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1.  Pretreatment 18 F-FDG uptake heterogeneity can predict survival in patients with locally advanced nasopharyngeal carcinoma——a retrospective study 
Intratumoural heterogeneity has been demonstrated to be a strong indicator of malignant transformation. Our study was to investigate pretreatment 18 F-FDG parameters, including 18 F-FDG based heterogeneity for predicting survival in patients with locally advanced nasopharyngeal carcinoma (NPC).
Forty newly diagnosed, biopsy-proven locally advanced NPC patients who underwent 18 F-FDG PET/CT were retrospectively included. The following PET parameters were assessed: maximum and mean standardised uptake value (SUVmax and SUVmean), metabolic tumour volume (MTV), total lesion glycolysis (TLG) and intratumoral heterogeneity index (HI). The previous parameters were recorded both for the primary tumor (-T) and neck lymph nodes (-N). The following endpoints were evaluated: local control (LC), progression-free survival (PFS) and overall survival (OS). The survival analyses were performed using the Kaplan–Meier method. Univariate analysis was performed using the log-rank test.
Patients with a lower HI-T, SUVmax-T, SUVmean-T and TLG-T had significantly better 2-year LC. In predicting PFS, we found that both lower HI-T and HI-N had significantly better prognosis. However, the OS was only statistically associated with HI-T.
18 F-FDG based heterogeneity appears to be an potential predicator of patient survival after treatment.
PMCID: PMC4311496  PMID: 25566697
Nasopharyngeal carcinoma; 18 F-FDG PET/CT; Prognosis; Heterogeneity
2.  Phenomics Research on Coronary Heart Disease Based on Human Phenotype Ontology 
BioMed Research International  2014;2014:240284.
The characteristics of holistic, dynamics, complexity, and spatial and temporal features enable “Omics” and theories of TCM to interlink with each other. HPO, namely, “characterization,” can be understood as a sorting and generalization of the manifestations shown by people with diseases on the basis of the phenomics. Syndrome is the overall “manifestation” of human body pathological and physiological changes expressed by four diagnostic methods' information. The four diagnostic methods' data could be the most objective and direct manifestations of human body under morbid conditions. In this aspect, it is consistent with the connation of “characterization.” Meanwhile, the four diagnostic methods' data also equip us with features of characterization in HPO. In our study, we compared 107 pieces of four diagnostic methods' information with the “characterization database” to further analyze data of four diagnostic methods' characterization in accordance with the common characteristics of four diagnostic methods' information and characterization and integrated 107 pieces of four diagnostic methods' data to relevant items in HPO and finished the expansion of characterization information in HPO.
PMCID: PMC4279366  PMID: 25610858
3.  Experimental Study on the Inhibitory Effect of Sodium Cantharidinate on Human Hepatoma HepG2 Cells 
Cantharidin, and its derivatives can not only inhibit the proliferation of tumor cells, but can also induce tumor cell apoptosis. It shows cantharidin exhibits a wide range of reactivity in anticancer. The objective of this paper was to study the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells.
Materials and Methods
MTT assay was used to detect the proliferation of HepG2 cells, and immunohisto-chemical method was used to detect the change in VEGF, protein level, and to determine the inhibitory effect of sodium cantharidinate on human hepatoma HepG2 cells.
As results, sodium cantharidinate significantly inhibited the growth of HepG2 cells in a time-and dose-dependent manner.
We conclude that sodium cantharidinate has an inhibitory effect on human hepatoma HepG2 cells.
PMCID: PMC3957254  PMID: 24653566
sodium cantharidinate; human hepatoma HepG2; MTT assay
4.  Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling 
Asian Journal of Andrology  2014;16(6):817-823.
Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.
PMCID: PMC4236322  PMID: 24994782
androgen receptor; keratin 33B; penis; testosterone
5.  Novel Cyclic di-GMP Effectors of the YajQ Protein Family Control Bacterial Virulence 
PLoS Pathogens  2014;10(10):e1004429.
