.e., decreased to 30% (6/20) at the early stage, to 3.4% (2/58) at the progressive stage, and to 0% (0/78) in metastatic lymph nodes. Among the 70 tumor tissues with negative TIMP3 expression, 64 (91.4%) were hypermethylated and 6 were unmethylated (8.6%), indicating a significant association between hypermethylation and reduced or negative TIMP3 expression (P < 0.01).Conclusion: The hypermethylation of the promoter region in CpG islands is the main mechanism of TIMP3 gene expression and may provide evidence for the molecular diagnosis and stage evaluation of gastric cancer.Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1756134016954958. © 2013 Guan et al.; licensee BioMed Central Ltd.