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1.  Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy 
Hepatology (Baltimore, Md.)  2014;60(2):576-587.
Wnt signaling is important for cancer pathogenesis and is often upregulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as co-receptors or modulators of Wnt activation. Glypican-3 (GPC3) is a HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/β-catenin signaling in these cells. Then, we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and non-sulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/β-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/β-catenin signaling in HCC cells and had potent anti-tumor activity in vivo.
Here, we provide one of the first examples of an antibody directed against the heparan sulfate of a proteoglycan that showed efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy.
PMCID: PMC4083010  PMID: 24492943
Cancer therapy; Wnt3a; heparan sulfate proteoglycan; phage display; antibody engineering
2.  Fully-Loaded Micromotors for Combinatorial Delivery and Autonomous Release of Cargoes 
PMCID: PMC4107182  PMID: 24706367
Self-destruction micromachines; Combinatorial drug delivery; Cargo release; Zinc; Drug delivery
3.  Dynamics of serotype 14 Streptococcus pneumoniae population causing acute respiratory infections among children in China (1997–2012) 
BMC Infectious Diseases  2015;15:266.
In the last decade, the Streptococcus pneumoniae population has changed, mainly due to the abuse of antibiotics. The aim of this study was to determine the genetic structure of 144 S. pneumonia serotype 14 isolates collected from children with acute respiratory infections during 1997–2012 in China.
All isolated pneumococci were tested for their sensitivity to 11 kinds of antibiotics with the E-test method or disc diffusion. The macrolides resistance genes ermB and mefA, as well as the sulfamethoxazole-trimethoprim resistance gene dihydrofolate reductase (DHFR) were detected by polymerase chain reaction (PCR). The sequence types (STs) were analyzed with multilocus sequence typing (MLST).
From 1997 to 2012, the percentage of serotype 14 S. pneumonia isolates in the whole isolates increased. All of the 144 serotype 14 S. pneumonia isolates were susceptible to amoxicillin-clavulanic acid, vancomycin and levofloxacin. No penicillin resistant isolate was found, and the intermediate rate was as low as 0.7 %. Erythromycin resistance was confirmed among 143 isolates. The ermB gene was determined in all erythromycin resistant isolates, and the mefA gene was positive additionally in 13 of them. The non-susceptibility rate to the tested cephalosporins increased from 1997–2012. All trimethoprim-resistant isolates contained the Ile100-Leu mutation. Overall, 30 STs were identified, among which ST876 was the most prevalent, followed by ST875. During the study period, the percentage of CC876 increased from 0 % in 1997–2000 to 96.4 % in 2010–2012, whereas CC875 decreased from 84.2 to 0 %. CC876 showed higher non-susceptibility rates to β-lactam antibiotics than CC875.
The percentage of serotype 14 S. pneumonia isolates increased over time in China. The increase of resistance to β-lactam antibiotics in this serotype isolates was associated with the spread of CC876.
PMCID: PMC4499228  PMID: 26163293
Streptococcus pneumoniae; Serotypes; Antibiotic resistance; Children; Epidemiology
4.  The Value of BISAP Score for Predicting Mortality and Severity in Acute Pancreatitis: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0130412.
The Bedside Index for Severity in Acute Pancreatitis (BISAP) score has been developed to identify patients at high risk for mortality or severe disease early during the course of acute pancreatitis. We aimed to undertake a meta-analysis to quantify the accuracy of BISAP score for predicting mortality and severe acute pancreatitis (SAP).
Materials and Methods
We searched the databases of Pubmed, Embase, and the Cochrane Library to identify studies using the BISAP score to predict mortality or SAP. The pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were calculated from each study and were compared with the traditional scoring systems.
Twelve cohorts from 10 studies were included. The overall sensitivity of a BISAP score of ≥3 for mortality was 56% (95% CI, 53%-60%), with a specificity of 91% (95% CI, 90%-91%). The positive and negative likelihood ratios were 5.65 (95% CI, 4.23-7.55) and 0.48 (95% CI, 0.41-0.56), respectively. Regarding the outcome of SAP, the pooled sensitivity was 51% (43%-60%), and the specificity was 91% (89%-92%). The pooled positive and negative likelihood ratios were 7.23 (4.21-12.42) and 0.56 (0.44-0.71), respectively. Compared with BISAP score, the Ranson criteria and APACHEⅡscore showed higher sensitivity and lower specificity for both outcomes.
