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1.  Application of immediate breast reconstruction with silicon prosthetic implantation following bilateral mammary gland excision in treatment of young patients with early breast cancer 
Journal of Thoracic Disease  2013;5(3):278-282.
Objective
To evaluate the application of immediate breast reconstruction (IBR) with silicon prosthetic implantation following bilateral nipple-preserving subcutaneous mammary gland excision in the treatment of young patients with early breast cancer.
Methods
We retrospectively analyzed the clinical data of 21 patients with breast cancer who were performed on IBR following bilateral nipple-preserving subcutaneous mammary gland excision in our hospital from January 2006 to March 2011.
Results
The operations were successful in all the 21 patients. Also, the treatment provided a good cosmetic effect. No local recurrence or distant metastasis was found in these 21 patients during the 6-66-month follow-up.
Conclusions
For the young patients with early breast cancer, mammary gland excision on the affected side along with prophylactic excision of the contralateral side, namely IBR following bilateral nipple-preserving subcutaneous mammary gland excision, provides good clinical effectiveness and cosmetological effects.
doi:10.3978/j.issn.2072-1439.2013.04.09
PMCID: PMC3698255  PMID: 23825759
Breast cancer; prophylactic mastectomy; immediate breast reconstruction
2.  Tanshinone IIA Inhibits HIF-1α and VEGF Expression in Breast Cancer Cells via mTOR/p70S6K/RPS6/4E-BP1 Signaling Pathway 
PLoS ONE  2015;10(2):e0117440.
Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.
doi:10.1371/journal.pone.0117440
PMCID: PMC4320086  PMID: 25659153
3.  Curcumin Disrupts the Mammalian Target of Rapamycin-Raptor Complex 
Cancer research  2009;69(3):1000-1008.
Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKα. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.
doi:10.1158/0008-5472.CAN-08-2367
PMCID: PMC4307947  PMID: 19176385
4.  Phosphate addition enhanced soil inorganic nutrients to a large extent in three tropical forests 
Scientific Reports  2015;5:7923.
Elevated nitrogen (N) deposition may constrain soil phosphorus (P) and base cation availability in tropical forests, for which limited evidence have yet been available. In this study, we reported responses of soil inorganic nutrients to full factorial N and P treatments in three tropical forests different in initial soil N status (N-saturated old-growth forest and two less-N-rich younger forests). Responses of microbial biomass, annual litterfall production and nutrient input were also monitored. Results showed that N treatments decreased soil inorganic nutrients (except N) in all three forests, but the underlying mechanisms varied depending on forests: through inhibition on litter decomposition in the old-growth forest and through Al3+ replacement of Ca2+ in the two younger forests. In contrast, besides great elevation in soil available P, P treatments induced 60%, 50%, 26% increases in sum of exchangeable (K++Ca2++Mg2+) in the old-growth and the two younger forests, respectively. These positive effects of P were closely related to P-stimulated microbial biomass and litter nutrient input, implying possible stimulation of nutrient return. Our results suggest that N deposition may result in decreases in soil inorganic nutrients (except N) and that P addition can enhance soil inorganic nutrients to support ecosystem processes in these tropical forests.
doi:10.1038/srep07923
PMCID: PMC4300498  PMID: 25605567
5.  Gut Microbiota of the Tick Vector Ixodes scapularis Modulate Colonization of the Lyme Disease Spirochete 
Cell host & microbe  2014;15(1):58-71.
SUMMARY
Arthopods, such as Ixodes ticks, serve as vectors for many human pathogens. The arthropod gut presents a pivotal microbial entry point and determines pathogen colonization and survival. We show that the gut microbiota of Ixodes scapularis, a major vector of the Lyme disease spirochete Borrelia burgdorferi, influence spirochete colonization of ticks. Perturbing the gut microbiota of larval ticks reduced Borrelia colonization, with dysbiosed larvae displaying decreased expression of the transcription factor STAT. Diminished STAT expression corresponded to lower expression of peritrophin, a key glycoprotein scaffold of the glycan-rich mucus-like peritrophic matrix (PM) that separates the gut lumen from the epithelium. The integrity of the I. scapularis PM was essential for B. burgdorferi to efficiently colonize the gut epithelium. These data elucidate a functional link between the gut microbiota, STAT-signaling, and pathogen colonization in the context of the gut epithelial barrier of an arthropod vector.
doi:10.1016/j.chom.2013.12.001
PMCID: PMC3905459  PMID: 24439898
Ixodes scapularis; gut microbiota; epithelial barrier; Borrelia burgdorferi
6.  Treatment of displaced talar neck fractures using delayed procedures of plate fixation through dual approaches 
International Orthopaedics  2013;38(1):149-154.
