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1.  Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure 
World Journal of Gastroenterology : WJG  2014;20(48):18458-18465.
AIM: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) for treating liver failure due to chronic hepatitis B.
METHODS: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a “tonifying qi and detoxification” (“TQD”) group (72 patients); and (3) a “tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”) group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the “TQD” group were given a TCM formula “tonifying qi and detoxification” and general internal medicine treatment; patients in the “TTK” group were given a TCM formula of “TTK” and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.
RESULTS: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, “TQD”, and “TTK” groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the “TTK” group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the “TQD” group and “TTK” group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the “TQD” group and one case of gastrointestinal side effect in the “TTK” group.
CONCLUSION: Treatment with “TTK” improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.
doi:10.3748/wjg.v20.i48.18458
PMCID: PMC4277987  PMID: 25561817
Clinical study; “Tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment” (“TTK”); Liver regeneration; Treatment with integrated traditional and Western medicine; Chronic hepatitis B-associated liver failure
2.  Integrating protein structural dynamics and evolutionary analysis with Bio3D 
BMC Bioinformatics  2014;15(1):399.
Background
Popular bioinformatics approaches for studying protein functional dynamics include comparisons of crystallographic structures, molecular dynamics simulations and normal mode analysis. However, determining how observed displacements and predicted motions from these traditionally separate analyses relate to each other, as well as to the evolution of sequence, structure and function within large protein families, remains a considerable challenge. This is in part due to the general lack of tools that integrate information of molecular structure, dynamics and evolution.
Results
Here, we describe the integration of new methodologies for evolutionary sequence, structure and simulation analysis into the Bio3D package. This major update includes unique high-throughput normal mode analysis for examining and contrasting the dynamics of related proteins with non-identical sequences and structures, as well as new methods for quantifying dynamical couplings and their residue-wise dissection from correlation network analysis. These new methodologies are integrated with major biomolecular databases as well as established methods for evolutionary sequence and comparative structural analysis. New functionality for directly comparing results derived from normal modes, molecular dynamics and principal component analysis of heterogeneous experimental structure distributions is also included. We demonstrate these integrated capabilities with example applications to dihydrofolate reductase and heterotrimeric G-protein families along with a discussion of the mechanistic insight provided in each case.
Conclusions
The integration of structural dynamics and evolutionary analysis in Bio3D enables researchers to go beyond a prediction of single protein dynamics to investigate dynamical features across large protein families. The Bio3D package is distributed with full source code and extensive documentation as a platform independent R package under a GPL2 license from http://thegrantlab.org/bio3d/.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0399-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-014-0399-6
PMCID: PMC4279791  PMID: 25491031
Protein structure; Protein dynamics; Allostery; Normal mode analysis; Molecular dynamics; Principal component analysis; Evolution
3.  Limited Density of an Antigen Presented by RMA-S Cells Requires B7-1/CD28 Signaling to Enhance T-Cell Immunity at the Effector Phase 
PLoS ONE  2014;9(11):e108192.
The association of B7-1/CD28 between antigen presenting cells (APCs) and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide.
doi:10.1371/journal.pone.0108192
PMCID: PMC4226464  PMID: 25383875
4.  Human Infection with West Nile Virus, Xinjiang, China, 2011 
Emerging Infectious Diseases  2014;20(8):1421-1423.
doi:10.3201/eid2008.131433
PMCID: PMC4111179  PMID: 25062043
West Nile virus; viruses; human infection; encephalitis; Xinjiang; China
5.  The Anoikis Effector Bit1 Displays Tumor Suppressive Function in Lung Cancer Cells 
PLoS ONE  2014;9(7):e101564.
The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES) protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC) tissues.
doi:10.1371/journal.pone.0101564
PMCID: PMC4086906  PMID: 25003198
6.  Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression 
Adoptive cell therapy with tumor infiltrating lymphocytes (TILs) represents an effective treatment for patients with metastatic melanoma. However, most of the antigen targets recognized by effective melanoma reactive TILs remain elusive. In this study, patient 2369 experienced a complete response, including regressions of bulky liver tumor masses ongoing beyond seven years following adoptive TILs transfer. The screening of a cDNA library generated from the autologous melanoma cell line resulted in the isolation of a mutated PPP1R3B (protein phosphatase 1, regulatory (inhibitor) subunit 3B) gene product. The mutated PPP1R3B peptide represents the immunodominant epitope recognized by tumor reactive T cells in TIL 2369. Five years following adoptive transfer, peripheral blood T lymphocytes obtained from patient 2369 recognized the mutated PPP1R3B epitope. These results demonstrate that adoptive T cell therapy targeting a tumor-specific antigen can mediate long-term survival for a patient with metastatic melanoma. This study also provides an impetus to develop personalized immunotherapy targeting tumor-specific, mutated antigens.