The BISAP score was a reliable tool to identify AP patients at high risk for unfavorable outcomes. Compared with the Ranson criteria and APACHEⅡscore, BISAP score outperformed in specificity, but having a suboptimal sensitivity for mortality as well as SAP.
PMCID: PMC4474919  PMID: 26091293
5.  Draft Genome Sequence of Shewanella sp. ECSMB14102, a Mussel Recruitment-Promoting Bacterium Isolated from the East China Sea 
Genome Announcements  2015;3(3):e00670-15.
Shewanella sp. ECSMB14102, which promotes recruitment of the mussel Mytilus coruscus, was isolated from natural biofilms formed on glass slides submerged in the East China Sea. Here, we present the draft genome sequence, which comprises 4.41 Mb with a G+C content of 52.2%. The genomic information in this strain will contribute to deepening our understanding of bacteria-animal interaction.
PMCID: PMC4472906  PMID: 26089429
6.  Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis 
This study investigates the role of Toll-like receptor 2 (TLR2) in the regulation of migratory and invasive mechanisms in rheumatoid arthritis (RA).
Invasion, migration, matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) expression, β-integrin binding, cytoskeletal rearrangement and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation in response to a TLR2-ligand, Pam3CSK4 (1 μg/ml), in ex vivo RA synovial tissue explants, primary RA synovial fibroblasts (RASFC) and microvascular endothelial cells (HMVEC) were assessed by Transwell Matrigel™ invasion chambers, enzyme-linked immunosorbent assay (ELISA), multiplex adhesion binding assay, reverse transcription polymerase chain reaction (RT-PCR), F-actin immunofluorescent staining, matrigel synovial outgrowths, Rac1 pull-down assays/Western blot and zymography. β1-integrin expression in RA/control synovial tissue was assessed by immunohistology. The effect of Pam3CSK4 on cell migration, invasion, MMP-3 and Rac1 activation was examined in the presence or absence of anti-β1-integrin (10 μg/ml) or anti-IgG control (10 μg/ml). The effect of an anti-TLR-2 mAb (OPN301)(1 μg/ml) or immunoglobulin G (IgG) control (1 μg/ml) on RASFC migration and RA synovial tissue MMP activity was assessed by wound assays, ELISA and zymography.
Pam3CSK4 significantly induced cell migration, invasion, MMP-1, MMP-3, MMP-2 and MMP-9 expression and induced the MMP-1/TIMP-3 and MMP-3/TIMP-3 ratio in RASFC and explants (p <0.05). β1-integrin expression was significantly higher in RA synovial tissue compared to controls (p <0.05). Pam3CSK4 specifically induced β1-integrin binding in RASFC (p <0.05), with no effect observed for β2-4, β6, αvβ5 or α5β1. Pam3CSK4 increased β1-integrin mRNA expression, Rac1 activation, RASFC outgrowths and altered cytoskeletal dynamic through induction of filopodia formation. Pam3CSK4-regulated cell migration and invasion processes, but not MMP-3, were inhibited in the presence of anti-β1-integrin (p <0.05), with no effect observed for anti-IgG control. Furthermore, anti-β1-integrin inhibited Pam3CSK4-induced Rac1 activation. Finally, blockade of TLR2 with OPN301 significantly decreased spontaneous release of MMP-3, MMP-2 and MMP-9 and increased TIMP-3 secretion from RA synovial explant cultures (p <0.05). Incubation of RASFC with OPN301 RA ex vivo conditioned media inhibited migration and invasion compared to IgG control.
TLR2 activation induces migrational and invasive mechanisms, which are critically involved in the pathogenesis of RA, suggesting TLR2 as a potential therapeutic target for the treatment of RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0664-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4495696  PMID: 26055925
8.  ADAM19 and HTR4 Variants and Pulmonary Function: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study 
The pulmonary function measures of forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome wide association studies (GWAS) have identified numerous loci associated with FEV1 and FEV1/FVC but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWAS may explain the significant associations between FEV1/FVC and two genes: ADAM19 and HTR4.