Purpose
Treatment of talar neck fractures is challenging. Various surgical approaches and fixation methods have been documented. Clinical outcomes are often dissatisfying due to inadequate reduction and fixation with high rates of complications. Obtaining satisfactory clinical outcomes with minimum complications remains a hard task for orthopaedic surgeons.
Methods
In the period from May 2007 to September 2010, a total of 31 cases with closed displaced talar neck fractures were treated surgically in our department. Injuries were classified according to the Hawkins classification modified by Canale and Kelly. Under general anaesthesia with sufficient muscle relaxation, urgent closed reduction was initiated once the patients were admitted; if the procedure failed, open reduction and provisional stabilisation with Kirschner wires through an anteromedial approach with tibiometatarsal external fixation were performed. When the soft tissue had recovered, definitive fixation was performed with plate and screws through dual approaches. The final follow-up examination included radiological analysis, clinical evaluation and functional outcomes which were carried out according to the Ankle-Hindfoot Scale of the American Orthopaedic Foot and Ankle Society (AOFAS), patient satisfaction and SF-36.
Results
Twenty-eight patients were followed up for an average of 25 months (range 18–50 months) after the injury. Only two patients had soft tissue complications, and recovery was satisfactory with conservative treatment. All of the fractures healed anatomically without malunion and nonunion, and the average union time was 14 weeks (range 12–24 weeks). Post-traumatic arthritis developed in ten cases, while six patients suffered from avascular necrosis of the talus. Secondary procedures included three cases of subtalar arthrodesis, one case of ankle arthrodesis and one case of total ankle replacement. The mean AOFAS hindfoot score was 78 (range 65–91). According to the SF-36, the average score of the physical component summary was 68 (range 59–81), and the average score of the mental component summary was 74 (range 63–85).
Conclusions
Talar neck fractures are associated with a high incidence of long-term disability and complications. Urgent reduction of the fracture-dislocation and delayed plate fixation through a dual approach when the soft tissue has recovered may minimise the complications and provide good clinical outcomes.
doi:10.1007/s00264-013-2164-2
PMCID: PMC3890131  PMID: 24297608
Ankle; Talar neck fracture; Dual approaches; Internal fixation
7.  Anti-virulence properties of an antifreeze protein 
Cell reports  2014;9(2):417-424.
Summary
As microbial drug-resistance increases, there is a critical need for new classes of compounds to combat infectious diseases. The Ixodes scapularis tick antifreeze glycoprotein, IAFGP, functions as an anti-virulence agent against diverse bacteria including methicillin-resistant Staphylococcus aureus. Recombinant IAFGP and a peptide, P1, derived from this protein bind to microbes and alter biofilm formation. Transgenic iafgp-expressing flies and mice challenged with bacteria, as well as wild-type animals administered P1, were resistant to infection, septic shock, or biofilm development on implanted catheter tubing. These data show that an antifreeze protein facilitates host control of bacterial infections and suggest new therapeutic strategies to counter pathogens.
doi:10.1016/j.celrep.2014.09.034
PMCID: PMC4223805  PMID: 25373896
8.  HmsB enhances biofilm formation in Yersinia pestis 
The hmsHFRS operon is responsible for biosynthesis and translocation of biofilm matrix exopolysaccharide. Yersinia pestis expresses the two sole diguanylate cyclases HmsT and HmsD and the sole phosphodiesterase HmsP, which are specific for biosynthesis and degradation, respectively, of 3′,5′-cyclic diguanosine monophosphate (c-di-GMP), a second messenger promoting exopolysaccharide production. In this work, the phenotypic assays indicates that Y. pestis sRNA HmsB enhances the production of c-di-GMP, exopolysaccharide, and biofilm. Further gene regulation experiments disclose that HmsB stimulates the expression of hmsB, hmsCDE, hmsT, and hmsHFRS but represses that of hmsP. HmsB most likely acts as a major activator of biofilm formation in Y. pestis. This is the first report of regulation of Yersinia biofilm formation by a sRNA. Data presented here will promote us to gain a deeper understanding of the complex regulatory circuits controlling Yersinia biofilm formation.
