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1.  New Clustered Regularly Interspaced Short Palindromic Repeat Locus Spacer Pair Typing Method Based on the Newly Incorporated Spacer for Salmonella enterica 
Journal of Clinical Microbiology  2014;52(8):2955-2962.
A clustered regularly interspaced short palindromic repeat (CRISPR) typing method has recently been developed and used for typing and subtyping of Salmonella spp., but it is complicated and labor intensive because it has to analyze all spacers in two CRISPR loci. Here, we developed a more convenient and efficient method, namely, CRISPR locus spacer pair typing (CLSPT), which only needs to analyze the two newly incorporated spacers adjoining the leader array in the two CRISPR loci. We analyzed a CRISPR array of 82 strains belonging to 21 Salmonella serovars isolated from humans in different areas of China by using this new method. We also retrieved the newly incorporated spacers in each CRISPR locus of 537 Salmonella isolates which have definite serotypes in the Pasteur Institute's CRISPR Database to evaluate this method. Our findings showed that this new CLSPT method presents a high level of consistency (kappa = 0.9872, Matthew's correlation coefficient = 0.9712) with the results of traditional serotyping, and thus, it can also be used to predict serotypes of Salmonella spp. Moreover, this new method has a considerable discriminatory power (discriminatory index [DI] = 0.8145), comparable to those of multilocus sequence typing (DI = 0.8088) and conventional CRISPR typing (DI = 0.8684). Because CLSPT only costs about $5 to $10 per isolate, it is a much cheaper and more attractive method for subtyping of Salmonella isolates. In conclusion, this new method will provide considerable advantages over other molecular subtyping methods, and it may become a valuable epidemiologic tool for the surveillance of Salmonella infections.
PMCID: PMC4136180  PMID: 24899040
2.  Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1 
Scientific Reports  2015;5:8066.
The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr6.63 forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr6.63 to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr3566.63 allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.
PMCID: PMC4308710  PMID: 25628267
3.  SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway 
Molecular Cancer  2015;14(1):12.
Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.
SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.
SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.
SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-014-0276-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4320842  PMID: 25623055
Gallbladder cancer; SPOCK1; Tumor progression; RNA interference; Epithelial-mesenchymal transition
4.  Perinatal stem cells: A promising cell resource for tissue engineering of craniofacial bone 
World Journal of Stem Cells  2015;7(1):149-159.
In facing the mounting clinical challenge and suboptimal techniques of craniofacial bone defects resulting from various conditions, such as congenital malformations, osteomyelitis, trauma and tumor resection, the ongoing research of regenerative medicine using stem cells and concurrent advancement in biotechnology have shifted the focus from surgical reconstruction to a novel stem cell-based tissue engineering strategy for customized and functional craniofacial bone regeneration. Given the unique ontogenetical and cell biological properties of perinatal stem cells, emerging evidence has suggested these extraembryonic tissue-derived stem cells to be a promising cell source for extensive use in regenerative medicine and tissue engineering. In this review, we summarize the current achievements and obstacles in stem cell-based craniofacial bone regeneration and subsequently we address the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone. We propose the promising feasibility and scope of perinatal stem cell-based craniofacial bone tissue engineering for future clinical application.
PMCID: PMC4300925  PMID: 25621114
Craniofacial bone regeneration; Bone tissue engineering; Extraembryonic tissue; Perinatal stem cells
5.  Baicalein Inhibits Progression of Gallbladder Cancer Cells by Downregulating ZFX 
PLoS ONE  2015;10(1):e0114851.
Baicalein, a widely used Chinese herbal medicine, has multiple pharmacological activities. However, the precise mechanisms of the anti-proliferation and anti-metastatic effects of baicalein on gallbladder cancer (GBC) remain poorly understood. Therefore, the aim of this study was to assess the anti-proliferation and anti-metastatic effects of baicalein and the related mechanism(s) on GBC. In the present study, we found that treatment with baicalein induced a significant inhibitory effect on proliferation and promoted apoptosis in GBC-SD and SGC996 cells, two widely used gallbladder cancer cell lines. Additionally, treatment with baicalein inhibited the metastasis of GBC cells. Moreover, we demonstrated for the first time that baicalein inhibited GBC cell growth and metastasis via down-regulation of the expression level of Zinc finger protein X-linked (ZFX). In conclusion, our studies suggest that baicalein may be a potential phytochemical flavonoid for therapeutics of GBC and ZFX may serve as a molecular marker or predictive target for GBC.