Methods and Results
We sequenced ADAM19 and its promoter region along with the approximately 21 kb portion of HTR4 harboring GWAS SNPs for pulmonary function and analyzed associations with FEV1/FVC among 3,983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). Meta-analysis of common variants in each region identified statistically significant associations (316 tests, P < 1.58×10−4) with FEV1/FVC for 14 ADAM19 SNPs and 24 HTR4 SNPs. After conditioning on the sentinel GWAS hit in each gene [ADAM19 rs1422795, minor allele frequency (MAF)=0.33 and HTR4 rs11168048, MAF=0.40] one SNP remained statistically significant (ADAM19 rs13155908, MAF = 0.12, P = 1.56×10−4). Analysis of rare variants (MAF < 1%) using Sequence Kernel Association Test did not identify associations with either region.
Sequencing identified one common variant associated with FEV1/FVC independently of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not appear to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
PMCID: PMC4136502  PMID: 24951661
genetic polymorphism; lung; population studies; DNA sequencing; Genome Wide Association Study
9.  New High Affinity Monoclonal Antibodies Recognize Non-Overlapping Epitopes On Mesothelin For Monitoring And Treating Mesothelioma 
Scientific Reports  2015;5:9928.
Mesothelin is an emerging cell surface target in mesothelioma and other solid tumors. Most antibody drug candidates recognize highly immunogenic Region I (296–390) on mesothelin. Here, we report a group of high-affinity non-Region I rabbit monoclonal antibodies. These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin. One pair of antibodies (YP218 and YP223) is suitable to detect soluble mesothelin in a sandwich ELISA with high sensitivity. The new assay can also be used to measure serum mesothelin concentration in mesothelioma patients, indicating its potential use for monitoring patients treated with current antibody therapies targeting Region I. The antibodies are highly specific and sensitive in immunostaining of mesothelioma. To explore their use in tumor therapy, we have generated the immunotoxins based on the Fv of these antibodies. One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice. Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for mesothelin-expressing cancer cells. In conclusion, with their unique binding properties, these antibodies may be promising candidates for monitoring and treating mesothelioma and other mesothelin-expressing cancers.
PMCID: PMC4440525  PMID: 25996440
10.  The Protecting Effect of Deoxyschisandrin and Schisandrin B on HaCaT Cells against UVB-Induced Damage 
PLoS ONE  2015;10(5):e0127177.
Schisandra chinensis is a traditional Chinese medicine that has multiple biological activities, including antioxidant, anticancer, tonic, and anti-aging effects. Deoxyschisandrin (SA) and schisandrin B (SB), the two major lignans isolated from S. chinensis, exert high antioxidant activities in vitro and in vivo by scavenging free radicals, such as reactive oxygen species (ROS). Ultraviolet B-ray (UVB) radiation induces the production of ROS and DNA damage, which eventually leads to cell death by apoptosis. However, it is unknown whether SA or SB protects cells against UVB-induced cellular DNA damage. Our study showed that both SA and SB effectively protected HaCaT cells from UVB-induced cell death by antagonizing UVB-mediated production of ROS and induction of DNA damage. Our results showed that both SA and SB significantly prevented UVB-induced loss of cell viability using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assays showed that the production of ROS following UVB exposure was inhibited by treatment with SA and SB. Moreover, SA and SB decreased the UVB-induced DNA damage in HaCaT cells by comet assays. In addition, SA and SB also prevented UVB-induced cell apoptosis and the cleavage of caspase-3, caspase-8 and caspase-9. In a word, our results imply that the antioxidants SA and SB could protect cells from UVB-induced cell damage via scavenging ROS.