doi:10.4049/jimmunol.1202830
PMCID: PMC3679246  PMID: 23690473
7.  PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors  
The Journal of Clinical Investigation  2014;124(5):2246-2259.
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8+ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8+ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8+ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8+ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8+ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8+PD-1+ compared with CD8+PD-1– TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8+ and the CD8+PD-1+ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8+ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.
doi:10.1172/JCI73639
PMCID: PMC4001555  PMID: 24667641
8.  Sputum myeloperoxidase in chronic obstructive pulmonary disease 
Background
Airway inflammation, especially neutrophilic airway inflammation, is a cardinal pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients. The ideal biomarkers characterizing the inflammation might have important potential clinical applications in disease assessment and therapeutic intervention. Sputum myeloperoxidase (MPO) is recognized as a marker of neutrophil activity. The purpose of this meta-analysis is to determine whether sputum MPO levels could reflect disease status or be regulated by regular medications for COPD.
Methods
Studies were identified by searching PubMed, Embase, the Cochrane Database, CINAHL and http://www.controlled-trials.com for relevant reports published before September 2012. Observational studies comparing sputum MPO in COPD patients and healthy subjects or asthmatics, or within the COPD group, and studies comparing sputum MPO before and after treatment were all included. Data were independently extracted by two investigators and analyzed using STATA 10.0 software.
Results
A total of 24 studies were included in the meta-analysis. Sputum MPO levels were increased in stable COPD patients when compared with normal controls, and this increase was especially pronounced during exacerbations as compared with MPO levels during the stable state. Theophylline treatment was able to reduce MPO levels in COPD patients, while glucocorticoid treatment failed to achieve the same result.
Conclusion
Sputum MPO might be a promising biomarker for guiding COPD management; however, further investigations are needed to confirm this.
doi:10.1186/2047-783X-19-12
PMCID: PMC4016613  PMID: 24588870
Chronic obstructive pulmonary disease; Myeloperoxidase; Sputum; Biomarker
9.  Psr is involved in regulation of glucan production, and double deficiency of BrpA and Psr is lethal in Streptococcus mutans 
Microbiology  2013;159(Pt 3):493-506.
Streptococcus mutans, the primary causative agent of dental caries, contains two paralogues of the LytR-CpsA-Psr family proteins encoded by brpA and psr, respectively. Previous studies have shown that BrpA plays an important role in cell envelope biogenesis/homeostasis and affects stress responses and biofilm formation by Strep. mutans, traits critical to cariogenicity of this bacterium. In this study, a Psr-deficient mutant, TW251, was constructed. Characterization of TW251 showed that deficiency of Psr did not have any major impact on growth rate. However, when subjected to acid killing at pH 2.8, the survival rate of TW251 was decreased dramatically compared with the parent strain UA159. In addition, TW251 also displayed major defects in biofilm formation, especially during growth with sucrose. When compared to UA159, the biofilms of TW251 were mainly planar and devoid of extracellular glucans. Real-time-PCR and Western blot analyses revealed that deficiency of Psr significantly decreased the expression of glucosyltransferase C, a protein known to play a major role in biofilm formation by Strep. mutans. Transmission electron microscopy analysis showed that deficiency of BrpA caused alterations in cell envelope and cell division, and the most significant defects were observed in TW314, a Psr-deficient and BrpA-down mutant. No such effects were observed with Psr mutant TW251 under similar conditions. These results suggest that while there are similarities in functions between BrpA and Psr, distinctive differences also exist between these two paralogues. Like Bacillus subtilis but different from Staphylococcus aureus, a functional BrpA or Psr is required for viability in Strep. mutans.
doi:10.1099/mic.0.063032-0
PMCID: PMC3709821  PMID: 23288544
10.  DiME: A Scalable Disease Module Identification Algorithm with Application to Glioma Progression 
PLoS ONE  2014;9(2):e86693.
Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II) - and high (GBM) - grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME.
doi:10.1371/journal.pone.0086693
PMCID: PMC3921127  PMID: 24523864
11.  Parametrically Amplified Bright-state Polariton of Four- and Six-wave Mixing in an Optical Ring Cavity 
Scientific Reports  2014;4:3619.
We report experimental studies of bright-state polaritons of four-wave mixing (FWM) and six-wave mixing (SWM) signals through cascade nonlinear optical parametric amplification processes in an atom-cavity composite system for the first time. Also, the coexisting cavity transmission modes of parametrically amplified FWM and SWM signals are observed. Finally, electromagnetically induced absorption by the FWM cavity modes in the probe beam is investigated. The investigations can find potential applications in multi-channel narrow-band long-distance quantum communication.
doi:10.1038/srep03619
PMCID: PMC3885996  PMID: 24401795
12.  Dynamic intrinsic optical signal monitoring of electrically stimulated inner retinal neural response 
Journal of modern optics  2012;59(11):10.1080/09500340.2012.687464.
Dynamic monitoring of stimulus-evoked inner neural response is important for functional validation of stimulation protocols of retinal prosthetic devices. In this paper, we demonstrate label-free intrinsic optical signal (IOS) imaging of electrically stimulated inner neural response in freshly isolated mouse retinas. While single-pulse stimulation evoked rapid IOS within 20 ms, pulse-train stimulation indicated that the fast IOS response can follow frequency stimulation up to at least 8 Hz. Fast IOS imaging promises a noninvasive method for high resolution examination of electrically evoked retinal response, without artifact contamination of electrical stimulus.
doi:10.1080/09500340.2012.687464
PMCID: PMC3882170  PMID: 24403725
intrinsic optical signal; retinal function; retinal prosthesis; ganglion cell
13.  Targeting Truncated Retinoid X Receptor-α by CF31 induces TNFα-dependent apoptosis 
Cancer research  2012;73(1):307-318.
A truncated version of retinoid X receptor-α, tRXRα, promotes cancer cell survival by activating the PI3K/AKT pathway. However, targeting the tRXRα-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. Pruniflorum, and the biological evaluation of its regulation of the tRXRα-mediated PI3K/AKT pathway. CF31 binds RXRα and its binding results in inhibition of RXRα transactivation. Through RXRα mutational analysis and computational studies, we show that Arg316 of RXRα, known to form salt bridges with certain RXRα ligands such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, demonstrating a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXRα. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNFα, it suppresses TNFα activation of AKT by inhibiting TNFα-induced tRXRα interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNFα activation of AKT also results in TNFα-dependent activation of caspase-8 and apoptosis. Together, our results demonstrate that CF31 is an effective converter of TNFα signaling from survival to death by targeting tRXRα in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/Akt may offer a new therapeutic strategy to kill cancer cells.
doi:10.1158/0008-5472.CAN-12-2038
PMCID: PMC3537848  PMID: 23151904
retinoid X receptor; CF31; AKT; TNFα; cancer; apoptosis
14.  Functional imaging of glucose-evoked rat islet activities using transient intrinsic optical signals 
Journal of modern optics  2012;59(9):10.1080/09500340.2012.674564.
We demonstrate intrinsic optical signal (IOS) imaging of intact rat islet, which consists of many endocrine cells working together. A near-infrared digital microscope was employed for optical monitoring of islet activities evoked by glucose stimulation. Dynamic NIR images revealed transient IOS responses in the islet activated by low-dose (2.75mM) and high-dose (5.5mM) glucose stimuli. Comparative experiments and quantitative analysis indicated that both glucose metabolism and calcium/insulin dynamics might contribute to the observed IOS responses. Further investigation of the IOS imaging technology may provide a high resolution method for ex vivo functional examination of the islet, which is important for advanced study of diabetes associated islet dysfunctions and for improved quality control of donor islets for transplantation.
doi:10.1080/09500340.2012.674564
PMCID: PMC3867949  PMID: 24363496
intrinsic optical signal; functional imaging; rat islet; glucose stimulation
15.  Clinical effects and complications of TIPS for portal hypertension due to cirrhosis: A single center 
AIM: To determine the clinical effects and complications of transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension due to cirrhosis.