Bis-(3′,5′) cyclic di-guanylate (cyclic di-GMP) is a key bacterial second messenger that is implicated in the regulation of many critical processes that include motility, biofilm formation and virulence. Cyclic di-GMP influences diverse functions through interaction with a range of effectors. Our knowledge of these effectors and their different regulatory actions is far from complete, however. Here we have used an affinity pull-down assay using cyclic di-GMP-coupled magnetic beads to identify cyclic di-GMP binding proteins in the plant pathogen Xanthomonas campestris pv. campestris (Xcc). This analysis identified XC_3703, a protein of the YajQ family, as a potential cyclic di-GMP receptor. Isothermal titration calorimetry showed that the purified XC_3703 protein bound cyclic di-GMP with a high affinity (Kd∼2 µM). Mutation of XC_3703 led to reduced virulence of Xcc to plants and alteration in biofilm formation. Yeast two-hybrid and far-western analyses showed that XC_3703 was able to interact with XC_2801, a transcription factor of the LysR family. Mutation of XC_2801 and XC_3703 had partially overlapping effects on the transcriptome of Xcc, and both affected virulence. Electromobility shift assays showed that XC_3703 positively affected the binding of XC_2801 to the promoters of target virulence genes, an effect that was reversed by cyclic di-GMP. Genetic and functional analysis of YajQ family members from the human pathogens Pseudomonas aeruginosa and Stenotrophomonas maltophilia showed that they also specifically bound cyclic di-GMP and contributed to virulence in model systems. The findings thus identify a new class of cyclic di-GMP effector that regulates bacterial virulence.
Author Summary
Cyclic di-GMP is a bacterial second messenger that acts to regulate a wide range of functions including those that contribute to the virulence of pathogens. Our knowledge of the different actions and receptors for this nucleotide is far from complete. An understanding of the action of these elements may be key to interference with the processes they control. Here we have used an affinity pull-down assay using cyclic di-GMP-coupled magnetic beads to identify cyclic di-GMP binding proteins in the plant pathogen Xanthomonas campestris. This analysis identified XC_3703, a protein of the YajQ family that was able to bind cyclic di-GMP with high affinity. Mutation of XC_3703 led to reduced virulence of X. campestris to plants and alteration in biofilm formation. Genetic and functional analysis of YajQ family members from the human pathogens Pseudomonas aeruginosa and Stenotrophomonas maltophilia showed that they also specifically bound cyclic di-GMP and contributed to virulence in model systems. The findings thus identify a new class of cyclic di-GMP effector that regulates bacterial virulence and raise the possibility that other members of the YajQ family, which occur widely in bacteria, also act in cyclic di-GMP signalling pathways.
PMCID: PMC4199771  PMID: 25329577
6.  Communication, Cooperation, and Social Interactions: a Report from the Third Young Microbiologists Symposium on Microbe Signalling, Organisation, and Pathogenesis 
Journal of Bacteriology  2014;196(20):3527-3533.
The third Young Microbiologists Symposium took place on the vibrant campus of the University of Dundee, Scotland, from the 2nd to 3rd of June 2014. The symposium attracted over 150 microbiologists from 17 different countries. The significant characteristic of this meeting was that it was specifically aimed at providing a forum for junior scientists to present their work. The meeting was supported by the Society for General Microbiology and the American Society for Microbiology, with further sponsorship from the European Molecular Biology Organization, the Federation of European Microbiological Societies, and The Royal Society of Edinburgh. In this report, we highlight some themes that emerged from the many exciting talks and poster presentations given by the young and talented microbiologists in the area of microbial gene expression, regulation, biogenesis, pathogenicity, and host interaction.
PMCID: PMC4187693  PMID: 25070739
7.  Meta-analysis of nonsteroidal anti-inflammatory drug intake and prostate cancer risk 
Epidemiological studies of the association between nonsteroidal anti-inflammatory drug (NSAID) intake and the risk of prostate cancer still remain controversial. Therefore, we conducted a meta-analysis to evaluate the potential association between NSAID intake and prostate cancer risk.
Eligible studies were retrieved by both computerized searches and reviews of references. Subgroup analyses on country and design of study were also performed. Random or fixed-effect models were used to pool estimates of odds ratios (ORs) with 95% confidence intervals (CIs).
We observed that the intake of aspirin was associated with a marginally decreased risk of prostate cancer (OR =0.95, 95% CI =0.93 to 0.98). A similar result was found between nonaspirin NSAIDs and prostate cancer risk (OR =0.94, 95% CI =0.90 to 0.98). However, a positive relation between all-NSAID intake and prostate cancer risk was observed (OR =1.18, 95% CI =1.15 to 1.22).
We observed a marginally inverse correlation between the intake of aspirin and prostate cancer risk. On the contrary, a positive relationship between all-NSAID intake and prostate cancer was detected. Further research needs to be conducted to better clarify potential biological mechanisms.