PMCID: PMC4433126  PMID: 25978330
11.  Mannose-capped Lipoarabinomannan from Mycobacterium tuberculosis induces IL-37 production via upregulating ERK1/2 and p38 in human type II alveolar epithelial cells 
The major surface lipoglycan of Mycobacterium tuberculosis (M. tb), mannose-capped lipoarabinomannan (ManLAM), is an immunosuppressive epitope of M. tb. Interleukin (IL)-37, is a newly identified anti-inflammatory cytokine, which reduces systemic and local inflammation. However, the correlation between ManLAM and IL-37 remains unknown. Therefore, in this study, we investigate the possible role and relative molecular mechanism of ManLAM in IL-37 production of human type II alveolar epithelial cells by using A549 cell line. Here, we report that M. tb induced IL-37 mRNA and protein expression in a time-dependent manner. We next fractionated components of M. tb using chloroform: methanol (C:M) and water. In sharp contrast to the C:M phase, water phase was mainly responsible for the production of IL-37. Since ManLAM is the major component of water phase, we found that ManLAM induced IL-37 mRNA and protein expression in a time and dose-dependent manner, while this activity was almost totally abolished by the ERK1/2 (U0126) and p38 (SB203580) inhibitor. ManLAM stimulation significantly induced ERK1/2 and p38 phosphorylation in A549 cells, as well as cell surface TLR2 expression. After interfering TLR2 expression, ERK1/2 and p38 phosphorylation levels were markedly decreased, and also IL-37 production. Though ManLAM also promoted TLR4 expression on A549 cells, TLR4 interference showed no influence on ManLAM-induced IL-37 production. Our results indicate that ManLAM induces IL-37 production in human type II alveolar epithelial cells via up-regulating TLR2/p38 or ERK1/2 pathway, and this provide an important evidence to explain the pathological role of ManLAM that contribute to the persistence of M. tb.
PMCID: PMC4509212  PMID: 26221267
ManLAM; tuberculosis; IL-37; TLR2; ERK1/2; p38
12.  Cellular and Subcellular Immunohistochemical Localization and Quantification of Cadmium Ions in Wheat (Triticum aestivum) 
PLoS ONE  2015;10(5):e0123779.
The distribution of metallic ions in plant tissues is associated with their toxicity and is important for understanding mechanisms of toxicity tolerance. A quantitative histochemical method can help advance knowledge of cellular and subcellular localization and distribution of heavy metals in plant tissues. An immunohistochemical (IHC) imaging method for cadmium ions (Cd2+) was developed for the first time for the wheat Triticum aestivum grown in Cd2+-fortified soils. Also, 1-(4-Isothiocyanobenzyl)-ethylenediamine-N,N,N,N-tetraacetic acid (ITCB-EDTA) was used to chelate the mobile Cd2+. The ITCB-EDTA/Cd2+ complex was fixed with proteins in situ via the isothiocyano group. A new Cd2+-EDTA specific monoclonal antibody, 4F3B6D9A1, was used to locate the Cd2+-EDTA protein complex. After staining, the fluorescence intensities of sections of Cd2+-positive roots were compared with those of Cd2+-negative roots under a laser confocal scanning microscope, and the location of colloidal gold particles was determined with a transmission electron microscope. The results enable quantification of the Cd2+ content in plant tissues and illustrate Cd2+ translocation and cellular and subcellular responses of T. aestivum to Cd2+ stress. Compared to the conventional metal-S coprecipitation histochemical method, this new IHC method is quantitative, more specific and has less background interference. The subcellular location of Cd2+ was also confirmed with energy-dispersive X-ray microanalysis. The IHC method is suitable for locating and quantifying Cd2+ in plant tissues and can be extended to other heavy metallic ions.
PMCID: PMC4420502  PMID: 25941807
13.  Molecular Cloning and Characterisation of Farnesyl Pyrophosphate Synthase from Tripterygium wilfordii 
PLoS ONE  2015;10(5):e0125415.
Farnesylpyrophosphate synthase (FPS) catalyzes the biosynthesis of farnesyl pyrophosphate (FPP), which is an important precursor of sesquiterpenoids such as artemisinin and wilfordine. In the present study, we report the molecular cloning and characterization of two full-length cDNAs encoding FPSs from Tripterygium wilfordii (TwFPSs). TwFPSs maintained their capability to synthesise FPP in vitro when purified as recombinant proteins from E. coli. Consistent with the endogenous role of FPS in FPP biosynthesis, TwFPSs were highly expressed in T. wilfordii roots, and were up-regulated upon methyl jasmonate (MeJA) treatment. The global gene expression profiles suggested that the TwFPSs might play an important regulatory role interpenoid biosynthesis in T. wilfordii, laying the groundwork for the future study of the synthetic biology of natural terpene products.