doi:10.3389/fmicb.2014.00685
PMCID: PMC4264472  PMID: 25566205
Yersinia pestis; HmsB; c-di-GMP; biofilm
9.  Nasopharyngeal carcinoma mimicking Aspergillosis rhinosinusitis: an unusual case report and review of the literature 
Clinical symptoms and imaging features of fungal infection are confused with those of atypical nasopharyngeal carcinoma (NPC), and therefore development of a more effective diagnostic method is essential. It is a common knowledge that there is a significant association between Epstein-Barr virus (EBV) and nonkeratinizing NPC. However, fungal infection may be considered to be a vital etiologic agent contributing to the NPC and more evidence is needed to be approved this theory. We report on a rare case of a patient with atypical nasopharyngeal carcinoma (NPC) who suffered from chronic fungal infection and was diagnosed initially as Aspergillosis. Following anti-aspergillus infection therapy, the repeated deep biopsy of the maxillary sinus and MRI confirmed the diagnosis of nasopharyngeal carcinoma (NPC).
PMCID: PMC4313968
Nasopharyngeal carcinoma; atypical symptom; Aspergillosis; fungal infection; diagnosis; pathogenic factor
10.  Geometric and Electronic Structure of the Mn(IV)Fe(III) Cofactor in Class Ic Ribonucleotide Reductase: Correlation to the Class Ia Binuclear Non-Heme Iron Enzyme 
Journal of the American Chemical Society  2013;135(46):10.1021/ja409510d.
The class Ic ribonucleotide reductase (RNR) from Chlamydia trachomatis (Ct) utilizes a Mn/Fe hetero-binuclear cofactor, rather than the Fe/Fe cofactor found in the β (R2) subunit of the class Ia enzymes, to react with O2. This reaction produces a stable MnIVFeIII cofactor that initiates a radical, which transfers to the adjacent α (R1) subunit and reacts with the substrate. We have studied the MnIVFeIII cofactor using nuclear resonance vibrational spectroscopy (NRVS) and absorption (Abs) / circular dichroism (CD) / magnetic CD (MCD) / variable temperature, variable field (VTVH) MCD spectroscopies to obtain detailed insight into its geometric/electronic structure and to correlate structure with reactivity; NRVS focuses on the FeIII, whereas MCD reflects the spin-allowed transitions mostly on the MnIV. We have evaluated 18 systematically varied structures. Comparison of the simulated NRVS spectra to the experimental data shows that the cofactor has one carboxylate bridge, with MnIV at the site proximal to Phe127. Abs/CD/MCD/VTVH MCD data exhibit 12 transitions that are assigned as d-d, and oxo and OH− to metal charge transfer (CT) transitions. Assignments are based on MCD/Abs intensity ratios, transition energies, polarizations, and derivative-shaped pseudo-A term CT transitions. Correlating these results with TD-DFT calculations defines the MnIVFeIII cofactor as having a µ-oxo, µ-hydroxo core and a terminal hydroxo ligand on the MnIV. From DFT calculations, the MnIV at site 1 is necessary to tune the redox potential to a value similar to that of the tyrosine radical in class Ia RNR, and the OH− terminal ligand on this MnIV provides a high proton affinity that could gate radical translocation to the α (R1) subunit.
doi:10.1021/ja409510d
PMCID: PMC3882272  PMID: 24131208
11.  NPY1R is a novel peripheral blood marker predictive of metastasis and prognosis in breast cancer patients 
Oncology Letters  2014;9(2):891-896.
The aim of the current study was to evaluate a novel tumor marker, neuropeptide Y receptor Y1 (NPY1R), for the detection of circulating cancer cells and to investigate its clinical significance in breast cancer patients. The Digital Gene Expression Displayer tool of the Cancer Genome Anatomy Project was used to identify the marker gene NPY1R, which is able to detect circulating cancer cells. Nested quantitative polymerase chain reaction was performed to correlate the NPY1R expression levels with the clinicopathological features of 142 breast cancer patients. A follow-up study of 131 of the breast cancer patients was conducted for 38 months. Compared with the 60 normal control individuals, NPY1R was highly expressed in the cancer patients (P<0.01). These high levels of NPY1R expression were positively correlated with the clinical stage and lymph node metastasis status of the disease, as well as with the status of the estrogen and progesterone receptors (P<0.05). Breast cancer patients with circulating cancer cells that expressed NPY1R exhibited shorter tumor-specific survival when compared with those with no NPY1R expression (P<0.01). Additionally, the mortality rate was associated with HER2 expression in the NPY1R positive and negative groups. These results indicate that NPY1R may serve as a useful marker to predict breast cancer metastasis and to evaluate the prognosis of breast cancer patients.