PMCID: PMC4305301  PMID: 25617627
6.  A novel role of kukoamine B: Inhibition of the inflammatory response in the livers of lipopolysaccharide-induced septic mice via its unique property of combining with lipopolysaccharide 
Kukoamine B (KB), derived from the traditional Chinese herb cortex Lycii, exerts anti-inflammatory effects due to its potent affinity with lipopolysaccharide (LPS) and CpG DNA; however, little is known regarding whether the in vivo administration of KB can effectively inhibit inflammation in septic mice. The present study thus aimed to investigate the inhibitory effects of KB on the inflammatory response in the livers of LPS-induced septic mice. KB treatment in the LPS-induced septic mice significantly decreased the plasma level of LPS. In addition, KB protected against liver injury, as confirmed by improved histology and decreased aminotransferase levels in the serum. Further experiments revealed that KB attenuated liver myeloperoxidase activity and reduced the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. These effects were accompanied by decreases in the levels of tumor necrosis factor α and interleukin-1β in the liver tissue. In parallel, the activity of nuclear factor-κ-gene binding (NF-κB) in the livers of LPS-induced septic mice was markedly inhibited with KB treatment. In combination, these results demonstrate that KB inhibits inflammation in septic mice by reducing the concentrations of plasma LPS, decreasing leukocyte sequestration and interfering with NF-κB activation, and, therefore, suppressing the pro-adhesive phenotype of endothelial cells.
PMCID: PMC4316986  PMID: 25667619
kukoamine B; lipopolysaccharide; liver; inflammatory response; nuclear factor κ-light-chain-enhancer of activated B cells
7.  GABAB Receptor Antagonist CGP46381 Inhibits Form-Deprivation Myopia Development in Guinea Pigs 
BioMed Research International  2015;2015:207312.
The aim was to investigate the effects of the GABAB receptor antagonist, CGP46381, on form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25). The deprived eyes were treated with daily subconjunctival injections (100 μl) of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD) and axial length (AL) using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes, P < 0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA, P < 0.0001). The highest dose tested, 2% CGP46381, significantly inhibited myopia development compared to saline (2% CGP46381: −1.08 ± 0.40 D, saline: −4.33 ± 0.67 D, P < 0.01). The majority of these effects were due to less AL (2% CGP46381: 0.03 ± 0.01 mm, saline: 0.13 ± 0.02 mm, P < 0.01) and VCD (2% CGP46381: 0.02 ± 0.01 mm, saline: 0.08 ± 0.01 mm, P < 0.01) elongation. The lower dose tested, 0.2% CGP46381, did not significantly inhibit FDM (P > 0.05). Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.
PMCID: PMC4306252  PMID: 25649745
8.  Emergence and Prevalence of Non-H2S-Producing Salmonella enterica Serovar Senftenberg Isolates Belonging to Novel Sequence Type 1751 in China 
Journal of Clinical Microbiology  2014;52(7):2557-2565.