METHODS: Two hundred and eighty patients with portal hypertension due to cirrhosis who underwent TIPS were retrospectively evaluated. Portal trunk pressure was measured before and after surgery. The changes in hemodynamics and the condition of the stent were assessed by ultrasound and the esophageal and fundic veins observed endoscopically.
RESULTS: The success rate of TIPS was 99.3%. The portal trunk pressure was 26.8 ± 3.6 cmH2O after surgery and 46.5 ± 3.4 cmH2O before surgery (P < 0.01). The velocity of blood flow in the portal vein increased. The internal diameters of the portal and splenic veins were reduced. The short-term hemostasis rate was 100%. Esophageal varices disappeared completely in 68% of patients and were obviously reduced in 32%. Varices of the stomach fundus disappeared completely in 80% and were obviously reduced in 20% of patients. Ascites disappeared in 62%, were markedly reduced in 24%, but were still apparent in 14% of patients. The total effective rate of ascites reduction was 86%. Hydrothorax completely disappeared in 100% of patients. The incidence of post-operative stent stenosis was 24% at 12 mo and 34% at 24 mo. The incidence of post-operative hepatic encephalopathy was 12% at 3 mo, 17% at 6 mo and 19% at 12 mo. The incidence of post-operative recurrent hemorrhage was 9% at 12 mo, 19% at 24 mo and 35% at 36 mo. The cumulative survival rate was 86% at 12 mo, 81% at 24 mo, 75% at 36 mo, 57% at 48 mo and 45% at 60 mo.
CONCLUSION: TIPS can effectively lower portal hypertension due to cirrhosis. It is significantly effective for hemorrhage of the digestive tract due to rupture of esophageal and fundic veins and for ascites and hydrothorax caused by portal hypertension.
doi:10.3748/wjg.v19.i44.8085
PMCID: PMC3848158  PMID: 24307804
Transjugular intrahepatic portosystemic shunt; Cirrhosis; Portal hypertension; Therapeutic effect; Complication
16.  The Cross-Neutralizing Activity of Enterovirus 71 Subgenotype C4 Vaccines in Healthy Chinese Infants and Children 
PLoS ONE  2013;8(11):e79599.
Background
EV71 is one of major etiologic causes of hand-foot-mouth disease (HFMD) and leads to severe neurological complications in young children and infants. Recently inactivated EV71 vaccines have been developed by five manufactures and clinically show good safety and immunogenicity. However, the cross-neutralizing activity of these vaccines remains unclear, and is of particular interest because RNA recombination is seen more frequently in EV71 epidemics.
Methodology/Principal Findings
In this post-hoc study, sera from a subset of 119 infants and children in two clinical trials of EV71 subgenotype C4 vaccines (ClinicalTrials.gov Identifier: NCT01313715 and NCT01273246), were detected for neutralizing antibody (NTAb) titres with sera from infected patients as controls. Cytopathogenic effect method was employed to test NTAb against EV71 subgenotype B4, B5, C2, C4 and C5, which were prominent epidemic strains worldwide over the past decade. To validate the accuracy of the results, ELISpot assay was employed in parallel to detect NTAb in all the post-vaccine sera. After two-dose vaccination, 49 out of 53 participants in initially seronegative group and 52 out of 53 participants in initially seropositive group showed less than 4-fold differences in NTAb titers against five EV71 strains, whereas corresponding values among sera from pediatric patients recovering from EV71-induced HFMD and subclinically infected participants were 8/8 and 41/43, respectively. The geometric mean titers of participants against five subgenotypes EV71 all grew significantly after vaccinations, irrespective of the baseline NTAb titer. The relative fold increase in antibody titers (NTAb-FI) against B4, B5, C2, and C5 displayed a positive correlation to the NTAb-FI against C4.
Conclusions/Significance
The results demonstrated broad cross-neutralizing activity induced by two C4 EV71 vaccines in healthy Chinese infants and children. However, the degree of induced cross-protective immunity, and the potential escape evolution for EV71 still need to be monitored and researched in future for these new vaccines.
doi:10.1371/journal.pone.0079599
PMCID: PMC3834186  PMID: 24260259
17.  In vivo Optical Coherence Tomography of Light-Driven Melanosome Translocation in Retinal Pigment Epithelium 
Scientific Reports  2013;3:2644.