doi:10.3892/ol.2014.2721
PMCID: PMC4301529  PMID: 25624911
breast cancer; neuropeptide Y receptor Y1; tumor marker; circulating cancer cells
12.  Geometric and Electronic Structure Contributions to Function in Non-Heme Iron Enzymes 
Accounts of chemical research  2013;46(11):2725-2739.
Conspectus
Mononuclear non-heme Fe (NHFe) enzymes play key roles in antibiotic biosynthesis, hypoxic response, DNA repair, anticancer therapy and many other biological processes. On a molecular level these enzymes catalyze a diverse range of oxidation reactions, including hydroxylation, halogenation, ring closure, desaturation and electrophilic aromatic substitution (EAS). Most of these enzymes use an FeII site to activate dioxygen. These ferrous active sites had been inaccessible to traditional spectroscopic methods. A methodology has been developed that provides detailed geometric and electronic structure insight for these NHFeII active sites. This has defined a general mechanistic strategy utilized by a wide range of these enzymes to control O2 activation by FeII coordination unsaturation only in the presence of cosubstrates to limit autooxidation and self-hydroxylation. Depending on the type of enzyme, O2 activation either involves a 2e− reduced FeIII–OOH intermediate or a 4e− reduced FeIV=O intermediate. The nature of these intermediates has been defined in terms of geometric structure using nuclear resonance vibrational spectroscopy (NRVS) and electronic structure using magnetic circular dichroism (MCD) to define the frontier molecular orbitals (FMOs) that control reactivity.
For FeIII–OOH intermediates the anticancer drug Activated Bleomycin is shown to be the non-heme Fe analog of compound 0 in heme (e.g. P450) chemistry but undergoes different reactivity where the low-spin (LS) FeIII–OOH can directly abstract an H atom from DNA. It is also shown that the transition states of LS and high-spin (HS) FeIII–OOH are fundamentally different in that the former goes through a hydroxyl radical while the latter is activated for EAS without O-O cleavage, which is important in one class of NHFe enzymes that utilizes a HS FeIII–OOH intermediate in dioxygenation.
For FeIV=O intermediates the LS form is shown to have a π-type FMO activated for attack perpendicular to the Fe–O bond while the HS form (present in the NHFe enzymes) has both π and σ FMOs that are activated for attack both perpendicular to and along the Fe–O bond, respectively. For the NHFe enzymes these π vs σ FMOs direct reactivity for EAS vs H-atom abstraction, and for the latter halogenation vs hydroxylation.
This study emphasizes that experimental spectroscopy is critical in evaluating the results of electronic structure calculations and thus key to bridging structure and reactivity with mechanism.
doi:10.1021/ar400149m
PMCID: PMC3905672  PMID: 24070107
13.  Effect of kidney-reinforcing and marrow-beneficial traditional Chinese medicine-intervened serum on the proliferation and osteogenic differentiation of bone marrow stromal cells 
The present study aimed to investigate the effect of kidney-reinforcing and marrow-beneficial traditional Chinese medicine (TCM)-intervened (KRMBTI)-serum on the proliferation and osteogenic differentiation of bone marrow stromal cells (BMSCs) in rats. Rat BMSCs were isolated and cultured in vitro with various concentrations of serum obtained from rats at different time-points following treatment with low, medium and high doses of KRMBT. The alkaline phosphatase (ALP) activity and proliferation of the BMCSs was assessed to determine the optimal serum sampling time-point and serum concentration. Transforming growth factor (TGF)-β1 expression of the BMSCs was detected using enzyme-linked immunosorbent assay (ELISA), and hepcidin mRNA expression in the rat livers was detected using reverse transcription polymerase chain reaction. The proliferation of BMCSs treated with serum obtained l h after dosing was observed to be significantly higher than that for BMCSs treated with serum obtained at the four other time-points (P<0.05). Furthermore, the proliferation following treatment with 25% KRMBTI-serum was significantly higher than that for the other KRMBTI-serum concentrations (P<0.01). For a 25% concentration of the serum collected at l h, the proliferation in the high- and low-dose KRMBTI-serum groups was significantly higher than that of the medium-dose and control groups (P<0.01) and no statistical significance was observed between the high- and low-dose groups. In the osteogenic differentiation process of the high-dose group, the ALP activity at every time-point was significantly higher than that of the low-dose group and the peak value of the former was achieved at concentrations between 20 and 30%. KRMBTI-serum was shown to promote the expression of TGF-β1. Furthermore, hepcidin was observed to be expressed at significantly higher levels in the high-dose group than in the control group, and hepcidin expression was significantly higher after 10 weeks compared with that after five weeks. These findings suggest that KRMBTI-serum increases TGF-β1 and hepcidin expression levels, which may be the mechanism underlying the promotion of osteogenic differentiation induced by KRMBTI-serum in BMSCs.