PMCID: PMC4418688  PMID: 25938487
14.  An analysis of patients receiving emergency CAG without PCI and the value of GRACE score in predicting PCI possibilities in NSTE-ACS patients 
There are patients who underwent emergency coronary angiography (CAG) but did not receive percutaneous coronary intervention (PCI). The aim of this study was to analyze these reasons.
This is a single-center retrospective study. We recruited 201 consecutive patients who received emergency CAG but did not receive PCI. To investigate the value of the Global Registry of Acute Coronary Events (GRACE) score in predicting PCI possibilities in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients, we recruited 80 consecutive patients who presented with NSTE-ACS and received emergency CAG as well as emergency PCI.
Among the 201 patients who received emergency CAG but did not receive PCI, 26% patients had final diagnosis other than coronary heart disease. In the patients with significant coronary artery stenosis, 23 patients (11.5%) were recommended to coronary artery bypass grafting (CABG), one patient (0.5%) refused PCI; 13 patients (6.5%) with significant thrombus burden were treated with glycoprotein IIb/IIIa receptor antagonist; 74 patients (36.8%) were treated with drug therapy because no severe stenosis (> 70%) was present in the crime vessel. Moreover, 80 of the 201 patients were presented with NSTE-ACS (excluding those patients with final diagnosis other than coronary heart disease, excluding those patients planned for CABG treatment), referred as non PCI NSTE-ACS. When comparing their GRACE scores with 80 consecutive patients presented with NSTE-ACS who received emergency CAG as well as emergency PCI (referred as PCI NSTE-ACS), we found that PCI NSTE-ACS patients had significantly higher GRACE scores compared with non PCI NSTE-ACS patients. We then used Receiver Operator Characteristic Curve (ROC) to test whether the GRACE score is good at evaluating the possibilities of PCI in NSTE-ACS patients. The area under the curve was 0.854 ± 0.030 (P < 0.001), indicating good predictive value. Furthermore, we analyzed results derived from ROC statistics, and found that a GRACE score of 125.5, as a cut-off, has high sensitivity and specificity in evaluating PCI possibilities in NSTE-ACS patients.
Our findings indicate that the GRACE score has predictive value in determining whether NSTE-ACS patients would receive PCI.
PMCID: PMC4460167  PMID: 26089848
Acute coronary syndrome; Coronary angiography; GRACE score; Percutaneous coronary intervention
15.  Vasospastic angina with J waves formation in patients with sudden loss of consciousness 
Vasospastic angina is caused by sudden occlusive vasoconstriction of a segment of an epicardial artery, which can present with a wide spectrum of clinical scenario. We report the cases of two patients diagnosed with vasospastic angina, with one of which presenting with sudden cardiac arrest, while the other presenting with a relatively benign syncope. But both of them have J waves formation on ECG during active ischemia. The diagnosis and management of vasospastic angina, as well as the proposed clinical significance of J waves during coronary spasm are discussed.
PMCID: PMC4460176  PMID: 26089857
Angina; Consciousness loss; J wave; Osborn wave
16.  Downregulation of long noncoding RNA ZMAT1 transcript variant 2 predicts a poor prognosis in patients with gastric cancer 
Gastric cancer is the second most common cause of cancer-related death partially because of its aggressive metastasis and the fact that it is often diagnosed at an advanced stage. Recent studies have shown that long noncoding RNAs (lncRNAs) play critical roles in multiple biological processes including oncogenesis. In the present study, we found for the first time that the lncRNA ZMAT1 transcript variant 2 is downregulated in gastric cancer tissues compared with adjacent normal tissues (P < 0.001). The expression of ZMAT1 transcript variant 2 was inversely correlated with lymph node metastasis (P < 0.05), depth of tumor invasion and tumor node metastasis stage (P < 0.05). Univariate and multivariate analyses showed that ZMAT1 transcript variant 2 expression was an independent predictor for overall survival (P < 0.05). Our study suggests that ZMAT1 transcript variant 2 is a potential diagnostic factor in patients with gastric cancer.