PMCID: PMC4194408  PMID: 25282624
Etiology; Meta-analysis; NSAIDs; Prostate cancer
8.  Calcium Channel Blockers and Risk of Breast Cancer: A Meta-Analysis of 17 Observational Studies 
PLoS ONE  2014;9(9):e105801.
Studies on the association between the use of calcium channel blockers (CCBs) and breast cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis based on the evidence from observational studies.
We searched PubMed, MEDLINE, EMBASE and the Cochrane Library for relevant studies published up to and including December 31, 2013. We calculated pooled risk ratios (RRs) for cancer risk.
A total of 17 studies (9 cohort studies, 8 case-control studies) were selected for further study. These studies included 149,607 female subjects, of which 53,812 were CCBs users, who were followed for 2–16 years. The risks of breast cancer among patients receiving CCBs were significantly different for the pooled RRs (95% confidence interval) of cohort studies 1.08 (0.95, 1.20) and case-control studies 0.98 (0.86, 1.09). Differences were also noted for cancer risk, for CCBs use of <5 years 0.96 (0.78, 1.15), and for >5 years 1.01 (0.74, 1.28), as well as for ever used 1.08 (0.95, 1.20), and for current use 1.13 (0.83, 1.42). The RR for studies longer than 10 years was 1.71 (1.01, 2.42), and for studies evaluating nifedipine was 1.10 (0.87, 1.33) and diltiazem was 0.75 (0.40, 1.10).
The long-term use of CCBs appears to have a significant relationship with breast cancer. Well-designed clinical trials are needed to optimize the doses and types of these drugs needed to minimize their carcinogenic potential.
PMCID: PMC4153551  PMID: 25184210
9.  Curcumin Promotes KLF5 Proteasome Degradation through Downregulating YAP/TAZ in Bladder Cancer Cells 
KLF5 (Krüppel-like factor 5) plays critical roles in normal and cancer cell proliferation through modulating cell cycle progression. In this study, we demonstrated that curcumin targeted KLF5 by promoting its proteasome degradation, but not by inhibiting its transcription in bladder cancer cells. We also demonstrated that lentivirus-based knockdown of KLF5 inhibited cancer cell growth, while over-expression of a Flag-tagged KLF5 could partially reverse the effects of curcumin on cell growth and cyclin D1 expression. Furthermore, we found that curcumin could down-regulate the expression of Hippo pathway effectors, YAP and TAZ, which have been reported to protect KLF5 protein from degradation. Indeed, knockdown of YAP by small interfering RNA caused the attenuation of KLF5 protein, but not KLF5 mRNA, which was reversed by co-incubation with proteasome inhibitor. A xenograft assay in nude mice finally proved the potent inhibitory effects of curcumin on tumor growth and the pro-proliferative YAP/TAZ/KLF5/cyclin D1 axis. Thus, our data indicates that curcumin promotes KLF5 proteasome-dependent degradation through targeting YAP/TAZ in bladder cancer cells and also suggests the therapeutic potential of curcumin in the treatment of bladder cancer.
PMCID: PMC4200832  PMID: 25170806
KLF5; curcumin; bladder cancer; protein degradation; YAP; TAZ
10.  Topology and biological function of enterovirus non-structural protein 2B as a member of the viroporin family 
Veterinary Research  2014;45(1):87.
Viroporins are a group of transmembrane proteins with low molecular weight that are encoded by many animal viruses. Generally, viroporins are composed of 50–120 amino acid residues and possess a minimum of one hydrophobic region that interacts with the lipid bilayer and leads to dispersion. Viroporins are involved in destroying the morphology of host cells and disturbing their biological functions to complete the life cycle of the virus. The 2B proteins encoded by enteroviruses, which belong to the family Picornaviridae, can form transmembrane pores by oligomerization, increase the permeability of plasma membranes, disturb the homeostasis of calcium in cells, induce apoptosis, and cause autophagy; these abilities are shared among viroporins. The present paper introduces the structure and biological characteristics of various 2B proteins encoded by enteroviruses of the family Picornaviridae and may provide a novel idea for developing antiviral drugs.
PMCID: PMC4155101  PMID: 25163654
11.  Adding Maximum Standard Uptake Value of Primary Lesion and Lymph Nodes in 18F-Fluorodeoxyglucose PET Helps Predict Distant Metastasis in Patients with Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(7):e103153.