doi:10.3892/etm.2014.2062
PMCID: PMC4247301  PMID: 25452801
kidney-reinforcing and marrow-beneficial traditional Chinese Medicine-intervened serum; bone marrow mesenchymal stem cells; osteogenic differentiation capacity
14.  Effect of epigallocatechin-3-gallate on proliferation and phenotype maintenance in rabbit articular chondrocytes in vitro 
In autologous chondrocyte implantation (ACI) to restore defective cartilage, limited cell numbers and dedifferentiation of chondrocytes are the major difficulties. An alternative is the use of growth factors, but their high cost and potential for tumorigenesis are major obstacles. To ensure successful ACI therapy, it is important to find an effective substitute pro-chondrogenic agent. Epigallocatechin-3-gallate (EGCG), one of the green tea catechins, has been widely investigated in studies of interleukin-1β-induced chondrocytes. In the present study, the effects of EGCG on rabbit articular chondrocytes were investigated through the examination of cell proliferation, morphology, glycosaminoglycan synthesis and cartilage-specific gene expression. The results showed that EGCG could effectively promote chondrocyte growth and enhance the secretion and synthesis of the cartilage extracellular matrix by upregulating expression levels of aggrecan, collagen II and Sox9 genes. Expression of the collagen I gene was downregulated, which showed that EGCG effectively inhibited the dedifferentiation of chondrocytes. Hypertrophy, which may lead to chondrocyte ossification, was also undetectable in the EGCG groups. In conclusion, the recommended dose of EGCG was found to be in the range of 5 to 20 μM, with the most marked response observed with 10 μM. The present study may provide a basis for the development of a novel agent as a substitute for growth factors in the treatment of articular cartilage defects.
doi:10.3892/etm.2014.2057
PMCID: PMC4247298  PMID: 25452805
epigallocatechin-3-gallate; pro-chondrogenic agent; chondrocyte; rabbit articular cartilage; dedifferentiation
15.  miR-200c Inhibits invasion, migration and proliferation of bladder cancer cells through down-regulation of BMI-1 and E2F3 
Background
MicroRNA-200c (miR-200c) is one of the short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. It also acts as considerable modulator in the process of epithelial-to-mesenchymal transition (EMT), a cell development regulating process that affects tumor development and metastasis. However, the role of miR-200c in bladder cancer cells and its mechanism has not been well studied. The purpose of this study was to determine the potential role of miR-200c in regulating EMT and how it contributed to bladder cancer cells in invasion, migration and proliferation.
Methods
Real-time reverse transcription-PCR was used to identify and validate the differential expression of MiR-200c involved in EMT in 4 bladder cancer cell lines and clinical specimens. A list of potential miR-200 direct targets was identified through the TargetScan database. The precursor of miR-200c was over-expressed in UMUC-3 and T24 cells using a lentivirus construct, respectively. Protein expression and signaling pathway modulation were validated through Western blot analysis and confocal microscopy, whereas BMI-1 and E2F3, direct target of miR-200c, were validated by using the wild-type and mutant 3′-untranslated region BMI-1/E2F3 luciferase reporters.
