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1.  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.
PMCID: PMC4322367  PMID: 25666058
2.  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.
PMCID: PMC4279004  PMID: 25553108
Angiogenesis; Imaging; Myocardial infarction; Remodeling; Stem cells.
3.  Brain-based Correlations Between Psychological Factors and Functional Dyspepsia 
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.
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.
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.
Our results suggested that the altered cerebral glycometabolism may be in a vicious cycle of psychological vulnerabilities and increased gastrointestinal symptoms.
PMCID: PMC4288085  PMID: 25540947
Cerebral cortex; Dyspepsia; Glucose
4.  In-vivo Optical Tomography of Small Scattering Specimens: time-lapse 3D imaging of the head eversion process in Drosophila melanogaster 
Scientific Reports  2014;4:7325.
Even though in vivo imaging approaches have witnessed several new and important developments, specimens that exhibit high light scattering properties such as Drosophila melanogaster pupae are still not easily accessible with current optical imaging techniques, obtaining images only from subsurface features. This means that in order to obtain 3D volumetric information these specimens need to be studied either after fixation and a chemical clearing process, through an imaging window - thus perturbing physiological development -, or during early stages of development when the scattering contribution is negligible. In this paper we showcase how Optical Projection Tomography may be used to obtain volumetric images of the head eversion process in vivo in Drosophila melanogaster pupae, both in control and headless mutant specimens. Additionally, we demonstrate the use of Helical Optical Projection Tomography (hOPT) as a tool for high throughput 4D-imaging of several specimens simultaneously.
PMCID: PMC4255187  PMID: 25471694
5.  Th17/Treg Cells Imbalance and GITRL Profile in Patients with Hashimoto’s Thyroiditis 
Hashimoto’s thyroiditis (HT) is an organ-specific immune disease characterized by the presence of lymphocytic infiltration and serum autoantibodies. Previous studies have confirmed the critical role of Th17 cells in the pathopoiesis of HT patients. Additionally, regulatory T cells (Treg) display a dysregulatory function in autoimmune disease. The purpose of this study is to investigate the alteration of Th17 and Treg cells in HT patients and explore contributing factors. We found there was an increased ratio of Th17/Treg in HT patients and a positive correlation with autoantibodies (anti-TgAb). In addition, there was an increased level of GITRL, which has been demonstrated to be correlated with the increassement of Th17 cells in the serum and thyroid glands of HT patients; the upregulated serum level of GITRL has a positive correlation with the percentage of Th17 cells in HT patients. In summary, an increase in GITRL may impair the balance of Th17/Treg, and contribute to the pathopoiesis of Hashimoto’s thyroiditis.
PMCID: PMC4284671  PMID: 25429429
Hashimoto’s thyroiditis; Th17 cells; Treg cells; GITRL
6.  Obesity: Pathophysiology and Intervention 
Nutrients  2014;6(11):5153-5183.
Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity.
PMCID: PMC4245585  PMID: 25412152
obesity; food addiction; neuroendocrinology; neuroimaging; reward-saliency; motivation-drive; learning/memory circuit; inhibitory control-emotional regulation-executive control; bariatric surgery; fecal microbiota transplantation
7.  Performance evaluation of endoscopic Cerenkov luminescence imaging system: in vitro and pseudotumor studies 
Biomedical Optics Express  2014;5(10):3660-3670.
By integrating the clinically used endoscope with the emerging Cerenkov luminescence imaging (CLI) technology, a new endoscopic Cerenkov luminescence imaging (ECLI) system was developed. The aim is to demonstrate the potential of translating CLI to clinical studies of gastrointestinal (GI) tract diseases. We systematically evaluated the feasibility and performance of the developed ECLI system with a series of in vitro and pseudotumor experiments. The ECLI system is comprised of an electron multiplying charge coupled device (EMCCD) camera coupled with a clinically used endoscope via an optical adapter. A 1951-USAF test board was used to measure the white-light lateral resolution, while a homemade test chart filled with 68Ga was employed to measure the CL lateral resolution. Both in vitro and pseudotumor experiments were conducted to obtain the sensitivity of the ECLI system. The results were validated with that of CLI using EMCCD only, and the relative attenuation ratio of the ECLI system was calculated. Results showed that The white-light lateral resolution of the ECLI system was 198 µm, and the luminescent lateral resolution was better than 1 mm. Sensitivity experiments showed a theoretical sensitivity of 0.186 KBq/μl (5.033×10−3 μCi/μl) and 1.218 KBq/μl (32.922×10−3 μCi/μl) for the in vitro and pseudotumor studies, respectively. The relative attenuation ratio of ECLI to CLI was about 96%. The luminescent lateral resolution of the ECLI system was comparable with that of positron emission tomography (PET). The pseudotumor study illustrated the feasibility and applicability of the ECLI system in living organisms, indicating the potential for translating the CLI technology to the clinic.