Optical coherence tomography (OCT) may revolutionize fundamental investigation and clinical management of age-related macular degeneration and other eye diseases. However, quantitative OCT interpretation is hampered due to uncertain sub-cellular correlates of reflectivity in the retinal pigment epithelium (RPE) and photoreceptor. The purpose of this study was twofold: 1) to test OCT correlates in the RPE, and 2) to demonstrate the feasibility of longitudinal OCT monitoring of sub-cellular RPE dynamics. A high resolution OCT was constructed to achieve dynamic imaging of frog eyes, in which light-driven translocation of RPE melanosomes occurred within the RPE cell body and apical processes. Comparative histological examination of dark- and light-adapted eyes indicated that the RPE melanin granule, i.e., melanosome, was a primary OCT correlate. In vivo OCT imaging of RPE melanosomes opens the opportunity for quantitative assessment of RPE abnormalities associated with disease, and enables longitudinal investigation of RPE kinetics correlated with visual function.
doi:10.1038/srep02644
PMCID: PMC3770963  PMID: 24025778
18.  Super-resolution scanning laser microscopy through virtually structured detection 
Biomedical Optics Express  2013;4(9):1673-1682.
High resolution microscopy is essential for advanced study of biological structures and accurate diagnosis of medical diseases. The spatial resolution of conventional microscopes is light diffraction limited. Structured illumination has been extensively explored to break the diffraction limit in wide field light microscopy. However, deployable application of the structured illumination in scanning laser microscopy is challenging due to the complexity of the illumination system and possible phase errors in sequential illumination patterns required for super-resolution reconstruction. We report here a super-resolution scanning laser imaging system which employs virtually structured detection (VSD) to break the diffraction limit. Without the complexity of structured illumination, VSD provides an easy, low-cost and phase-artifact free strategy to achieve super-resolution in scanning laser microscopy.
doi:10.1364/BOE.4.001673
PMCID: PMC3771838  PMID: 24049688
(100.6640) Superresolution; (110.3080) Infrared imaging; (170.3880) Medical and biological imaging; (180.5810) Scanning microscopy
19.  Progress on the research and development of inactivated EV71 whole-virus vaccines 
Human Vaccines & Immunotherapeutics  2013;9(8):1701-1705.
The prevalence of diseases caused by EV71 infection has become a serious public health problem in the Western Pacific region. Due to a lack of effective treatment options, controlling EV71 epidemics has mainly focused on the research and development (R&D) of EV71 vaccines. Thus far, five organizations have completed pre-clinical studies focused on the development of inactivated EV71 whole-virus vaccines, including vaccine strain screening, process optimization, safety and immunogenicity evaluation, and are in different stages of clinical trials. Among these organizations, three companies in Mainland China [Beijing Vigoo Biological Co., Ltd. (Vigoo), Sinovac Biotech Ltd. (Sinovac) and Institute of Medical Biology, Chinese Academy of Medical Science (CAMS)] have recently completed Phase III trials for the vaccines they developed. In addition, the other two vaccines, developed by National Health Research Institutes (NHRI) of Taiwan and Inviragen Pte., Ltd (Inviragen), of Singapore, have also completed Phase I clinical trials. Published clinical trial results indicate that the inactivated EV71 vaccines have good safety and immunogenicity in the target population (infants) and confer a relatively high rate of protection against EV71 infection-related diseases. The results of clinical trials suggest a promising future for the clinical use of EV71 vaccines. Here, we review and highlight the recent progress on the R&D of inactivated EV71 whole-virus vaccines.
doi:10.4161/hv.24949
PMCID: PMC3906269  PMID: 23744508
enterovirus 71; hand-foot-mouth diseases (HFMD); inactivated whole-virus vaccine; immunogenicity; protective effect; standard
20.  Investigation of the hyper-reflective inner/outer segment band in optical coherence tomography of living frog retina 
Journal of Biomedical Optics  2012;17(6):060504.
Abstract.