Results
We demonstrate that MiR-200c is down-regulated in bladder cancer specimens compared with adjacent ones in the same patient. Luciferase assays showed that the direct down-regulation of BMI-1 and E2F3 were miR-200c-dependent because mutations in the two putative miR-200c-binding sites have rescued the inhibitory effect. Over-expression of miR-200c in bladder cancer cells resulted in significantly decreased the capacities of cell invasion, migration and proliferation. miR-200c over-expression resulted in conspicuous down-regulation of BMI-1and E2F3 expression and in a concomitant increase in E-cadherin levels.
Conclusions
miR-200c appears to control the EMT process through BMI-1 in bladder cancer cells, and it inhibits their proliferation through down-regulating E2F3. The targets of miR-200c include BMI-1 and E2F3, which are a novel regulator of EMT and a regulator of proliferation, respectively.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0305-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0305-z
PMCID: PMC4226852  PMID: 25367080
miR-200c; BMI-1; E2F3; Bladder cancer cells
16.  Crystallization and preliminary crystallographic analysis of 2-aminophenol 1,6-dioxygenase complexed with substrate and with an inhibitor 
The crystallization of 2-aminophenol 1,6-dioxygenase in complexes with its substrate and with an inhibitor is reported.
Dioxygen activation implemented by nonhaem FeII enzymes containing the 2-­His-1-carboxylate facial triad has been extensively studied in recent years. Extradiol dioxygenase is the archetypal member of this superfamily and catalyzes the oxygenolytic ring opening of catechol analogues. Here, the crystallization and preliminary X-ray analysis of 2-aminophenol 1,6-dioxygenase, an enzyme representing a minor subset of extradiol dioxygenases that catalyze the fission of 2-aminophenol rather than catecholic compounds, is reported. Crystals of the holoenzyme with FeII and of complexes with the substrate 2-aminophenol and the suicide inhibitor 4-nitrocatechol were grown using the cocrystallization method under the same conditions as used for the crystallization of the apoenzyme. The crystals belonged to space group C2 and diffracted to 2.3–2.7 Å resolution; the crystal that diffracted to the highest resolution had unit-cell parameters a = 270.24, b = 48.39, c = 108.55 Å, β = 109.57°. All X-ray data sets collected from diffraction-quality crystals were suitable for structure determination.
doi:10.1107/S1744309112038705
PMCID: PMC3515376  PMID: 23143244
2-aminophenol 1,6-dioxygenase; extradiol dioxygenases; 2-aminophenol; catechol
17.  Dexmedetomidine pretreatment alleviates propofol injection pain 
Upsala Journal of Medical Sciences  2014;119(4):338-342.
Objective
The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexmedetomidine (DEX) for reducing the incidence and severity of propofol injection pain.
Methods
Patients undergoing elective surgical procedures were randomly allocated into seven groups of 30 patients each. Experimental treatments were intravenously administered over 10 min (total volume 10 mL) prior to intravenous propofol injection, as follows: group I, the control group, was given isotonic saline. Patients in groups II, III, and IV received DEX 0.25 µg/kg, 0.5 µg/kg, or 1.0 µg/kg, respectively, mixed with isotonic saline immediately before propofol injection. Patients in groups V, VI, and VII received DEX as above, but 5 minutes before propofol injection. Propofol consisted of 1% long-chain triglyceride propofol (2.5 mg/kg) injected at 1 mL/s.
Results
Median propofol injection pain score was 0.00 (IQR 0.00–3.00) in patients who received 1.0 µg/kg DEX 5 min before the propofol injection (group VII), and only 1 patient (of 30) in this group received a pain score >2. The median pain score and number of patients with pain scores >2 in group VII were both significantly less than in the control (group I; p = 0.000, both). There were no differences in either mean arterial pressure or heart rate at any time point after DEX injection among the groups.
Conclusions
Pretreatment with intravenous DEX 1 µg/kg 5 min prior to injection of long-chain triglyceride propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.
doi:10.3109/03009734.2014.941049
PMCID: PMC4248074  PMID: 25342205
Dexmedetomidine; injection pain; propofol
20.  Comparison of three plate system for lateral malleolar fixation 
Background
This study was to compare clinical and radiographic outcomes with three different implants and evaluate the effectiveness of minimally invasive plate osteosynthesis (MIPO) technique for the distal fibular fractures.
Methods
We performed a retrospective cohort single-surgical team single-facility study between 2000 and 2011. 147 patients receiving surgical interventions for closed, displaced distal fibular fractures were included. Based on the different implants, patients were divided into three groups: Group A: one-third tubular plate; Group B: locking compression (LCP) metaphyseal plate; Group C: LCP distal fibula plate. Clinical and radiographic outcomes were compared among the three groups.
