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1.  Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery 
Scientific Reports  2016;6:21959.
Difficulties in the highly sensitive detection of tumour microfoci represent a critical obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons’ subjective experience are limited by their inability to effectively detect tumour lesions measuring less than 2 mm; however, intraoperative fluorescence molecular imaging may overcome this limitation. Here, we synthesised an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumour-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumour specificity enabled the identification of residual microtumours and satellite lesions measuring less than 1 mm in living mice. Histological analysis validated the sensitivity and accuracy of this approach. We believe this technique utilising a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.
doi:10.1038/srep21959
PMCID: PMC4770417  PMID: 26923919
2.  Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green 
Scientific Reports  2016;6:21013.
Tissue necrosis commonly accompanies the development of a wide range of serious diseases. Therefore, highly sensitive detection and precise boundary delineation of necrotic tissue via effective imaging techniques are crucial for clinical treatments; however, no imaging modalities have achieved satisfactory results to date. Although fluorescence molecular imaging (FMI) shows potential in this regard, no effective necrosis-avid fluorescent probe has been developed for clinical applications. Here, we demonstrate that indocyanine green (ICG) can achieve high avidity of necrotic tissue owing to its interaction with lipoprotein (LP) and phospholipids. The mechanism was explored at the cellular and molecular levels through a series of in vitro studies. Detection of necrotic tissue and real-time image-guided surgery were successfully achieved in different organs of different animal models with the help of FMI using in house-designed imaging devices. The results indicated that necrotic tissue with a 0.6 mm diameter could be effectively detected with precise boundary definition. We believe that the new discovery and the associated imaging techniques will improve personalized and precise surgery in the near future.
doi:10.1038/srep21013
PMCID: PMC4749996  PMID: 26864116
3.  Polarization-sensitive optical projection tomography for muscle fiber imaging 
Scientific Reports  2016;6:19241.
Optical projection tomography (OPT) is a tool used for three-dimensional imaging of millimeter-scale biological samples, with the advantage of exhibiting isotropic resolution typically in the micron range. OPT can be divided into two types: transmission OPT (tOPT) and emission OPT (eOPT). Compared with eOPT, tOPT discriminates different tissues based on their absorption coefficient, either intrinsic or after specific staining. However, it fails to distinguish muscle fibers whose absorption coefficients are similar to surrounding tissues. To circumvent this problem, in this article we demonstrate a polarization sensitive OPT system which improves the detection and 3D imaging of muscle fibers by using polarized light. We also developed image acquisition and processing protocols that, together with the system, enable the clear visualization of muscles. Experimental results show that the muscle fibers of diaphragm and stomach, difficult to be distinguished in regular tOPT, were clearly displayed in our system, proving its potential use. Moreover, polarization sensitive OPT was fused with tOPT to investigate the stomach tissue comprehensively. Future applications of polarization sensitive OPT could be imaging other fiber-like structures such as myocardium or other tissues presenting high optical anisotropy.
doi:10.1038/srep19241
PMCID: PMC4707546  PMID: 26752330
4.  The Long Noncoding RNA IFNG-AS1 Promotes T Helper Type 1 Cells Response in Patients with Hashimoto’s Thyroiditis 
Scientific Reports  2015;5:17702.
The long noncoding (lnc) RNA-Ifng-AS1 plays an essential role in the transcription of the gene encoding IFN-γ by Th1 cells, and its human ortholog, IFNG-AS1, is expressed in human Th1 cells. However, IFNG-AS1 contributing to Th1 cells’ response in Hashimoto’s thyroiditis (HT) patients has not been reported. Twenty-eight HT patients and 20 healthy controls were enrolled in the study. The proportion of circulating Th1 cells and the level of T-bet, IFNG mRNA were increased in HT patients, the expression of IFNG-AS1 was upregulated and positively correlated with the proportion of circulating Th1 cells or T-bet, and IFNG expression, or serum level of anti-thyroglobulin antibody/thyroperoxidase antibody in HT patients. IFNG-AS1 regulated the expression of IFNG at both transcriptional and translational level in human CD4+ T cells. Furthermore, strong positive correlations between the increased transcript level of IFNG-AS1 and the increased transcript level of T-bet or IFNG were revealed in thyroid tissues from HT patients. Our results indicate that enhanced expression of lncRNA-IFNG-AS1 contributes to Th1 cell response in HT patients and may be involved in the pathogenesis of HT.