To find out the most valuable parameter of 18F-Fluorodeoxyglucose positron emission tomography for predicting distant metastasis in nasopharyngeal carcinoma.
From June 2007 through December 2010, 43 non-metastatic NPC patients who underwent 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) before radical Intensity-Modulated Radiation Therapy were enrolled and reviewed retrospectively. PET parameters including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glucose (TLG) of both primary tumor and cervical lymph nodes were calculated. Total SUVmax were recorded as the sum of SUVmax of primary tumor and cervical lymph nodes. Total SUVmean, Total MTV and Total TLG were calculated in the same way as Total SUVmax.
The median follow-up was 32 months (range, 23–68 months). Distant metastasis was the main pattern of treatment failure. Univariate analysis showed higher SUVmax, SUVmean, MTV, and TLG of primary tumor, Total SUVmax, Total MTV, Total TLG, and stage T3-4 were factors predicting for significantly poorer distant metastasis-free survival (p = 0.042, p = 0.008, p = 0.023, p = 0.023, p = 0.024, p = 0.033, p = 0.016, p = 0.015). In multivariate analysis, Total SUVmax was the independent predictive factor for distant metastasis (p = 0.046). Spearman Rank correlation analysis showed mediate to strong correlationship between Total SUVmax and SUVmax-T, and between Total SUVmax and SUVmax-N(Spearman coefficient:0.568 and 0.834;p = 0.000 and p = 0.000).
Preliminary results indicated that Total SUVmax was an independently predictive factor for distant metastasis in patients of nasopharyngeal carcinoma treated with Intensity-Modulated Radiation Therapy.
PMCID: PMC4113368  PMID: 25068373
12.  External iliac vein – transplant ureteral fistula combined with renal cell carcinoma: an unusual case of hematuria 
OncoTargets and therapy  2014;7:1339-1342.
Iliac vein-ureteral fistula is a rare cause of hematuria. The diagnosis of an iliac vein-ureteral fistula can be elusive even with the use of multiple methods. With regards to the treatment, there appears to be a shift in management from primarily open surgical to primarily angiographic management. We present a unique case of an external iliac vein – transplant ureteral fistula. A 48 year-old female complained of recurrent gross hematuria. She underwent transplant nephrectomy and radical left nephrectomy because of rejection of transplanted kidney and cystic renal cell carcinoma when the hematuria arose for the first time. Ten months later, the hematuria recurred again, and cystoscopy showed bleeding from the right transplant ureteral orifice. Open exploration confirmed the diagnosis of external iliac vein – transplant ureteral fistula. Diagnostic difficulties and treatment dilemma of such a rare cause of hematuria are also discussed.
PMCID: PMC4114910  PMID: 25092990
iliac vein; ureteral fistula; renal transplantation; hematuria
13.  Performance of osteopontin in the diagnosis of malignant pleural mesothelioma: a meta-analysis 
It is reported that osteopontin has shown promising diagnostic value for malignant pleural mesothelioma (MPM), this meta-analysis aimed to establish the overall diagnostic accuracy of the osteopontin measurement for diagnosing MPM. Based on a systematic review of English language studies, the sensitivity, specificity and other measures of accuracy of osteopontin in the diagnosis of MPM were pooled using random-effects model. Summary receiver operating characteristic curves were used to summarize overall test performance. Seven publications met our inclusion criteria, the pooled sensitivity was 0.57 (95%CI: 0.52-0.61), specificity was 0.81, 95%CI: 0.79-0.84). The PLR was 3.78 (95%CI: 2.23-6.41), the NLR was 0.51 (95%CI: 0.38-0.67) and the DOR was 9.04 (95%CI: 5.28-15.48), the area under the summary receiver operating characteristic curve was 0.80. Our data suggest that osteopontin is likely to be a useful diagnostic marker for MPM, considering for the limited studies and patients included, larger studies are needed to confirm these findings.
PMCID: PMC4073746  PMID: 24995085
Osteopontin; malignant pleural mesothelioma; meta-analysis
14.  Monocarbonyl Curcumin Analogs: Heterocyclic Pleiotropic Kinase Inhibitors that Mediate Anti-Cancer Properties 
Journal of medicinal chemistry  2013;56(9):3456-3466.
Curcumin is a biologically active component of curry powder. A structurally-related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for ten of the enzymes at 5 μM, while twenty-two of the proteins were blocked at ≥40%. IC50’s for an expanded set of curcumin analogs established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogs are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways.