Results
Totally, we found that patients in Group C had significant higher functional scores than those in Group A (p1 = 0.004; p2 = 0.002) (p1 stands for the p value for Olerud & Molandar Score, p2 stands for the p value for American Orthopaedic Foot & Ankle Society score). The healing time was significant less in Group C than that in Group A (p < 0.0001) and Group B (p < 0.0001). Subgroup analysis showed that: (1) For Weber A fracture, the functional scores of the Group C were higher than those in Group A (p1 = 0.020; p2 = 0.029) and B (p1 = 0.020; p2 = 0.034). (2) For Weber B fracture, the functional scores of the Group B (p1 = 0.033; p2 = 0.030) and C (p1 = 0.027; p2 = 0.017) were higher than those in Group A. No significant differences were observed in terms of the ankle range of motion, reduction accuracy and complication rate.
Conclusions
Our study demonstrated using LCP metaphyseal plate in patients associated with lateral malleolar fracture could achieve significantly better OMS & AOFAS scores and less healing time than using one-third tubular plate. Specifically, For Weber A fracture, LCP distal fibula plate is much better than one-third tubular plate and LCP metaphyseal plate. While for Weber B fracture, LCP distal fibula plate and LCP metaphyseal plate are better than one-third tubular plate. As to the complications, using MIPO technique in patients with distal fibular fractures is at least comparable to the traditional one.
doi:10.1186/1471-2474-15-360
PMCID: PMC4223732  PMID: 25358474
Lateral malleolar fracture; One-third tubular plate; Locking compression plates; Minimally invasive plate osteosynthesis (MIPO) technique; Complications
21.  A Gain-of-Function Mutation in Tnni2 Impeded Bone Development through Increasing Hif3a Expression in DA2B Mice 
PLoS Genetics  2014;10(10):e1004589.
Distal arthrogryposis type 2B (DA2B) is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del) in troponin I type 2 (skeletal, fast) (TNNI2), which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice) showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.
Author Summary
Distal arthrogryposis type 2B (DA2B) is an autosomal dominant genetic disorder. The typical clinical features of DA2B include hand and/or foot contracture and shortness of stature in patients. To date, mutations in TNNI2 can explain approximately 20% of familial incidences of DA2B. TNNI2 encodes a subunit of the Tn complex, which is required for calcium-dependent fast twitch muscle fiber contraction. In the absence of Ca2+ ions, TNNI2 impedes sarcomere contraction. Here, we reported a knock-in mouse carrying a DA2B mutation TNNI2 (K175del) had typical limb abnormality and small body size that observed in human DA2B. However, the small body did not seem to be convincingly explained using the present knowledge of TNNI2 associated skeletal muscle contraction. Our findings showed that the Tnni2K175del mutation impaired bone development of Tnni2K175del mice. Our data further showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein and led to a reduction in Vegf expression in bone of DA2B mice. Taken together, our findings demonstrated that the disease-associated Tnni2K175del mutation caused bone defects, which accounted for, at least in part, the small body size of Tnni2K175del mice. Our data also suggested, for the first time, a novel role of tnni2 in the regulation of bone development of mice by affecting Hif-vegf signaling.
doi:10.1371/journal.pgen.1004589
PMCID: PMC4207604  PMID: 25340332
22.  Prevalence of and Risk Factors for Dry Eye Symptom in Mainland China: A Systematic Review and Meta-Analysis 
Journal of Ophthalmology  2014;2014:748654.
Purpose. To evaluate the pooled prevalence rate and risk factors of dry eye symptoms (DES) in mainland China. Methods. All the published population-based studies investigating the prevalence of DES in China were searched and evaluated against inclusion criteria. A systematic review and meta-analysis were performed. Results. Twelve out of the 119 identified studies were included in the meta-analysis. The pooled prevalence of DES in China was 17.0%. Female individuals, subjects living in the Northern and Western China, and over 60 years of age had significantly higher prevalent rates (21.6%, 17.9%, 31.3%, and 34.4%, resp.) compared with their counterparts. Patients with diabetes were also found to be more vulnerable to DES. Conclusions. The pooled prevalence rate of DES in mainland China was lower than that in other Asian regions and countries. A remarkable discrepancy in the prevalence in different geographic regions was noted. Aging, female gender, and diabetes were found to be risk factors for DES in China.
doi:10.1155/2014/748654
PMCID: PMC4216702  PMID: 25386359
23.  Association between Single Nucleotide Polymorphisms in the ADD3 Gene and Susceptibility to Biliary Atresia 
PLoS ONE  2014;9(10):e107977.