doi:10.1038/srep17702
PMCID: PMC4669486  PMID: 26634912
5.  Leptin and its receptor in hematologic malignancies 
Leptin is an adipocyte-derived cytokine coded by the obese gene, not only regulates metabolism, but also participates in hematopoiesis. Aberrant leptin levels in patients with hematologic malignancies were observed and associates with clinical characters, such as body mass index (BMI), gender, blast cell percentage. Leptin concentrations alter while diseases progress or remission. Leptin receptor is expressed in hematopoietic CD34+ stem cells, erythrocytes, lymphocytes, blast cells and samples in leukemia and lymphoma patients. The adipokine stimulates cell proliferation, cytokine secretion and protects malignant cells from apoptosis through Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and extracellular signal activated kinase 1/2 (MAPK/ERK1/2), or 3 kinase (PI3K) signaling pathways. These findings indicate leptin signaling possibility take part in occurrence, progression and prognosis of hematologic malignancies. This article reviews leptin/leptin receptor expression and the correlations with clinical characters, treatment and prognosis in myeloid and lymphoid neoplasms.
PMCID: PMC4723739  PMID: 26884894
Leptin; leptin receptor; hematologic malignancies; signaling pathway; pathogenesis
6.  Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis 
OncoTargets and therapy  2015;8:3349-3359.
Background
Premature ovarian failure and infertility following chemotherapy are major concerns for premenopausal women with breast cancer. A potential ovarian function preservation strategy is administration of gonadotropin-releasing hormone (GnRH) agonists during adjuvant chemotherapy; however, studies of the clinical efficacy of GnRH agonists to protect chemotherapy-induced ovarian damage have shown mixed results.
Objective
This meta-analysis study was designed to estimate the efficacy of GnRH agonists administered concurrently with chemotherapy to prevent chemotherapy-induced ovarian damage in premenopausal women with breast cancer.
Methods
Electronic literature databases (PubMed, EMBASE, MEDLINE, Cochrane Library databases searching, China National Knowledge Infrastructure, Web of Science, and the Wanfang Data) were searched for relevant randomized controlled trials (RCTs) published until September 2015. Only RCTs that examined the effect of GnRH agonists for chemotherapy-induced ovarian failure in premenopausal women with breast cancer were selected. The rate of spontaneous resumption of menses and spontaneous pregnancy were collected. All data were analyzed by RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Stata 12.0 (StataCorp, College Station, TX, USA).
Results
Eleven RCTs with a total of 1,062 participants (GnRH agonists administered concurrently with chemotherapy, n=541; chemotherapy alone, n=521) were included in the meta-analysis. A significantly greater number of women treated with GnRH agonist experienced spontaneous resumption of menses after the adjuvant chemotherapy, yielding a pooled odds ratio of 2.57 (versus chemotherapy alone, 95% confidence interval (CI)=1.65, 4.01; P<0.0001). A subgroup analysis showed that addition of GnRH agonists significantly improved the resumption of menses rate in patients who were hormone-insensitive. However, the two treatment groups experienced similar spontaneous pregnancy (odds ratio =0.177; 95% CI=0.92, 1.40; P=0.09).
Conclusion
GnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility.
doi:10.2147/OTT.S95936
PMCID: PMC4654551  PMID: 26622183
GnRH agonists; ovarian damage; breast cancer; chemotherapy; meta-analysis
7.  Integrated three-dimensional digital assessment of accuracy of anterior tooth movement using clear aligners 
Korean Journal of Orthodontics  2015;45(6):275-281.
Objective
To assess the accuracy of anterior tooth movement using clear aligners in integrated three-dimensional digital models.
Methods
Cone-beam computed tomography was performed before and after treatment with clear aligners in 32 patients. Plaster casts were laser-scanned for virtual setup and aligner fabrication. Differences in predicted and achieved root and crown positions of anterior teeth were compared on superimposed maxillofacial digital images and virtual models and analyzed by Student's t-test.