PMCID: PMC4503135  PMID: 26191264
Gastric cancer; ZMAT1 transcript; prognosis
17.  Exploring meanings of illness causation among those severely affected by multiple sclerosis: a comparative qualitative study of Black Caribbean and White British people 
BMC Palliative Care  2015;14:13.
Illness attributions, particularly for those living with life limiting illnesses, are associated with emotional adjustment or psychological distress. Few studies have examined attributions among people severely affected by multiple sclerosis (PwMS), and specifically among from diverse communities. This study aimed to explore and compare the presence and construction of meanings among Black Caribbean and White British PwMS.
Cross sectional qualitative interviews were conducted among Black Caribbean (BC) and White British (WB) PwMS with an EDSS of ≥6.0 (severe disease). Data were analysed using the framework approach.
15 BC and 15 WB PwMS were interviewed. Attributions were complex with most PwMS reporting multiple explanations. Uncertainty, represents the first theme surrounding the aetiology of MS where participants constantly rehearsed the “why me?” question in relation to their illness, a number expressing considerable frustration. The second theme, ‘logical and scientific’, was voiced more often by WB PwMS and accounts for a range of genetic/viral influences, stress, environmental and lifestyle factors. Third, the ‘supernatural’ illness attribution theme departs from a biomedical perspective and was reported often among BC PwMS. This theme included the sub-categories of tests of faith and divine punishment, a view although exclusive to BC participants but was sometimes in conflict with notions of modernity.
Our findings identify evidence of cross-cultural and intra-group diversity in relation to MS causation. A greater professional awareness of the processes used by PwMS from diverse communities to make sense of their situation will enable health care professionals to facilitate effective support for those in their care and channel relevant psychosocial resources to them. This requires heightened skills in communication and cultural competency.
PMCID: PMC4475620  PMID: 25927425
Multiple sclerosis; Culture; Ethnicity; Palliative care; Neurology; Attributions
18.  Determination of HIV-1 coreceptor tropism using proviral DNA in women before and after viral suppression 
An HIV-1 tropism test is recommended prior to CCR5 antagonist administration to exclude patients harboring non-R5 virus from treatment with this class of antiretrovirals. HIV-1 tropism determination based on proviral DNA (pvDNA) may be useful in individuals with plasma viral RNA suppression. We developed a genotypic tropism assay for pvDNA and assessed its performance in a retrospective analysis of samples collected longitudinally.
We randomly selected paired plasma/PBMC samples from the Women’s Interagency HIV Study with plasma viral load ≥5,000 cp/mL at time 1 (T1), undetectable viral load maintained for ≥1 year and CD4+ >200 cells/μL at time 2 (T2). pvDNA was isolated from cryopreserved PBMCs. Sequences were analyzed in triplicate from 49/50 women, with tropism assigned using the geno2pheno (g2p) algorithm. The median time between T1 and T2 was 4.1 years. CXCR4-using virus was detected in 24% of the RNA samples and 33% of the pvDNA samples at T1, compared to 37% of the pvDNA samples at T2. Concordance between plasma RNA and pvDNA tropism was 88% at T1 and 80% at T2. The g2p scores for RNA (T1) vs DNA (T1, T2) were strongly correlated (Spearman rho: 0.85 (T1); 0.78 (T2)). In women with evidence of tropism switch at T2 (either R5 to non-R5 or non-R5 to R5), there was a correlation between change in tropism and time. Mean pvDNA viral load decreased by 0.4 log10 copies/106 cells between T1 and T2 (p < 0.0001), but this decrease was not significantly associated with tropism status.