This study is to test anatomic correlates, including connecting cilium (CC) and inner segment (IS) ellipsoid, to the hyper-reflective band visualized by optical coherence tomography (OCT) and commonly attributed to the photoreceptor inner/outer segment (IS/OS) junction. A line-scan OCT (LS-OCT) was constructed to achieve sub-cellular resolution (lateral: ∼2  μm; axial: ∼4  μm) of excised living frog retinas. An electro-optic phase modulator was employed for rapid and vibration-free phase modulation. Comparison of normalized distance measurements between LS-OCT images and histological images revealed that the dominant source of the signal reported as the IS/OS OCT band actually originates from the IS.
doi:10.1117/1.JBO.17.6.060504
PMCID: PMC3381034  PMID: 22734727
retina; optical coherence tomography; photoreceptor; inner segment; outer segment
21.  Development and Evaluation of a Pseudovirus-Luciferase Assay for Rapid and Quantitative Detection of Neutralizing Antibodies against Enterovirus 71 
PLoS ONE  2013;8(6):e64116.
The level of neutralizing antibodies (NtAb) induced by vaccine inoculation is an important endpoint to evaluate the efficacy of EV71 vaccine. In order to evaluate the efficacy of EV71 vaccine, here, we reported the development of a novel pseudovirus system expression firefly luciferase (PVLA) for the quantitative measurement of NtAb. We first evaluated and validated the sensitivity and specificity of the PVLA method. A total of 326 serum samples from an epidemiological survey and 144 serum specimens from 3 clinical trials of EV71 vaccines were used, and the level of each specimen's neutralizing antibodies (NtAb) was measured in parallel using both the conventional CPE-based and PVLA-based assay. Against the standard neutralization assay based on the inhibition of the cytopathic effect (CPE), the sensitivity and specificity of the PVLA method are 98% and 96%, respectively. Then, we tested the potential interference of NtAb against hepatitis A virus, Polio-I, Polio-II, and Polio-III standard antisera (WHO) and goat anti-G10/CA16 serum, the PVLA based assay showed no cross-reactivity with NtAb against other specific sera. Importantly, unlike CPE based method, no live replication-competent EV71 is used during the measurement. Taken together, PVLA is a rapid and specific assay with higher sensitivity and accuracy. It could serve as a valuable tool in assessing the efficacy of EV71 vaccines in clinical trials and disease surveillance in epidemiology studies.
doi:10.1371/journal.pone.0064116
PMCID: PMC3673970  PMID: 23755115
22.  In Vivo Confocal Intrinsic Optical Signal Identification of Localized Retinal Dysfunction 
Purpose.
The purposes of this study were to investigate the physiological mechanism of stimulus-evoked fast intrinsic optical signals (IOSs) recorded in dynamic confocal imaging of the retina, and to demonstrate the feasibility of in vivo confocal IOS mapping of localized retinal dysfunctions.
Methods.
A rapid line-scan confocal ophthalmoscope was constructed to achieve in vivo confocal IOS imaging of frog (Rana pipiens) retinas at cellular resolution. In order to investigate the physiological mechanism of confocal IOS, comparative IOS and electroretinography (ERG) measurements were made using normal frog eyes activated by variable-intensity stimuli. A dynamic spatiotemporal filtering algorithm was developed to reject the contamination of hemodynamic changes on fast IOS recording. Laser-injured frog eyes were employed to test the potential of confocal IOS mapping of localized retinal dysfunctions.
Results.
Comparative IOS and ERG experiments revealed a close correlation between the confocal IOS and retinal ERG, particularly the ERG a-wave, which has been widely used to evaluate photoreceptor function. IOS imaging of laser-injured frog eyes indicated that the confocal IOS could unambiguously detect localized (30 μm) functional lesions in the retina before a morphological abnormality is detectable.
Conclusions.
The confocal IOS predominantly results from retinal photoreceptors, and can be used to map localized photoreceptor lesion in laser-injured frog eyes. We anticipate that confocal IOS imaging can provide applications in early detection of age-related macular degeneration, retinitis pigmentosa, and other retinal diseases that can cause pathological changes in the photoreceptors.
This study investigated the physiological mechanism of stimulus-evoked fast intrinsic optical signal (IOS) recorded in dynamic confocal imaging of the retina, and demonstrated the feasibility of in vivo confocal IOS mapping of localized retinal dysfunctions.
doi:10.1167/iovs.12-10732
PMCID: PMC3522438  PMID: 23150616
23.  Comparative intrinsic optical signal imaging of wild-type and mutant mouse retinas 
Optics Express  2012;20(7):7646-7654.