Results
The mean discrepancies in maxillary and mandibular crown positions were 0.376 ± 0.041 mm and 0.398 ± 0.037 mm, respectively. Maxillary and mandibular root positions differed by 2.062 ± 0.128 mm and 1.941 ± 0.154 mm, respectively.
Conclusions
Crowns but not roots of anterior teeth can be moved to designated positions using clear aligners, because these appliances cause tooth movement by tilting motion.
doi:10.4041/kjod.2015.45.6.275
PMCID: PMC4664903  PMID: 26629473
Clear aligners; Registration; Cone-beam computed tomography
8.  DNA methylation regulates mouse cardiac myofibril gene expression during heart development 
Background
It is well known that epigenetic modifications play an important role in controlling the regulation of gene expression during the development. Our previous studies have demonstrated that the expression of fetal troponin I gene (also called slow skeletal troponin I, ssTnI) is predominated in the fetal stage, reduced after birth and disappeared in the adulthood. The mechanism underlying the developmentally related ssTnI gene regulation is not clear. In this study, we have explored the epigenetic role of DNA methylation in the regulation of ssTnI expression in the heart during the development.
Results
The DNA methylation levels of CpG island and CpG dinucleotides region were detected using methylation specific PCR (MSP) and bisulfite sequence PCR (BSP) in 2000 bp upstream and 100 bp upstream of ssTnI gene promoter. Real time RT-PCR and Western blot were used to detect ssTnI mRNA and protein expression levels. We found that DNA methylation levels of the CpG dinucleotides region in ssTnI gene promoter were increased with the development, corresponding to a decreased expression of ssTnI gene in mouse heart. However the DNA methylation levels of CpG islands in this gene were not changed during the development. Application of a methylation inhibitor, 5-Azacytidine, in cultured myocardial cells partially prevented the decline of ssTnI expression.
Conclusion
Our results indicate that DNA methylation, as an epigenetic intervention, plays a role in the regulation of the fetal TnI gene expression in the heat during the development.
doi:10.1186/s12929-015-0203-6
PMCID: PMC4609054  PMID: 26475623
Troponin I; DNA methylation; 5-Azacytidine; Epigenetic regulation
9.  Estimating Population Exposure to Fine Particulate Matter in the Conterminous U.S. using Shape Function-based Spatiotemporal Interpolation Method 
This paper investigates spatiotemporal interpolation methods for the application of air pollution assessment. The air pollutant of interest in this paper is fine particulate matter PM2.5. The choice of the time scale is investigated when applying the shape function-based method. It is found that the measurement scale of the time dimension has an impact on the quality of interpolation results. Based upon the result of 10-fold cross validation, the most effective time scale out of four experimental ones was selected for the PM2.5 interpolation. The paper also estimates the population exposure to the ambient air pollution of PM2.5 at the county-level in the contiguous U.S. in 2009. The interpolated county-level PM2.5 has been linked to 2009 population data and the population with a risky PM2.5 exposure has been estimated. The risky PM2.5 exposure means the PM2.5 concentration exceeding the National Ambient Air Quality Standards. The geographic distribution of the counties with a risky PM2.5 exposure is visualized. This work is essential to understanding the associations between ambient air pollution exposure and population health outcomes.
PMCID: PMC4583366  PMID: 26413256
spatiotemporal interpolation; fine particulate matter; air pollution exposure; time scale
10.  Increased precision of orthotopic and metastatic breast cancer surgery guided by matrix metalloproteinase-activatable near-infrared fluorescence probes 
Scientific Reports  2015;5:14197.
Advanced medical imaging technology has allowed the use of fluorescence molecular imaging-guided breast cancer surgery (FMI-guided BCS) to specifically label tumour cells and to precisely distinguish tumour margins from normal tissues intra-operatively, a major challenge in the medical field. Here, we developed a surgical navigation system for real-time FMI-guided BCS. Tumours derived from highly metastatic 4T1-luc breast cancer cells, which exhibit high expression of matrix metalloproteinase (MMP) and human epidermal growth factor receptor 2 (HER2), were established in nude mice; these mice were injected with smart MMP-targeting and “always-on” HER2-targeting near-infrared (NIR) fluorescent probes. The fluorescence signal was imaged to assess in vivo binding of the probes to the tumour and metastatic sites. Then, orthotopic and metastatic breast tumours were precisely removed under the guidance of our system. The post-operative survival rate of mice was improved by 50% with the new method. Hematoxylin and eosin staining and immunohistochemical staining for MMP2 and CD11b further confirmed the precision of tumour dissection. Our method facilitated the accurate detection and complete removal of breast cancer tumours and provided a method for defining the molecular classification of breast cancer during surgery, thereby improving prognoses and survival rates.
doi:10.1038/srep14197
PMCID: PMC4585795  PMID: 26395067
11.  Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages 
Oncotarget  2015;6(28):26018-26028.
Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment.
To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR.
In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth.
Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.
PMCID: PMC4694882  PMID: 26305552
zoledronic acid; mesenchymal stem cells; breast carcinoma; tumor associated macrophages; monocyte chemotactic protein-1
12.  Impact of Natural IgM Concentration on Gene Therapy with Adenovirus Type 5 Vectors 
Journal of Virology  2014;89(6):3412-3416.
Natural IgM inhibits gene transfer by adenovirus type 5 (Ad5) vectors. We show that polyreactive natural IgM antibodies bind to Ad5 and that inhibition of liver transduction by IgM depends on Kupffer cells. By manipulating IgM concentration in vivo, we demonstrate that IgM inhibits liver transduction in a concentration-dependent manner. We further show that differences in natural IgM between BALB/c and C57BL/6 mice contribute to lower efficiency of Ad5 gene transfer in BALB/c mice.
doi:10.1128/JVI.03217-14
PMCID: PMC4337529  PMID: 25552715
13.  Expression of human papillomavirus and prognosis of juvenile laryngeal papilloma 
The aim of this study was to evaluate the correlation between clinical behavior and expression of human papillomavirus (HPV) in patients with juvenile laryngeal papillomatosis, in an attempt to develop an effective molecular biological method to predict prognosis. We included 37 patients with juvenile laryngeal papillomatosis in the study group and 10 cases each of juvenile vocal cord polyps and juvenile normal laryngeal mucosa as the control group. We detected HPV by immunocytochemistry and in situ hybridization, identified the virus type, and measured HPV-DNA content using a computer-assisted, color pathological image-analysis system. Additionally, we conducted a retrospective study with regard to the patients’ clinical history to evaluate the prognosis. The data of the 2 groups were compared and statistically analyzed, including a correlation with prognosis. In the study group, 67.3% (25/37) were positive for HPV-Ag by immunocytochemistry; whereas 53.2%, 45.8%, and 25.4% were positive for HPV6b-DNA, HPV11-DNA, and HPV6b+11-DNA, respectively, by in situ hybridization. HPV was not detected in the control group. There was a significant difference between two groups (P < 0.05). Compared to HPV11-DNA-positive cases, those that were positive for HPV6b-DNA and HPV6b+11-DNA showed lower results on average, for age at first diagnosis and self-relief, number of surgeries, and interval between surgeries. Our findings suggest that immunocytochemistry and in situ hybridization are useful methods to evaluate the prognosis of juvenile laryngeal papilloma (JLP) and that HPV6b-positivity can be used as an index to predict the development and outcome of JLP.
PMCID: PMC4658932  PMID: 26629043
Laryngeal neoplasm; papillomavirus; human papilloma; DNA probes; human papillomavirus
14.  Effects of insulin-like growth factor 2 and its receptor expressions on corneal repair 
Limbal stem cell (LSC) on the basal layer of cornea plays an important role in the epithelial repair after corneal injury as it can proliferate, differentiate and migrate into injury sites under the direction of cytokines. This study explored the signaling pathway and cellular mechanism between corneal epithelial cells LSC, on a mouse model with mechanic corneal injury. Ipsilateral corneal mechanic injury model was prepared on mice using the contralateral eye as the control. Tissues from both central and peripheral regions of cornea were collected, cultured and quantified for expression of various cytokines including epidermal growth factor (EGF), fibroblast growth factor-β (FGF-β), heparin-like growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-β1 (TGF-β1), IGF-1 and IGF-2. The effects of these factors on the differentiation of LSC and fibroblasts were also studied. Most of those cytokines had elevated gene expressions after the corneal injury. Among those IGF-2 had significantly increased expression, along with the high expression of IGF-2 receptor in corneal peripheral cells. IGF-2 also induced the differentiation of LSC into keratin-12-positive cells. Further studies showed the prominent expression of α-actin in injured tissues, suggesting the potential transformation of fibroblasts into myofibroblasts. Both IGF-2 and its receptor had elevated expressions after corneal injury. They may facilitate the transformation of LSC into epithelial cells, in addition to the role in transformation from fibroblasts to myofibroblasts.