PMCID: PMC3927397  PMID: 23550937
curcumin analogs; EF31; kinase screening; kinase interaction network; cancer inhibitors; ATP competition; kinase docking; mixed model inhibition; pleiotropic kinase inhibition
15.  Rare V203I mutation in the PRNP gene of a Chinese patient with Creutzfeldt–Jakob disease 
Prion  2013;7(3):259-262.
Here, we report a Chinese case of Creutzfeldt–Jakob disease (CJD) with a rare mutation in the prion protein gene (PRNP) leading to an exchange of amino acid from valine (Val) to isoleucine (I) at codon 203 (V203I). The 80-y-old male presented with sudden memory loss, rapid loss of vocabulary, inattention and slow responses, accompanied by dizziness, blurred vision and ataxia. Two weeks after admission, he exhibited tremor, myoclonus and bilateral Babinski signs. At the end of the clinical course, he developed severe akinetic mutism. The cerebrospinal fluid (CSF) was positive for 14-3-3 protein. Increased bilateral signal intensity in the frontal and parietal lobes was seen on diffusion-weighted imaging (DWI); periodic activity was recorded on an electroencephalogram (EEG). There was no family history of similar symptoms. The total clinical course was approximately two months.
PMCID: PMC3783113  PMID: 23764840
14-3-3 protein; PRNP; Creutzfeldt–Jakob disease; V203I; mutation
16.  Protective Effect of Ligustrazine on Lumbar Intervertebral Disc Degeneration of Rats Induced by Prolonged Upright Posture 
Most chronic low back pain is the result of degeneration of the lumbar intervertebral disc. Ligustrazine, an alkaloid from Chuanxiong, reportedly is able to relieve pain, suppress inflammation, and treat osteoarthritis and it has the protective effect on cartilage and chondrocytes. Therefore, we asked whether ligustrazine could reduce intervertebral disc degeneration. To determine the effect of ligustrazine on disc degeneration, we applied a rat model. The intervertebral disc degeneration of the rats was induced by prolonged upright posture. We found that pretreatment with ligustrazine for 1 month recovered the structural distortion of the degenerative disc; inhibited the expression of type X collagen, matrix metalloproteinase (MMP)-13, and MMP3; upregulated type II collagen; and decreased IL-1β, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression. In conclusion, ligustrazine is a promising agent for treating lumbar intervertebral disc degeneration disease.
PMCID: PMC4020374  PMID: 24872832
17.  Study on Qi Deficiency Syndrome Identification Modes of Coronary Heart Disease Based on Metabolomic Biomarkers 
Coronary heart disease (CHD) is one of the most important types of heart disease because of its high incidence and mortality. With the era of systems biology bursting into reality, the analysis of the whole biological systems whether they are cells, tissues, organs, or the whole organisms has now become the norm of biological researches. Metabolomics is the branch of science concerned with the quantitative understandings of the metabolite complement of integrated living systems and their dynamic responses to the changes of both endogenous and exogenous factors. The aim of this study is to discuss the characteristics of plasma metabolites in CHD patients and CHD Qi deficiency syndrome patients and explore the composition and concentration changes of the plasma metabolomic biomarkers. The results show that 25 characteristic metabolites related to the CHD patients comparing with the healthy people, and 4 identifiable variables had significant differences between Qi deficiency and non-Qi deficiency patients. On the basis of identifying the different plasma endogenous metabolites between CHD patients and healthy people, we further prompted the metabolic rules, pathogenesis, and biological essence in Qi deficiency syndrome patients.
PMCID: PMC3985201  PMID: 24795766
18.  Serum Albumin and Prealbumin Predict the Poor Outcome of Traumatic Brain Injury 
PLoS ONE  2014;9(3):e93167.
Serum albumin and prealbumin are both negative acute-phase reactants, and usually at low levels in stress. We aim to determine their predictive values for poor outcome of traumatic brain injury (TBI).
A total of 326 patients of TBI were enrolled and followed-up by telephone 6 months after discharge. They were divided into a favorable group (GOS: 3 to 5) and an unfavorable group (GOS: 1 to 2). Serum albumin and prealbumin were measured from vein blood within 24 h after admission.