Background and Objectives
Based on the results of previous studies, the ADD3 gene, located in the 10q24.2 region, may be a susceptibility gene of biliary atresia (BA). In this study, two single nucleotide polymorphisms (SNPs) in the ADD3 gene, rs17095355 C/T and rs10509906 G/C, were selected to investigate whether there is an association between these SNPs and susceptibility to BA in a Chinese population.
Methods
A total of 752 Han Chinese (134 BA cases and 618 ethnically matched healthy controls) were included in the present study. The ADD3 gene polymorphisms were genotyped using a TaqMan genotyping assay.
Results
Positive associations were found for the SNP rs17095355 in the codominant model; specifically, the frequencies of the CT and TT genotypes and the T allele were higher in the cases than the controls, demonstrating a significant risk for BA (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.02–2.58; OR = 2.89, 95% CI = 1.72–4.86; and OR = 1.75, 95% CI = 1.34–2.29, respectively). Regarding rs10509906, the per-C-allele conferred an OR of 0.70 (95% CI = 0.49–1.00) under the additive model. A greater risk of BA was associated with the Ta-Gb (a for rs17095355 and b for rs10509906) haplotype (OR = 1.82, 95% CI = 1.27–2.61) compared with the Ca-Cb haplotype.
Conclusion
This study suggests that the ADD3 gene plays an important role in BA pathogenesis and reveals a significant association between two SNPs, rs17095355 and rs10509906, and BA.
doi:10.1371/journal.pone.0107977
PMCID: PMC4186752  PMID: 25285724
24.  Cyclophilin A Associates with Enterovirus-71 Virus Capsid and Plays an Essential Role in Viral Infection as an Uncoating Regulator 
PLoS Pathogens  2014;10(10):e1004422.
Viruses utilize host factors for their efficient proliferation. By evaluating the inhibitory effects of compounds in our library, we identified inhibitors of cyclophilin A (CypA), a known immunosuppressor with peptidyl-prolyl cis-trans isomerase activity, can significantly attenuate EV71 proliferation. We demonstrated that CypA played an essential role in EV71 entry and that the RNA interference-mediated reduction of endogenous CypA expression led to decreased EV71 multiplication. We further revealed that CypA directly interacted with and modified the conformation of H-I loop of the VP1 protein in EV71 capsid, and thus regulated the uncoating process of EV71 entry step in a pH-dependent manner. Our results aid in the understanding of how host factors influence EV71 life cycle and provide new potential targets for developing antiviral agents against EV71 infection.
Author Summary
Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) in Asia-Pacific region and caused over one million infection cases and nine hundred deaths in the year of 2010 in China mainland. EV71 is known to infect the young children for the sake of their undeveloped immune system. Unlike other Enterovirus (e.g. coxsackievirus), EV71 could cause severe aseptic meningitis, encephalitis, myocarditis, and acute flaccid paralysis, thus leading to high fatality rates. There is no clinically applied therapeutics. In this work, we used CypA inhibitors as bioprobes to show that CypA played an essential role in EV71 proliferation. We also elucidated the mechanism by which CypA interacted with the EV71 VP1 H-I loop and functioned as an uncoating regulator in EV71 entry step. Since there are several non-immunosuppressive CypA inhibitors, e.g. NIM-811 and Debio-025, have been reported to show antiviral potency, our results provide a potential way to discover clinical therapeutics against EV71 infection.
doi:10.1371/journal.ppat.1004422
PMCID: PMC4183573  PMID: 25275585
25.  Air pollution exposure and lung function in highly exposed subjects in Beijing, China: a repeated-measure study 
Background
Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China.
Methods
The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase.
Results
The two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 μg/m3 (IQR: 48.5-126.6) in office workers and 126.8 μg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; -0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers.
Conclusion
Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0051-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12989-014-0051-7
PMCID: PMC4192276  PMID: 25272992
Lung function; Metals; Particulate matter; Traffic exposure; FEV1; FVC

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