PMCID: PMC4637542  PMID: 26617727
Corneal injury and repair; insulin-like growth factor-2; fibroblasts; myofibroblasts
15.  The effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment 
To investigate the effect and action mechanism of resveratrol on the vascular endothelial cell by high glucose treatment. Primarily cultured human umbilical vein endothelial cells (HUVECs) were pretreated by resveratrol (0.2 μmol/L) and holding for 6 h, and then cultured in Dulbecco Modified Eagle Medium (DMEM) within 0.45 mmol/L of palmimte acid and 32.8 mmol/L of glucose, which is holding for 12 h. The cells were collected to analyze the expression of E-selected element. Supernatant of cultured cells, induced by 100 nmol/L insulin for 30 min, was used to analyze the nitric oxide content. Compared with normal control cells, the secretion of nitric oxide is stimulated by insulin decrease, however, the expression of E-selected element increased in HUVEC. Resveratrol treatment increased the secretion of nitric oxide stimulated by insulin and decreased the expression of E-selected element and partly counteracts the impairment of high glucose and palmitate acid on the function of endothelial cells. Resveratrol can improve and protect the function of high glucose and fatty acid cultured endothelial cell, and therefore may be a promising medicine in the prevention or therapy of diabetic macrovascular diseases.
doi:10.1016/j.sjbs.2015.06.021
PMCID: PMC4705268  PMID: 26858561
Effect and action mechanism; Resveratrol; Vascular endothelial cell; High glucose
16.  Neural Correlates of Covert Face Processing: fMRI Evidence from a Prosopagnosic Patient 
Cerebral Cortex (New York, NY)  2013;24(8):2081-2092.
Brains can perceive or recognize a face even though we are subjectively unaware of the existence of that face. However, the exact neural correlates of such covert face processing remain unknown. Here, we compared the fMRI activities between a prosopagnosic patient and normal controls when they saw famous and unfamiliar faces. When compared with objects, the patient showed greater activation to famous faces in the fusiform face area (FFA) though he could not overtly recognize those faces. In contrast, the controls showed greater activation to both famous and unfamiliar faces in the FFA. Compared with unfamiliar faces, famous faces activated the controls', but not the patient's lateral prefrontal cortex (LPFC) known to be involved in familiar face recognition. In contrast, the patient showed greater activation in the bilateral medial frontal gyrus (MeFG). Functional connectivity analyses revealed that the patient's right middle fusiform gyrus (FG) showed enhanced connectivity to the MeFG, whereas the controls' middle FG showed enhanced connectivity to the LPFC. These findings suggest that the FFA may be involved in both covert and overt face recognition. The patient's impairment in overt face recognition may be due to the absence of the coupling between the right FG and the LPFC.
doi:10.1093/cercor/bht059
PMCID: PMC4089382  PMID: 23448870
fMRI; face processing; fusiform gyrus; prosopagnosia; covert recognition
17.  Correlation between miR-126 expression and DNA hypomethylation of CD4+ T cells in rheumatoid arthritis patients 
It has been known that the occurrence of rheumatoid arthritis (RA) was closely correlated with DNA hypomethylation in CD4+ T cells, in which DNA methyltransferase plays a certain role. This study therefore investigated the effect of miR-126 on CD4+ T cell subgroup in RA patients and the alternation of DNA hypomethylation, in an attempt to provide new sights into the pathogenesis and treatment of RA. CD4+ T cells separated from RA patients were transfected with miRNA (miR)-126 expression vector or miR-126 inhibitor expression vector. The expression levels of CD11a, CD70 and DNMT1 mRNA were examined by real-time PCR. Protein levels of CD11a and CD70 were tested by flow cytometry while DNMT1 protein level was quantified by Western blotting. DNA was modified by sodium bisulfite and was sequenced for the methylation status of promoters of CD11a and CD70 genes. Both mRNA and protein expressions of CD11a and CD70 genes in CD4+ T cells were elevated by miR-126 transfection, along with decreased DNMT1 protein level but not mRNA level. The methylation degree of promoters of both CD11a and CD70 genes were significantly depressed after miR-126 transfection. The transfection by miR-126 inhibitor effectively reversed such effects. In RA patients, elevated miR-126 may promote the expression of CD11a and CD70 via the induction of hypomethylation of gene promoters by depressing DNMTI1 protein levels.