Ninety one (27.9%) patients were with poor outcome (GOS: 1 to 2). The unfavorable group had lower albumin and prealbumin (P<0.001). Albumin and prealbumin were both positively correlated with GCS (r = 0.489, P<0.001; r = 0.222, P<0.001, respectively) and GOS (r = 0.518, P<0.001; r = 0.314, P<0.001, respectively). After adjustment for confounding factors, the odds ratios of albumin and prealbumin were 0.866, 95% CI: 0.829 to 0.904 and 0.990, 95% CI: 0.985 to 0.995, respectively. In subgroup of GCS≤8 (n = 101), the crude and adjusted odds ratios of serum albumin were both statistically significant (P = 0.027, P = 0.033, respectively), while prealbumin were not (P = 0.553, P = 0.576, respectively). The AUC of albumin for predicting poor outcome was 0.762, 95% CI: 0.712 to 0.807, which was significantly higher than that of prealbumin (0.664, 95% CI: 0.610 to 0.715). In analyses of all patients and subgroup of GCS≤8, the AUCs of serum albumin were both significantly higher than those of prealbumin (P = 0.001, P = 0.045, respectively).
Both serum albumin and prealbumin could predict the poor outcome of TBI, but the former is much better, especially, in patients with severe TBI.
PMCID: PMC3966890  PMID: 24671050
19.  A 12-Words-for-Life-Nurturing Exercise Program as an Alternative Therapy for Cervical Spondylosis: A Randomized Controlled Trial 
In this paper, we carried out a randomized controlled clinical trial to explore the effect of 12-words-for-life-nurturing exercise on patients presenting with cervical spondylosis. After exercise intervention, the mean VAS and NDI scores of the patients decreased significantly and the scores of BP, VT, and MH in SF-36 Health Questionnaire were significantly higher. Exercise therapy showed significant effect on relieving pain and improving vitality and mental health. The 12-words-for-life-nurturing exercise may be a potential effective therapy for patients with cervical spondylosis.
PMCID: PMC3978904  PMID: 24778707
20.  Diagnosing Dengue at the Point-of-Care: Utility of a Rapid Combined Diagnostic Kit in Singapore 
PLoS ONE  2014;9(3):e90037.
WHO recommendations for dengue diagnosis require laboratory facilities. Antibody-based rapid diagnostic tests (RDTs) have performed poorly, and clinical diagnosis remains the mainstay in dengue-endemic countries. We evaluated a combination antigen-antibody RDT for point-of-care testing in a high-prevalence setting. In this prospective cohort study, adults were enrolled from a tertiary infectious disease centre for evaluation of undifferentiated febrile illness from October 2011 to May 2012. SD Bioline Dengue Duo was evaluated at point-of-care against a WHO-based reference standard of viral isolation, RT-PCR, NS1-, IgM-, and IgG-ELISA. 246 adults were enrolled (median age 34 years, range 18–69), of which 197 could be confirmed definitively as either dengue or non-dengue. DENV-2 was the predominant serotype (79.5%) and the ratio of primary to secondary cases was 1∶1.1. There were no test failures and minimal interobserver variation with a Fleiss’ kappa of 0.983 (95% CI 0.827–1.00). Overall sensitivity and specificity were 93.9% (95% CI 88.8–96.8%) and 92.0% (95% CI 81.2–96.9%) respectively. Using WHO clinical criteria alone for diagnosis had similar sensitivities (95.9%, 95% CI 91.4–98.1%) and lower specificities (20.0%, 95% CI 11.2–33.0%). No significant difference in performance was found when testing early versus late presenters, primary versus secondary cases, or DENV-1 versus DENV-2 infections. The use of a combination RDT fulfills WHO ASSURED criteria for point-of-care testing and can enhance dengue diagnosis in an endemic setting. This has the potential to markedly improve clinical management of dengue in the field.
PMCID: PMC3960091  PMID: 24646519
21.  Chondrocyte-Specific Inhibition of β-Catenin Signaling Leads to Dysplasia of the Caudal Vertebrae in Mice 
Spine  2013;38(24):2079-2084.
Study Design
To inhibit β-catenin specifically signaling in chondrocytes Col2-ICAT transgenic mice were generated. Anomalies in caudal vertebrae were detected during embryonic and postnatal stages of Col2-ICAT transgenic mice.
To determine the role of canonical β-catenin signaling in caudal vertebral development.
Summary of Background Data
β-catenin signaling plays a critical role in skeletal development. Col2-ICAT transgenic mice were generated to selectively block β-catenin signaling by overexpression of the ICAT gene in chondrocytes.