Salmonella enterica serovar Senftenberg is a common nontyphoidal Salmonella serotype which causes human Salmonella infections worldwide. In this study, 182 S. Senftenberg isolates, including 17 atypical non-hydrogen sulfide (H2S)-producing isolates, were detected in China from 2005 to 2011. The microbiological and genetic characteristics of the non-H2S-producing and selected H2S-producing isolates were determined by using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and clustered regularly interspaced short palindromic repeat (CRISPR) analysis. The phs operons were amplified and sequenced. The 17 non-H2S-producing and 36 H2S-producing isolates belonged to 7 sequence types (STs), including 3 new STs, ST1751, ST1757, and ST1758. Fourteen of the 17 non-H2S-producing isolates belonged to ST1751 and had very similar PFGE patterns. All 17 non-H2S-producing isolates had a nonsense mutation at position 1621 of phsA. H2S-producing and non-H2S-producing S. Senftenberg isolates were isolated from the same stool sample from three patients; isolates from the same patients displayed the same antimicrobial susceptibility, ST, and PFGE pattern but could be discriminated based on CRISPR spacers. Non-H2S-producing S. Senftenberg isolates belonging to ST1751 have been prevalent in Shanghai, China. It is possible that these emerging organisms will disseminate further, because they are difficult to detect. Thus, we should strengthen the surveillance for the spread of this atypical S. Senftenberg variant.
PMCID: PMC4097678  PMID: 24829240
9.  The TCR γδ Repertoire and Relative Gene Expression Characteristics of T-ALL Cases with Biclonal Malignant Vδ1 and Vδ2 T Cells 
DNA and Cell Biology  2014;33(1):49-56.
Despite significant improvement in our understanding of T-cell acute lymphoblastic leukemia (T-ALL) biology and pathogenesis, many questions remain unanswered. In previous studies, we found a T-ALL case with two malignant T-cell clones with Vδ1Dδ2Dδ3Jδ1 and Vδ2Dδ3Jδ2 rearrangements. In this study, we further characterized T-ALL cases with two malignant clones containing Vδ1Dδ3Jδ1 and Vδ2Dδ1Jδ1 rearrangements using fine-tiling array comparative genomic hybridization, ligation-mediated polymerase chain reaction (LM-PCR), sequencing, and reverse transcription polymerase chain reaction (RT-PCR) analysis. We further analyzed the distribution and clonality of the T-cell receptor (TCR) Vγ and Vδ subfamily T cells in the two T-ALL cases by RT-PCR and GeneScan. Monoclonal Vδ1 and Vδ2 subfamilies were confirmed in both samples, the Vδ3 through Vδ7 subfamilies could not be detected in the T-ALL samples, whereas the oligoclonal Vδ8 subfamily could be identified. Based on the clinical finding that both of the T-ALL cases with two malignant T-cell clones had a poor outcome, we attempted to compare the expression pattern of genes related to T-cell activation and proliferation between cases with the malignant Vδ1 and Vδ2 T-cell clones and T-ALL cases with a mono-malignant Vα T-cell clone. We selected two T-ALL cases with VαJα rearrangements and analyzed the expression level of Notch1, TAL1, and the CARMA-BCL10-MALT-A20-NF-κB pathway genes by real-time PCR. A20 had significantly higher expression in the biclonal compared with the monoclonal T-ALL group (p=0.0354), and there was a trend toward higher expression for the other genes in the biclonal group with the exception of TAL1, although the differences were not statistically significant. In conclusion, we identified two T-ALL cases with biclonal malignant T-cell clones and described the characteristics of the biclonal T-ALL subtype and its gene expression pattern. Thus, our findings may improve the understanding of biclonal T-ALL.
PMCID: PMC3880916  PMID: 24329526
10.  Luteolin nanoparticle in chemoprevention – in vitro and in vivo anticancer activity 
Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest due to the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach towards chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13μM, and that of luteolin was 6.96μM. In H292 cells, the IC50 of luteolin was 15.56μM, and Nano-Luteolin was 14.96μM. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings.
PMCID: PMC3888883  PMID: 24403290
Cancer; chemoprevention; luteolin; nanotechnology; nanomedicine
11.  Prostatic metastases and polycythemia vera on bone magnetic resonance imaging: A case report 
Oncology Letters  2014;9(3):1317-1320.