PMCID: PMC4583866  PMID: 26464634
Rheumatoid arthritis; miRNA-126; CD4+ T cells; DNA methylation
18.  In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging 
Nature Communications  2015;6:7560.
Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications.
Insufficient imaging sensitivity can make it challenging to assess early stage tumour lesions in vivo. Here, the authors present the radiopharmaceutical-excited fluorescence imaging technique that can detect tumour lesions less than 2 mm in size in living mice.
doi:10.1038/ncomms8560
PMCID: PMC4491820  PMID: 26123615
19.  Distinctive effects of CD34- and CD133-specific antibody-coated stents on re-endothelialization and in-stent restenosis at the early phase of vascular injury 
Regenerative Biomaterials  2015;2(2):87-96.
It is not clear what effects of CD34- and CD133-specific antibody-coated stents have on re-endothelialization and in-stent restenosis (ISR) at the early phase of vascular injury. This study aims at determining the capabilities of different coatings on stents (e.g. gelatin, anti-CD133 and anti-CD34 antibodies) to promote adhesion and proliferation of endothelial progenitor cells (EPCs). The in vitro study revealed that the adhesion force enabled the EPCs coated on glass slides to withstand flow-induced shear stress, so that allowing for the growth of the cells on the slides for 48 h. The in vivo experiment using a rabbit model in which the coated stents with different substrates were implanted showed that anti-CD34 and anti-CD133 antibody-coated stents markedly reduced the intima area and restenosis than bare mental stents (BMS) and gelatin-coated stents. Compared with the anti-CD34 antibody-coated stents, the time of cells adhesion was longer and earlier present in the anti-CD133 antibody-coated stents and anti-CD133 antibody-coated stents have superiority in re-endothelialization and inhibition of ISR. In conclusion, this study demonstrated that anti-CD133 antibody as a stent coating for capturing EPCs is better than anti-CD34 antibody in promoting endothelialization and reducing ISR.
doi:10.1093/rb/rbv007
PMCID: PMC4669017  PMID: 26813006
stent; CD133; CD34; endothelial progenitor cells; re-endothelialization
20.  GX1-conjugated poly(lactic acid) nanoparticles encapsulating Endostar for improved in vivo anticolorectal cancer treatment 
Tumor angiogenesis plays a key role in tumor growth and metastasis; thus, targeting tumor-associated angiogenesis is an important goal in cancer therapy. However, the efficient delivery of drugs to tumors remains a key issue in antiangiogenesis therapy. GX1, a peptide identified by phage-display technology, is a novel tumor vasculature endothelium-specific ligand and possesses great potential as a targeted vector and antiangiogenic agent in the diagnosis and treatment of human cancers. Endostar, a novel recombinant human endostatin, has been shown to inhibit tumor angiogenesis. In this study, we developed a theranostic agent composed of GX1-conjugated poly(lactic acid) nanoparticles encapsulating Endostar (GPENs) and labeled with the near-infrared dye IRDye 800CW to improve colorectal tumor targeting and treatment efficacy in vivo. The in vivo fluorescence molecular imaging data showed that GPENs (IRDye 800CW) more specifically targeted tumors than free IRDye 800CW in colorectal tumor-bearing mice. Moreover, the antitumor efficacy was evaluated by bioluminescence imaging and immunohistology, revealing that GPENs possessed improved antitumor efficacy on subcutaneous colorectal xenografts compared to other treatment groups. Thus, our study showed that GPENs, a novel GX1 peptide guided form of nanoscale Endostar, can be used as a theranostic agent to facilitate more efficient targeted therapy and enable real-time monitoring of therapeutic efficacy in vivo.