Functional measurement is important for retinal study and disease diagnosis. Transient intrinsic optical signal (IOS) response, tightly correlated with functional stimulation, has been previously detected in normal retinas. In this paper, comparative IOS imaging of wild-type (WT) and rod-degenerated mutant mouse retinas is reported. Both 2-month and 1-year-old mice were measured. In 2-month-old mutant mice, time course and peak value of the stimulus-evoked IOS were significantly delayed (relative to stimulus onset) and reduced, respectively, compared to age matched WT mice. In 1-year-old mutant mice, stimulus-evoked IOS was totally absent. However, enhanced spontaneous IOS responses, which might reflect inner neural remodeling in diseased retina, were observed in both 2-month and 1-year-old mutant retinas. Our experiments demonstrate the potential of using IOS imaging for noninvasive and high resolution identification of disease-associated retinal dysfunctions. Moreover, high spatiotemporal resolution IOS imaging may also lead to advanced understanding of disease-associated neural remodeling in the retina.
doi:10.1364/OE.20.007646
PMCID: PMC3387536  PMID: 22453443
(170.2655) Functional monitoring and imaging; (170.4580) Optical diagnostics for medicine; (170.3880) Medical and biological imaging; (330.5380) Physiology
24.  Fast access and early ligation of the renal pedicle significantly facilitates retroperitoneal laparoscopic radical nephrectomy procedures: modified laparoscopic radical nephrectomy 
Background
The objective of this study was to develop a modified retroperitoneal laparoscopic nephrectomy and compare its results with the previous technique.
Methods
One hundred retroperitoneal laparoscopic nephrectomies were performed from February 2007 to October 2011. The previous technique was performed in 60 cases (Group 1). The modified technique (n = 40) included fast access to the renal pedicle according to several anatomic landmarks and early ligation of renal vessels (Group 2). The mean operation time, mean blood loss, duration of hospital stay conversion rate and complication rate were compared between the groups.
Results
No significant differences were detected regarding mean patient age, mean body mass index, and tumor size between the two groups (P >0.05). The mean operation time was 59.5 ± 20.0 and 39.5 ± 17.5 minutes, respectively, in Groups 1 and 2 (P <0.001). The mean intraoperative blood loss was 147 ± 35 and 100 ± 25 ml, respectively, in Groups 1 and 2 (P <0.001). No significant differences were detected regarding the conversion rate and the complication rate between the two groups (P >0.05).
Conclusions
Early ligature using fast access to the renal vessels during retroperitoneal laparoscopic radical nephrectomy contributed to less operation time and intraoperative blood loss compared with the previous technique. In addition, the modified technique permits the procedure to be performed following the principles of open radical nephrectomy.
doi:10.1186/1477-7819-11-27
PMCID: PMC3565935  PMID: 23363489
Retroperitoneal laparoscopic nephrectomy; Technical modification; Operation time; Experience; Surgical outcomes
25.  Significant Association of Glutathione S-Transferase T1 Null Genotype with Prostate Cancer Risk: A Meta-Analysis of 26,393 Subjects 
PLoS ONE  2013;8(1):e53700.
Background
Recent studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and risk of prostate cancer showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies.
Methods
Data were collected from the following electronic databases: Pubmed, Embase, and Chinese Biomedical Database (CBM). The odds ratio (OR) and its 95% confidence interval (95%CI) was used to assess the strength of the association. We summarized the data on the association between GSTT1 null genotype and risk of prostate cancer in the overall population, and performed subgroup analyses by ethnicity, adjusted ORs, and types of controls.
Results
Ultimately, a total of 43 studies with a total of 26,393 subjects (9,934 cases and 16,459 controls) were eligible for meta-analysis. Overall, there was a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.14, 95%CI 1.01–1.29, P = 0.034). Meta-analysis of adjusted ORs also showed a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.34, 95%CI 1.09–1.64, P = 0.006). Similar results were found in the subgroup analyses by ethnicity and types of controls.
Conclusion
This meta-analysis demonstrates that GSTT1 null genotype is associated with prostate cancer susceptibility, and GSTT1 null genotype contributes to increased risk of prostate cancer.
doi:10.1371/journal.pone.0053700
PMCID: PMC3554715  PMID: 23365641

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