Tails of E16.5 transgenic embryos and adult Col2-ICAT transgenic mice and their wild-type littermates were collected and analyzed. Skeletal preparation, 3-dimensional micro-computed tomographic and histological analyses were performed to evaluate changes in the structure of caudal vertebrae. Bromodeoxyuridine labeling was performed to evaluate changes in chondrocyte proliferation in caudal vertebrae.
Skeletal preparation and 3-dimensional micro-computed tomographic analyses revealed bone deformation and angulated deformities in tail tissue in Col2-ICAT transgenic mice. Histological studies revealed abnormal bone development and dysplastic caudal vertebrae in Col2-ICAT transgenic mice. Inhibition of β-catenin signaling in cartilage resulted in vertebral dysplasia leading to aberrant resegmenting process. Thus, 2 poorly developed sclerotomes failed to fuse to form a complete vertebrae. BrdU labeling revealed a decreased chondrocyte proliferation in both cartilageous templates of transgenic embryos and the growth plate of adult Col2-ICAT transgenic mice.
Wnt/β-catenin signaling plays an important role in vertebral development. Inhibition of β-catenin signaling in chondrocytes results in caudal vertebra deformity in mice, which may occur as early as in the stage of sclerotome formation.
PMCID: PMC3928445  PMID: 24026150
β-catenin; ICAT; chondrocyte; caudal vertebral dysplasia
22.  Evodiamine Induces Apoptosis and Enhances TRAIL-Induced Apoptosis in Human Bladder Cancer Cells through mTOR/S6K1-Mediated Downregulation of Mcl-1 
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anti-cancer agents, has been considered as a new strategy for anti-cancer therapy. In this study, we demonstrated that evodiamine, a quinolone alkaloid isolated from the fruit of Evodia fructus, induced apoptosis and enhanced TRAIL-induced apoptosis in human bladder cancer cells. To elucidate the underlying mechanism, we found that evodiamine significantly reduced the protein levels of Mcl-1 in 253J and T24 bladder cancer cells, and overexpression of this molecule attenuated the apoptosis induced by evodiamine alone, or in combination with TRAIL. Further experiments revealed that evodiamine did not affect the mRNA level, proteasomal degradation and protein stability of Mcl-1. On the other hand, evodiamine inhibited the mTOR/S6K1 pathway, which usually regulates protein translation; moreover, knockdown of S6K1 with small interfering RNA (siRNA) effectively reduced Mcl-1 levels, indicating evodiamine downregulates c-FLIP through inhibition of mTOR/S6K1 pathway. Taken together, our results indicate that evodiamine induces apoptosis and enhances TRAIL-induced apoptosis possibly through mTOR/S6K1-mediated downregulation of Mcl-1; furthermore, these findings provide a rationale for the combined application of evodiamine with TRAIL in the treatment of bladder cancer.
PMCID: PMC3958903  PMID: 24566141
evodiamine; TRAIL; Mcl-1; mTOR; S6K1; bladder cancer
23.  Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway 
Scientific Reports  2014;4:3840.
Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-κB pathway.
PMCID: PMC3899591  PMID: 24452475
24.  Involvement of both Cervical Lymph Nodes and Retropharyngeal Lymph Nodes has prognostic value for N1 patients with Nasopharyngeal Carcinoma 
The N1 definition of 2010 UICC/AJCC staging system for nasopharyngeal carcinoma (NPC) covers quite a large range of nodal pattern. The objective of this research is to investigate prognostic value of lymph nodes related factors including involvement of both cervical lymph nodes (CLNs) and retropharyngeal lymph nodes (RLNs) or not, size and number of cervical lymph nodes (CLNs) in N1 patients with NPC.
142 newly diagnosed non-metastatic N1 patients with NPC, staged according to the 2010 AJCC staging system for NPC were retrospectively enrolled. All patients had undergone contrast-enhanced magnetic resonance imaging (MRI), and received radiotherapy, with or without chemotherapy as their primary treatment.
The median follow-up was 48 months. The 5-year local recurrence-free survival (LFS), nodal recurrence-free survival (NFS), local-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) of the whole group were 82.3%, 83.0%, 81.0%, 82.1%, 75.3% and 89.8%, respectively. In univariate analysis, patients with both CLNs and RLNs involvement showed a significant lower DMFS, PFS and LRFS than the rest patients (p = 0.004 p = 0.003 and p = 0.034, respectively). Neither size nor number of CLNs affected the survival. In multivariate analysis, involvement of both CLNs and RLNs was an independent prognostic factor for DMFS and PFS (p = 0.019, p = 0.019), but there was no enough evidence confirming its prognostic value for LRFS (p = 0.051).