doi:10.2147/IJN.S82029
PMCID: PMC4454195  PMID: 26060399
GX1 peptide; Endostar; colorectal cancer; angiogenesis; IRDye 800CW; molecular imaging
21.  Seeing Jesus in toast: Neural and behavioral correlates of face pareidolia 
Face pareidolia is the illusory perception of non-existent faces. The present study, for the first time, contrasted behavioral and neural responses of face pareidolia with those of letter pareidolia to explore face-specific behavioral and neural responses during illusory face processing. Participants were shown pure-noise images but were led to believe that 50% of them contained either faces or letters; they reported seeing faces or letters illusorily 34% and 38% of the time, respectively. The right fusiform face area (rFFA) showed a specific response when participants “saw” faces as opposed to letters in the pure-noise images. Behavioral responses during face pareidolia produced a classification image that resembled a face, whereas those during letter pareidolia produced a classification image that was letter-like. Further, the extent to which such behavioral classification images resembled faces was directly related to the level of face-specific activations in the right FFA. This finding suggests that the right FFA plays a specific role not only in processing of real faces but also in illusory face perception, perhaps serving to facilitate the interaction between bottom-up information from the primary visual cortex and top-down signals from the prefrontal cortex (PFC). Whole brain analyses revealed a network specialized in face pareidolia, including both the frontal and occipito-temporal regions. Our findings suggest that human face processing has a strong top-down component whereby sensory input with even the slightest suggestion of a face can result in the interpretation of a face.
doi:10.1016/j.cortex.2014.01.013
PMCID: PMC3980010  PMID: 24583223
face processing; fMRI; fusiform face area; top-down processing; face pareidolia
22.  Connectivity Study of the Neuromechanism of Acute Acupuncture Needling during fMRI in “Overweight” Subjects 
This functional connectivity study depicts how acupoints ST 36 and SP 9 and their sham acupoints acutely act on blood glucose (GLU), core body temperature (CBT), hunger, and sensations pertaining to needling (De-qi) via the limbic system and dopamine (DA) to affect various brain areas in fasting, adult, and “overweight” Chinese males using functional magnetic resonance imaging. Functional connectivity (FC) analysis utilized the amygdala (AMY) and hypothalamus (HYP) as regions of interest (ROIs) in the discrete cosine transform and seed correlation analysis methods. There was a significant difference in the spatial patterns of the distinct brain regions between groups. Correlation results showed that increased HYP-hippocampus FC after ACU was positively correlated with ACU-induced change in CBT; increased HYP-putamen-insula FC after ACU was positively correlated with ACU-induced change in GLU; and increased HYP-anterior cingulate cortex FC after ACU was positively correlated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was probably associated with increased poststimulation limbic system and spinothalamic tract connectivity. Decreased HYP-thalamus FC after ACU was negatively correlated or anticorrelated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was possibly associated with decreased poststimulation limbic system and spinothalamic tract connectivity. No correlation was found for min SHAM. This was an important study in addressing acute acupuncture effects and neural pathways involving physiology and appetite regulation in overweight individuals.
doi:10.1155/2015/384389
PMCID: PMC4363637  PMID: 25821486
23.  Aurora B-dependent phosphorylation of Ataxin-10 promotes the interaction between Ataxin-10 and Plk1 in cytokinesis 
Scientific Reports  2015;5:8360.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurologic disorder caused by ATTCT expansion in the ATXN10 gene. Previous investigations have identified that depletion of Ataxin-10, the gene product, leads to cellular apoptosis and cytokinesis failure. Herein we identify the mitotic kinase Aurora B as an Ataxin-10 interacting partner. Aurora B interacts with and phosphorylates Ataxin-10 at S12, as evidenced by in vitro kinase and mass spectrometry analysis. Both endogenous and S12-phosphorylated Ataxin-10 localizes to the midbody during cytokinesis, and cytokinetic defects induced by inhibition of ATXN10 expression is not rescued by the S12A mutant. Inhibition of Aurora B or expression of the S12A mutant renders reduced interaction between Ataxin-10 and polo-like kinase 1 (Plk1), a kinase previously identified to regulate Ataxin-10 in cytokinesis. Taken together, we propose a model that Aurora B phosphorylates Ataxin-10 at S12 to promote the interaction between Ataxin-10 and Plk1 in cytokinesis. These findings identify an Aurora B-dependent mechanism that implicates Ataxin-10 in cytokinesis.