We demonstrated that pvDNA tropism in women with HIV-1 suppression is concordant with prior RNA tropism results, even after a median time of >4 years. pvDNA tropism testing may be useful to determine eligibility of patients with viral suppression to switch to a CCR5-antagonist based regimen as well as for research purposes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12981-015-0055-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4403710  PMID: 25897314
HIV; Tropism; pvDNA
19.  Chemokine receptor CXCR4 expression and lung cancer prognosis: a meta-analysis 
The chemokine receptor CXCR4 is a G protein-coupled receptor that plays an important role in several biological processes, such as trafficking and homeostasis of immune cells (like T lymphocytes), alteration of cell skeleton rearrangement and cell migration. To investigate whether the CXCR4 protein impacts on lung cancer prognosis, a meta-analysis was performed. Our meta-analysis study involved 2,037 lung cancer patients from 24 studies by a comprehensive search from PubMed, Embase and CNKI databases up to September 2014. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship. We found that the CXCR4 expression was significantly associated with lymph node metastasis (OR = 3.79, 95% CI: 2.15-6.68), distant metastasis (OR = 3.67, 95% CI: 1.84-7.32), tumor stage (OR = 2.78, 95% CI: 1.77-4.39) and overall survival (HR = 1.63, 95% CI: 1.16-2.30). In conclusion, CXCR4 might be a new prognostic biomarker, and it might become a new diagnosis and therapeutic target in lung cancer.
PMCID: PMC4483894  PMID: 26131090
CXCR4; lung cancer; prognosis; meta-analysis
20.  Regulation and Methylation of Tumor Suppressor MiR-124 by Androgen Receptor in Prostate Cancer Cells 
PLoS ONE  2015;10(4):e0116197.
Prostate cancer (PCa) is the most frequently diagnosed cancer for men in the developed world. Androgen receptor signaling pathway plays an important role in prostate cancer progression. Recent studies show that microRNA miR-124 exerts a tumor suppressive function in prostate cancer. However, the relationship between AR and miR-124 is unclear. In the present study, we found a negative feedback loop between AR and miR-124 expression. On one hand, miR-124 was a positively regulated target gene of the AR, on the other hand, overexpression of miR-124 inhibited the expression of AR. In addition, we found that miR-124-2 and miR-124-3 promoters were hypermethylated in AR-negative PCa cells. Furthermore, overexpression of miR-124 inhibited proliferation rates and invasiveness capacity of PCa cells in vitro, and suppressed xenograft tumor growth in vivo. Taken together, our results support a negative feedback loop between AR and miR-124 expression. Methylation of miR-124-2 and miR-124-3 may serve as a biomarker for AR-negative PCa cells, and overexpression of miR-124 might be of potential therapeutic value for the treatment of PCa.
PMCID: PMC4393226  PMID: 25860954
21.  Correlation of Plasma Catestatin Level and the Prognosis of Patients with Acute Myocardial Infarction 
PLoS ONE  2015;10(4):e0122993.
Catestatin is a peptide which is a potent inhibitor of catecholamine secretion and played essential functions in the cardiovascular system. Previous research found that dramatic changes of catestatin were associated with hemodynamics in acute myocardial infarction (AMI) during the first week after the AMI symptoms onset, but whether catestatin is also involved in the pathophysiological progression after AMI and then a predictor for outcomes is not clear. The aim of this study is to determine the correlation of plasma catestatin levels at different time points and the prognosis of AMI. 100 participants recruited were all patients with AMI, all of who received successful primary percutaneous coronary intervention (PCI) within 12h from the AMI symptom onset in our center; the concentrations of plasma catestatin were evaluated from blood samples of those 100 participants. Subsequent 65 months' follow-up was performed after discharging to evaluate cardiac adverse events and the association between catestatin levels and prognosis of AMI was examined. We confirmed the dramatic change of catestatin concentrations in the first week of AMI, and the levels of catestatin on D3 were much higher in adverse events group than those in non-adverse events group (p<0.0001), but the ratio of D7/D3 was significantly lower. In addition, the Kaplan-Meier analysis showed that the groups in which the levels on D3 were higher (p<0.0001) and the ratios of D7/D3 were lower (p<0.0001), patients trended to be more susceptive to adverse events after AMI. Furthermore, according to the analysis, we surmised catestatin level on D3 as an appropriate predictor for outcomes in patients with AMI with good specificity as well as sensitivity. All of the evidence confirmed that catestatin plays an important role in the progress of AMI, and may act as a promising target for prognostic prediction.