Localized prostate cancer and polycythemia vera (PV) are rare, and can be difficult to distinguish from bone marrow metastatic prostate cancer. The present study describes a case of prostate cancer occurring with PV. Magnetic resonance imaging revealed diffusely inhomogeneous bone marrow of the pelvis and a localized prostatic mass. The bone marrow biopsy indicated erythrocytosis and leukocytosis. The patient was treated with aspirin and twice-weekly phlebotomy procedures for two weeks, followed by a radical prostatectomy. Following the surgery, the patient was continually treated with interferon-α2b and aspirin, and demonstrated no abnormalities within the one-year follow-up period. The findings of the present study may aid in the future diagnosis and treatment of patients with prostate cancer and PV.
PMCID: PMC4314976  PMID: 25663905
prostate cancer; polycythemia vera; bone metastases
12.  Impact of thrombospondin-2 gene variations on the risk of thoracic aortic dissection in a Chinese Han population 
Objective: Genetic factors play an important role in thoracic aortic dissection (TAD) etiology and thrombospondin-2 gene (THBS2) polymorphisms may be involved. This study tried to examine the single-nucleotide polymorphisms (SNP) rs8089 of THBS2 for their association with TAD susceptibility in Chinese Han population. Methods: The rs8089 SNP of THBS2 was genotyped in 112 subjects who were diagnosed as TAD and in 184 age- and gender-matched matched controls. Results: The THBS2 rs8089 SNP was associated with increased TAD susceptibility for allele level comparison (P < 0.0001), and for dominant model (P = 0.0073) or extreme genotype model (P = 0.0459) in Chinese Han Population. But for the recessive model, no statistical difference was found (P = 0.099), which may be resulted from the relatively small sample size and low genotype frequency. Conclusion: In conclusion, the present study suggested that the THBS2 rs8089 variant was associated with TAD, with the G allele representing a risk factor in a Chinese Han population.
PMCID: PMC4307556  PMID: 25664109
Thrombospondin-2; gene polymorphisms; thoracic aortic dissection
13.  Trientine Reduces BACE1 Activity and Mitigates Amyloidosis via the AGE/RAGE/NF-κB Pathway in a Transgenic Mouse Model of Alzheimer's Disease 
Antioxidants & Redox Signaling  2013;19(17):2024-2039.
Aims: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice. Results: We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aβ deposition and synapse loss in brain of APP/PS1 mice. Importantly, we found that Trien blocked the receptor for AGEs (RAGE), downregulated β-site APP cleaving enzyme 1 (BACE1), inhibited amyloidogenic APP cleavage, and subsequently reduced Aβ levels. In vitro, in SH-SY5Y cells overexpressing Swedish mutant APP, Trien-mediated downregulation of BACE1 occurred via inhibition of the NF-κB signaling pathway. Innovation: In this study, we demonstrated for the first time that Trien inhibited amyloidogenic pathway including targeting the downregulation of RAGE and NF-κB. Conclusion: Trien might mitigate amyloidosis in AD by inhibiting the RAGE/NF-κB/BACE1 pathway. Our study demonstrates that Trien may be a viable therapeutic strategy for the intervention and treatment of AD and other AD-like pathologies. Antioxid. Redox Signal. 19, 2024–2039.
PMCID: PMC3869419  PMID: 23541064
14.  Insight to the Epidemiology and Risk Factors of Extrapulmonary Tuberculosis in Tianjin, China during 2006-2011 
PLoS ONE  2014;9(12):e112213.
The proportion of extrapulmonary tuberculosis (EPTB) among all the reported tuberculosis (TB) cases has increased in different populations. Despite the large burden of TB in China, the epidemiology of EPTB in China remains largely understudied and the risk factors for having EPTB diagnosis in China have not been identified.
To gain insight to EPTB epidemiology in China, we analyzed TB surveillance data collected in Tianjin, China, during 2006 to 2011. The frequency of EPTB among all TB cases and within different socio-demographic groups of the study patients aged 15 years and older was determined for EPTB in general and by specific types. The distribution of socio-demographic characteristics was compared between pulmonary TB (PTB) group and EPTB group by chi-square test. Crude and multiple logistic regression-derived adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined to assess the associations between having EPTB diagnosis and each individual explanatory variable in question.