doi:10.1038/srep08360
PMCID: PMC4322367  PMID: 25666058
24.  Percutaneous Intramyocardial Delivery of Mesenchymal Stem Cells Induces Superior Improvement in Regional Left Ventricular Function Compared with Bone Marrow Mononuclear Cells in Porcine Myocardial Infarcted Heart 
Theranostics  2015;5(2):196-205.
Aim: To investigate the efficacy and feasibility of percutaneous intramyocardial injection of bone marrow mesenchymal stem cells (MSC) and autologous bone marrow-derived mononuclear cells (BMMNC) on cardiac functional improvement in porcine myocardial infarcted hearts. Methods and Results: Acute myocardial infarction (AMI) was induced in 22 minipigs by temporary balloon occlusion of the left anterior descending coronary artery for 60min.Two weeks post AMI, BMMNC (n = 7, 245 ± 98×106), MSC (n = 8, 56 ± 17×106), or phosphate buffered saline (PBS; n = 7) were injected intramyocardially. Cardiac function and myocardial perfusion were analyzed by echocardiography and gated single-photon emission computed tomography/computed tomography (SPECT/CT) at 1 week before AMI and 2 and 10 weeks after AMI. Cell engraftment, proliferation, vascular density, and cardiac fibrosis were evaluated by histology analysis. In all groups, the echocardiography revealed no significant change in the left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), or left ventricular end-diastolic volume (LVEDV) at 10 weeks after AMI compared with those at 2 weeks after AMI. However, the wall motion score index (WMSI) and left ventricular systolic wall thickening (WT%) were significantly improved at 10 weeks compared with those at 2 weeks after AMI in the MSC group (WMSI 1.55 ± 0.06 vs. 1.87 ± 0.10, WT 33.4 ± 2.3% vs.24.8 ± 2.7%,p < 0.05) but not in the BMMNC group. In addition, myocardial perfusion quantified by SPECT/CT was improved in both the MSC and BMMNC groups, whereas the MSC group showed a superior improvement in vascular density and collagen volume fraction (p < 0.05). Conclusion: This preclinically relevant study suggests that when delivered by percutaneous (transcatheter) intramyocardial injection, MSC might be more effective than BMMNC to improve ischemia and reperfusion after AMI.
doi:10.7150/thno.7976
PMCID: PMC4279004  PMID: 25553108
Angiogenesis; Imaging; Myocardial infarction; Remodeling; Stem cells.
25.  Brain-based Correlations Between Psychological Factors and Functional Dyspepsia 
Background/Aims
Increasing evidence shows involvement of psychological disorders in functional dyspepsia (FD), but how psychological factors exert their influences upon FD remains largely unclear. The purpose of the present study was to explore the brain-based correlations of psychological factors and FD.
Methods
Based on Fluorine-18-deoxyglucose positron emission tomography-computed tomography, the altered cerebral glycometabolism was investigated in 40 FD patients compared with 20 healthy controls during resting state using statistical parametric mapping software.
Results
FD patients exhibited increased glucose metabolism in multiple regions relative to controls (P < 0.001, family-wise error corrected). After controlling for the dyspeptic symptoms, increased aberrations persisted within the insula, anterior cingulate cortex (ACC), middle cingulate cortex (MCC) and middle frontal cortex (midFC), which was related to anxiety and depression score. Interestingly, FD patients without anxiety/depression symptoms also showed increased glycometabolism within the insula, ACC, MCC and midFC. Moreover, FD patients with anxiety/depression symptoms exhibited more significant hypermetabolism within the above 4 sites compared with patients without anxiety/depression symptoms.
Conclusions
Our results suggested that the altered cerebral glycometabolism may be in a vicious cycle of psychological vulnerabilities and increased gastrointestinal symptoms.
doi:10.5056/jnm14096
PMCID: PMC4288085  PMID: 25540947
Cerebral cortex; Dyspepsia; Glucose

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