PMCID: PMC4388679  PMID: 25848973
22.  The Potential of Infant fMRI Research and the Study of Early Life Stress as a Promising Exemplar 
Functional magnetic resonance imaging (fMRI) research with infants and toddlers has increased rapidly over the past decade, and provided a unique window into early brain development. In the current report, we review the state of the literature, which has established the feasibility and utility of task-based fMRI and resting state functional connectivity MRI (rs-fcMRI) during early periods of brain maturation. These methodologies have been successfully applied beginning in the neonatal period to increase understanding of how the brain both responds to environmental stimuli, and becomes organized into large-scale functional systems that support complex behaviors. We discuss the methodological challenges posed by this promising area of research. We also highlight that despite these challenges, early work indicates a strong potential for these methods to influence multiple research domains. As an example, we focus on the study of early life stress and its influence on brain development and mental health outcomes. We illustrate the promise of these methodologies for building on, and making important contributions to, the existing literature in this field.
PMCID: PMC4385461  PMID: 25459874
infancy; natural sleep fMRI; resting state functional connectivity MRI; developmental neuroimaging; early life stress
23.  Rumen Degradability and Post-ruminal Digestion of Dry Matter, Nitrogen and Amino Acids of Three Protein Supplements 
This study evaluated the in situ ruminal degradability, and subsequent small intestinal digestibility (SID) of dry matter, crude protein (CP), and amino acids (AA) of cottonseed meal (CSM), sunflower seed meal (SFSM) and distillers dried grains with solubles (DDGS) by using the modified three-step in vitro procedure. The ruminal degradability and subsequent SID of AA in rumen-undegradable protein (RUP-AA) varied among three protein supplements. The result show that the effective degradability of DM for SFSM, CSM, and DDGS was 60.8%, 56.4%, and 41.0% and their ruminal fermentable organic matter was 60.0%, 55.9%, and 39.9%, respectively. The ruminal degradable protein (RDP) content in CP for SFSM, CSM, and DDGS was 68.3%, 39.0%, and 32.9%, respectively, at the ruminal solid passage rate of 1.84%/h. The SFSM is a good source of RDP for rumen micro-organisms; however, the SID of RUP of SFSM was lower. The DDGS and CSM are good sources of RUP for lambs to digest in the small intestine to complement ruminal microbial AA of growing lambs. Individual RUP-AA from each protein source was selectively removed by the rumen micro-organisms, especially for Trp, Arg, His, and Lys (p<0.01). The SID of individual RUP-AA was different within specific RUP origin (p<0.01). Limiting amino acid was Leu for RUP of CSM and Lys for both RUP of SFSM and DDGS, respectively. Therefore, different protein supplements with specific limitations should be selected and combined carefully in growing lambs ration to optimize AA balance.
PMCID: PMC4341097  PMID: 25656208
Ruminal Degradability; Intestinal Digestibility; Protein Supplement; Amino Acids; Lamb
25.  Dexamethasone added to Local Lidocaine for Infiltration along the Spinal-Epidural Needle Pathway Decreases Incidence and Severity of Backache after Gynecological Surgery 
The aim of this study was to evaluate the effect of dexamethasone added to local lidocaine infiltration on incidence and severity of backache after combined spinal-epidural anesthesia for gynecological surgery.
We randomly allocated 160 patients to receive either local lidocaine infiltration along the pathway of the spinal-epidural needle (Group L) or local dexamethasone and lidocaine infiltration (Group DL). The incidence and scores for back pain were evaluated on the first, second, and third day (acute lumbago) and first, second, and sixth month (chronic lumbago) after surgery. Fentanyl consumption for management of back pain was recorded.
The incidence of acute, subacute, and chronic back pain was significantly lower in the DL group than the L group (P<0.05 for all comparisons). The VAS score for back pain on the first and second day and first and second month, were significantly lower in the DL group than the L group (P=0.0028, P=0.017; P<0.001, both), but there were no significant differences on the third day and sixth month. Fentanyl consumption in the first 3 postoperative days was significantly lower in the DL group than in the L group (P<0.001). The incidence of back pain during the first, second, and sixth month in patients who did not have preoperative lumbago were significantly lower in the DL group than in the L group (P<0.001, both).
Addition of dexamethasone to local lidocaine infiltration effectively decreases the incidence and severity of back pain after combined spinal-epidural anesthesia implemented for gynecological surgery.
PMCID: PMC4374485  PMID: 25785683
Anesthesia; Dexamethasone; Gynecologic Surgical Procedures

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