About one-tenth (1,512/14,561) of the patients investigated in this study had EPTB. Of these 1,512 EPTB cases, about two thirds were pleural TB. Significant difference in age, occupation, and urbanity of residence were found between PTB and EPTB groups (p<0.05). Patients with EPTB diagnosis were more likely to be 65 years or older (aOR = 1.22, 95% CI: 1.02, 1.46), to be retired (aOR = 1.37, 95% CI: 1.08, 1.75), and to live in urban areas (aOR = 1 38, 95% CI: 1.22, 1.55).
The findings of this study extends the knowledgebase of EPTB epidemiology in developing countries and highlight the need for improved EPTB detection in China, especially in subpopulations with high risk for EPTB or having limited access to medical facilities with adequate capacity for EPTB diagnosis.
PMCID: PMC4262301  PMID: 25494360
16.  Dying at home: a qualitative study of family carers’ views of support provided by GPs community staff 
The British Journal of General Practice  2014;64(629):e796-e803.
Dying at home is the preference of many patients with life-limiting illness. This is often not achieved and a key factor is the availability of willing and able family carers.
To elicit family carers’ views about the community support that made death at home possible.
Design and setting
Qualitative study in East Devon, North Lancashire, and Cumbria.
Participants were bereaved family carers who had provided care at the end of life for patients dying at home. Semi-structured interviews were conducted 6–24 months after the death.
Fifty-nine bereaved family carers were interviewed (54% response rate; 69% female). Two-thirds of the patients died from cancer with median time of home care being 5 months and for non-cancer patients the median time for home care was 30 months. An overarching theme was of continuity of care that divided into personal, organisational, and informational continuity. Large numbers and changes in care staff diluted personal continuity and failure of the GPs to visit was viewed negatively. Family carers had low expectations of informational continuity, finding information often did not transfer between secondary and primary care and other care agencies. Organisational continuity when present provided comfort and reassurance, and a sense of control.
The requirement for continuity in delivering complex end-of-life care has long been acknowledged. Family carers in this study suggested that minimising the number of carers involved in care, increasing or ensuring personal continuity, and maximising the informational and organisational aspects of care could lead to a more positive experience.
PMCID: PMC4240153  PMID: 25452545
community care; end of life; home palliative care; informal care givers; qualitative study
17.  Posterior tibialis tendon transfer via the circumtibial route: a cadaveric limb analysis 
Studies have yet to determine the optimal height at which the posterior tibial tendon (PTT) can be re-routed and the tendon length discrepancy at different height levels in terms of PTT transfer via the circumtibial route. This cadaveric study was conducted to determine the optimal height of PTT subcutaneous transfer and to compare tendon length discrepancies at different heights.
Materials and methods
Twenty-five fresh normal cadaveric lower legs were used for measurements. PTT was exposed and then isolated. An incision along the calf was made to re-route PTT outside the fascia. The upper edge of the incision was classified as point “a.” The distal tip of the tendon was classified as point “b.” The midpoints of the intermediate cuneiform, the lateral cuneiform, and the cuboid were defined as points “c,” “d,” and “e,” respectively. The lengths of “ab,” “ac,” “ad,” and “ae” were measured and compared at different height levels above the distal tip of the medial malleolus. Angles α, β, and γ between the tendon outside the fascia connecting to different bones and the tendon inside the fascia were also measured as tendons were transferred at different bones and different height levels. Experimental data were collected and analyzed.
At a height of ≥5 cm, all of the PTTs could reach the midpoints of the three bones. The lengths of ac, ad, and ae were significantly less than the length of ab (p < 0.05). At a height of 10 cm, angles α, β, and γ were 177° ± 2.1°, 170° ± 3.1°, and 164° ± 3.7°, respectively. These angles were not significantly different from those at a height of 11 cm (p >0.05).
PTT transfer via the subcutaneous route could achieve an adequate length to be transferred to the intermediate cuneiform, the lateral cuneiform, and the cuboid from a height of 5 cm above the distal tip of the medial malleolus. A height of 10 cm could be optimal for PTT transfer in the three bones via the subcutaneous route.