For N1 patients with NPC, involvement of both RLNs and CLNs may be a potentially prognostic factor for distant metastasis and disease progression. The N stage for N1 patients with involvement of both cervical lymph nodes and retropharyngeal lymph nodes might need to be deliberated.
PMCID: PMC3996203  PMID: 24393418
Nasopharyngeal carcinoma; Lymph nodes; Prognosis
25.  Inhibition of sperm capacitation and fertilizing capacity by adjudin is mediated by chloride and its channels in humans 
Does adjudin disrupt chloride ion (Cl−) ion transport function in human sperm and impede sperm capacitation and fertilizing ability in vitro?
In this study the results indicate that adjudin is a potent blocker of Cl− channels: disrupting Cl− ion transport function results in a decline in sperm capacitation and fertilizing ability in humans in vitro.
Although our previous studies have demonstrated that adjudin exerts its effect by disrupting sertoli-germ cell adhesion junctions, most notably apical ectoplasmic specialization by targeting testin and actin filament bundles that disrupts the actin-based cytoskeleton in sertoli cells, it remains unclear whether adjudin impedes Cl− ion transport function in the human sperm.
Semen samples were obtained from 45 fertile men (aged 25–32). Spermatozoa were isolated from the semen in the human tube fluid (HTF) medium by centrifugation through a discontinuous Percoll gradient, and incubated with adjudin at 10 nM–10 µM and/or other reagents under capacitating conditions for 0–5 h.
We evaluated the effect of adjudin and different reagents on sperm functions with which they were incubated at 37°C. Sperm motility and hyperactivation were analyzed by a computer-assisted sperm analysis (CASA) system. Sperm capacitation and the acrosome reaction were assessed by chlortetracycline fluorescence staining. Sperm fertilizing ability was evaluated by sperm penetration of zona-free hamster egg assay, and cellular cAMP levels in spermatozoa were quantified by the EIA kit. The proteins tyrosine, serine and threonine phosphorylation in the presence or absence of adjudin were analyzed by means of a immunodetection of spermatozoa, especially, compared the effect of adjudin on sperm hyperactivation and capacitation in the complete HTF medium with the Cl−-deficient HTF medium as well as the various Cl− channel blockers.
Adjudin significantly inhibited sperm hyperactivation but not sperm motility. Adjudin-induced inhibition of sperm capacitation was reversible, and it was found to block the rhuZP3β- and progesterone-induced acrosome reaction in a dose-dependent manner. Adjudin also blocked sperm penetration of zona-free hamster eggs, and significantly inhibited both forskolin-activated transmembrane adenylyl cyclase and soluble adenylyl cyclase activities leading to a significant decline in the cellular cAMP levels in human spermatozoa. Adjudin failed to reduce sperm protein tyrosine phosphorylation but it did prevent sperm serine and threonine protein phosphorylation. Interestingly, adjudin was found to exert its inhibitory effects on sperm capacitation and capacitation-associated events only in the complete Cl−-HTF medium but not Cl−-deficient medium, illustrating the likely involvement of Cl−. Adjudin inhibits the fertility capacity of human sperm is mediated by disrupting chloride ion and its transport function.
This study has examined the effect of adjudin only on human sperm capacitation and fertilizing ability in vitro and thus has some limitations. Further investigations in vivo are needed to confirm adjudin is a potent male contraceptive.
Our studies demonstrated that adjudin inhibition of capacitation is reversible and its toxicity is low, opening the door for the examination of adjudin as a mediator of male fertility control. Adjudin may be a safe, efficient and reversible male antifertility agent and applicable to initial clinical trials of adjudin as a male antifertility agent in humans.
This work was supported by the National Basic Research Program of China (2006CB504002), the Nature Science Foundation of China (Nos. 81000244 and 81170554), Zhejiang Project of Science and Technology (2011C23046), the Nature Science Fund of Zhejiang province (Nos.Y2100058 and Y2090236), the key Science and Technology Innovation Team of Zhejiang Province (No.2012R10048-07) and the National Institutes of Health (NICHD U54 HD029990 project 5), USA. The authors declare no conflict of interest.
PMCID: PMC3522416  PMID: 23117128
adjudin; human sperm; fertilizing capacity; chloride

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