PMCID: PMC4255935  PMID: 25471044
18.  Novel heparin-binding motif in decorin binding protein A from strain B31 of Borrelia burgdorferi explains higher binding affinity 
Biochemistry  2013;52(46):8237-8245.
Decorin-binding protein A (DBPA), a glycosaminoglycan (GAG) binding lipoprotein found in Borrelia burgdorferi, is crucial to the transmission of Lyme disease in its earliest stages. Due to its role in the initial transmission of the disease, DBPA is an ideal target for vaccine development. DBPA sequences from different strains also contain considerable heterogeneity, leading to differing affinities for GAGs and proteoglycans among different DBPA sequences. Through biophysical and structural analysis of DBPA from the strain B31, we have discovered a novel and important GAG-binding epitope in B31 DBPA. Removal of the epitope greatly attenuated its affinity for DBPA and may explain the differential GAG affinities seen in DBPAs from other strains of Borrelia burgdorferi. Paramagnetic perturbation of the protein with TEMPO-labeled heparin fragments showed bound GAGs are located close to the linker region containing the BXBB motif plays a significant role in determining affinity and orientation of GAG-binding to DBPA is specific. Thermodynamic contributions of the new motif to GAG binding was also characterized with both NMR and ITC and compared with other DBPA residues previously known to be involved in GAG interactions. These analyses showed the motif is as important as other known binding epitopes. The discovery of the motif offers a possible structural explanation to the previous observed differences in GAG affinities of DBPA variants from different Borrelia strains and increases our understanding of DBPA-GAG interactions.
PMCID: PMC3896217  PMID: 24148022
glycosaminoglycan; bacterial adhesin; GAG-protein interactions; solution NMR; paramagnetic GAG ligand
19.  Neuroprotective Effects of Geniposide in SH-SY5Y Cells and Primary Hippocampal Neurons Exposed to Aβ42 
BioMed Research International  2014;2014:284314.
Our former studies have suggested that TongLuoJiuNao (TLJN) is clinically efficacious in the treatment of dementia and improving learning and memory in AD models. When Aβ aggregated with oligomer, it is known to be able to induce cellular toxicity as well as cognitive impairment. We tested the possibility that TLJN affects the formation of Aβ oligomers. In our experiment, TLJN improved cell viability, inhibited LDH release, and promoted the outgrowth of neurites of neurons treated with Aβ. Geniposide, the main component of TLJN, could increase the cell viability of SY5Y-APP695sw cells. The cytotoxicity of pretreated Aβ with geniposide was decreased in a dose-dependent manner. SDS-PAGE and Western blotting showed that geniposide and TLJN stimulated Aβ oligomer assembly. Compared with the control, more and longer fibrils of Aβ in the presence of geniposide were observed under electron microscope though the fibrils became less sensitive to thioflavin T staining. In sum, geniposide is able to protect neurons from Aβ-induced damage by remodeling Aβ.
PMCID: PMC4255058  PMID: 25506055
20.  Vitamin C and E intake and risk of bladder cancer: a meta-analysis of observational studies 
Epidemiologic studies that investigate whether vitamin C and E intake protects against bladder cancer have yielded inconsistent results. We conducted a systematic review and meta-analysis of published cohort and case-control studies to summarize the epidemiologic evidence investigating vitamin C and E intake and bladder cancer. Studies were identified through a search of PubMed and Embase databases and of references from relevant publications. Meta-analyses were conducted to estimate summary risk estimates (REs) and 95% confidence intervals (CIs) for vitamin C and E intake using fixed- or random-effects model depending on the heterogeneity of the studies. Subgroup analyses were performed according to study design, sex, geographical regions and source of vitamins intake. The summary REs of bladder cancer for all published studies was 0.90 (95% CI, 0.79-1.00) and 0.82 (95% CI, 0.72-0.90) for vitamin C and E intake, respectively, with no evidence of between-study heterogeneity for vitamin E, but some heterogeneity for vitamin C intake. Although some of the summary effects were non-significant, subgroup analyses showed that these inverse relationships were not modified by study design, sex, geographical regions and source of vitamins intake for vitamin E intake. Our results indicated that high intake of vitamin E could reduce bladder cancer risk. However, the inverse association between vitamin C and bladder cancer seemed to be limited. Further studies using larger samples and a rigorous methodology are warranted.
PMCID: PMC4276184  PMID: 25550926
Antioxidants; urinary bladder neoplasms; meta-analysis; vitamin C; vitamin E
21.  Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia 
Knowledge of the oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) remains limited. Constitutive aberrant activation of the nuclear factor kappa B (NF-κB) signaling pathway has been detected in various lymphoid malignancies and plays a key role in the development of these carcinomas. The zinc finger-containing protein, A20, is a central regulator of multiple NF-κB-activating signaling cascades. A20 is frequently inactivated by deletions and/or mutations in several B-and T-cell lymphoma subtypes. However, few A20 mutations and polymorphisms have been reported in T-ALL. Thus, it is of interest to analyze the expression characteristics of A20 and its regulating factors, including upstream regulators and the CBM complex, which includes CARMA1, BCL10, and MALT1.
The expression levels of CARMA1, BCL10, MALT1, A20, and NF-κB were detected in peripheral blood mononuclear cells (PBMCs) from 21 patients with newly diagnosed T-ALL using real-time PCR, and correlations between the aberrant expression of these genes in T-ALL was analyzed. Sixteen healthy individuals, including 10 males and 6 females, served as controls.
Significantly lower A20 expression was found in T-ALL patients (median: 4.853) compared with healthy individuals (median: 8.748; P = 0.017), and significantly increased expression levels of CARMA1 (median: 2.916; P = 0.034), BCL10 (median: 0.285; P = 0.033), and MALT1 (median: 1.201; P = 0.010) were found in T-ALL compared with the healthy individuals (median: 1.379, 0.169, and 0.677, respectively). In contrast, overexpression of NF-κB (median: 0.714) was found in T-ALL compared with healthy individuals (median: 0.335; P = 0.001). A negative correlation between the MALT1 and A20 expression levels and a positive correlation between CARMA1 and BCL10 were found in T-ALL and healthy individuals. However, no negative correlation was found between A20 and NF-κB and the MALT1 and NF-κB expression level in the T-ALL group.
We characterized the expression of the CARMA-BCL10-MALT1-A20-NF-κB pathway genes in T-ALL. Overexpression of CARMA-BCL10-MALT in T-ALL may contribute to the constitutive cleavage and inactivation of A20, which enhances NF-κB signaling and may be related to T-ALL pathogenesis.
PMCID: PMC4228272  PMID: 25384343
A20; CARMA1-BCL10-MALT1; T-cell acute lymphoblastic leukemia
22.  Potentially Functional SNPs (pfSNPs) as Novel Genomic Predictors of 5-FU Response in Metastatic Colorectal Cancer Patients 
PLoS ONE  2014;9(11):e111694.
5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.
PMCID: PMC4221105  PMID: 25372392
23.  Magnetic Bead-Based Colorimetric Immunoassay for Aflatoxin B1 Using Gold Nanoparticles 
Sensors (Basel, Switzerland)  2014;14(11):21535-21548.
A competitive colorimetric immunoassay for the detection of aflatoxin B1 (AFB) has been established using biofunctionalized magnetic beads (MBs) and gold nanoparticles (GNPs). Aflatoxin B1-bovine serum albumin conjugates (AFB-BSA) modified MBs were employed as capture probe, which could specifically bind with GNP-labeled anti-AFB antibodies through immunoreaction, while such specific binding was competitively inhibited by the addition of AFB. After magnetic separation, the supernatant solution containing unbound GNPs was directly tested by UV-Vis spectroscopy. The absorption intensity was directly proportional to the AFB concentration. The influence of GNP size, incubation time and pH was investigated in detail. After optimization, the developed method could detect AFB in a linear range from 20 to 800 ng/L, with the limit of detection at 12 ng/L. The recoveries for spiked maize samples ranged from 92.8% to 122.0%. The proposed immunoassay provides a promising approach for simple, rapid, specific and cost-effective detection of toxins in the field of food safety.
PMCID: PMC4279548  PMID: 25405511
aflatoxin B1; magnetic beads; gold nanoparticles; colorimetric detection; competitive immunoassay
24.  Ursolic acid induces cell cycle arrest and apoptosis of gallbladder carcinoma cells 
Cancer Cell International  2014;14(1):96.
Ursolic acid (UA), a plant extract used in traditional Chinese medicine, exhibits potential anticancer effects in various human cancer cell lines in vitro. In the present study, we evaluated the anti-tumoral properties of UA against gallbladder carcinoma and investigated the potential mechanisms responsible for its effects on proliferation, cell cycle arrest and apoptosis in vitro.
The anti-tumor activity of UA against GBC-SD and SGC-996 cells was assessed using MTT and colony formation assays. An annexin V/PI double-staining assay was used to detect cell apoptosis. Cell cycle changes were detected using flow cytometry. Rhodamine 123 staining was used to assess the mitochondrial membrane potential (ΔΨm) and validate UA’s ability to induce apoptosis in both cell lines. The effectiveness of UA in gallbladder cancer was further verified in vivo by establishing a xenograft GBC model in nude mice. Finally, the expression levels of cell cycle- and apoptosis-related proteins were analyzed by western blotting.
Our results suggest that UA can significantly inhibit the growth of gallbladder cancer cells. MTT and colony formation assays indicated dose-dependent decreases in cell proliferation. S-phase arrest was observed in both cell lines after treatment with UA. Annexin V/PI staining suggested that UA induced both early and late phases of apoptosis. UA also decreased ΔΨm and altered the expression of molecules regulating the cell cycle and apoptosis. In vivo study showed intraperitoneally injection of UA can significantly inhibited the growth of xenograft tumor in nude mice and the inhibition efficiency is dose related. Activation of caspase-3,-9 and PARP indicated that mitochondrial pathways may be involved in UA-induced apoptosis.
Taken together, these results suggest that UA exhibits significant anti-tumor effects by suppressing cell proliferation, promoting apoptosis and inducing 7cell cycle arrest both in vitro and in vivo. It may be a potential agent for treating gallbladder cancer.
PMCID: PMC4224689  PMID: 25383044
Ursolic acid; Gallbladder cancer; Proliferation; Cell cycle; Apoptosis; Mitochondrial-mediated pathway
25.  Morphological Variation in Leaf Dissection of Rheum palmatum Complex (Polygonaceae) 
PLoS ONE  2014;9(10):e110760.
Rheum palmatum complex comprises all taxa within section Palmata in the genus Rheum, including R. officinale, R. palmatum, R. tanguticum, R. tanguticum var. liupanshanense and R. laciniatum. The identification of the taxa in section Palmata is based primarily on the degree of leaf blade dissection and the shape of the lobes; however, difficulties in species identification may arise from their significant variation. The aim of this study is to analyze the patterns of variation in leaf blade characteristics within and among populations through population-based sampling covering the entire distribution range of R. palmatum complex.
Samples were taken from 2340 leaves from 780 individuals and 44 populations representing the four species, and the degree of leaf blade dissection and the shape of the lobe were measured to yield a set of quantitative data. Furthermore, those data were statistically analyzed.
Important Findings
The statistical analysis showed that the degree of leaf blade dissection is continuous from lobed to parted, and the shape of the lobe is also continuous from broadly triangular to lanceolate both within and between populations. We suggested that taxa in section Palmata should be considered as one species. Based on the research on the R. palmatum complex, we considered that the quantitative characteristics were greatly influenced by the environment. Therefore, it is not reliable to delimitate the species according to the continuously quantitative vegetative characteristics.
PMCID: PMC4211699  PMID: 25349989

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