PMCID: PMC4206332  PMID: 25360380
(170.3660) Light propagation in tissues; (170.7050) Turbid media; (170.6935) Tissue characterization
8.  Inhibition of Histone H3K9 Acetylation by Anacardic Acid Can Correct the Over-Expression of Gata4 in the Hearts of Fetal Mice Exposed to Alcohol during Pregnancy 
PLoS ONE  2014;9(8):e104135.
Cardiovascular malformations can be caused by abnormalities in Gata4 expression during fetal development. In a previous study, we demonstrated that ethanol exposure could lead to histone hyperacetylation and Gata4 over-expression in fetal mouse hearts. However, the potential mechanisms of histone hyperacetylation and Gata4 over-expression induced by ethanol remain unclear.
Methods and Results
Pregnant mice were gavaged with ethanol or saline. Fetal mouse hearts were collected for analysis. The results of ethanol fed groups showed that global HAT activity was unusually high in the hearts of fetal mice while global HDAC activity remained unchanged. Binding of P300, CBP, PCAF, SRC1, but not GCN5, were increased on the Gata4 promoter relative to the saline treated group. Increased acetylation of H3K9 and increased mRNA expression of Gata4, α-MHC, cTnT were observed in these hearts. Treatment with the pan-histone acetylase inhibitor, anacardic acid, reduced the binding of P300, PCAF to the Gata4 promoter and reversed H3K9 hyperacetylation in the presence of ethanol. Interestingly, anacardic acid attenuated over-expression of Gata4, α-MHC and cTnT in fetal mouse hearts exposed to ethanol.
Our results suggest that P300 and PCAF may be critical regulatory factors that mediate Gata4 over-expression induced by ethanol exposure. Alternatively, P300, PCAF and Gata4 may coordinate over-expression of cardiac downstream genes in mouse hearts exposed to ethanol. Anacardic acid may thus protect against ethanol-induced Gata4, α-MHC, cTnT over-expression by inhibiting the binding of P300 and PCAF to the promoter region of these genes.
PMCID: PMC4125174  PMID: 25101666
9.  Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction 
PLoS ONE  2014;9(7):e101769.
Elderly people often suffer from sarcopenia in their lower extremities, which gives rise to the increased susceptibility of fall. Comparing the mechanical properties of the knee extensor/flexors on elderly and young subjects is helpful in understanding the underlying mechanisms of the muscle aging process. However, although the stiffness of skeletal muscle has been proved to be positively correlated to its non-fatiguing contraction intensity by some existing methods, this conclusion has not been verified above 50% maximum voluntary contraction (MVC) due to the limitation of their measurement range. In this study, a vibro-ultrasound system was set up to achieve a considerably larger measurement range on muscle stiffness estimation. Its feasibility was verified on self-made silicone phantoms by comparing with the mechanical indentation method. The system was then used to assess the stiffness of vastus intermedius (VI), one of the knee extensors, on 10 healthy elderly female subjects (56.7±4.9 yr) and 10 healthy young female subjects (27.6±5.0 yr). The VI stiffness in its action direction was confirmed to be positively correlated to the % MVC level (R2 = 0.999) over the entire range of isometric contraction, i.e. from 0% MVC (relaxed state) to 100% MVC. Furthermore, it was shown that there was no significant difference between the mean VI shear modulus of the elderly and young subjects in a relaxed state (p>0.1). However, when performing step isometric contraction, the VI stiffness of young female subjects was found to be larger than that of elderly participants (p<0.001), especially at the relatively higher contraction levels. The results expanded our knowledge on the mechanical property of the elderly’s skeletal muscle and its relationship with intensity of active contraction. Furthermore, the vibro-ultrasound system has a potential to become a powerful tool for investigating the elderly’s muscle diseases.
PMCID: PMC4081795  PMID: 24991890
10.  Ficus carica Polysaccharides Promote the Maturation and Function of Dendritic Cells 
Various polysaccharides purified from plants are considered to be biological response modifiers and have been shown to enhance immune responses. Ficus carica L. is a Chinese traditional plant and has been widely used in Asian countries for its anti-tumor properties. Ficus carica polysaccharides (FCPS), one of the most essential and effective components in Ficus carica L., have been considered to be a beneficial immunomodulator and may be used in immunotherapy. However, the immunologic mechanism of FCPS is still unclear. Dectin-1 is a non-toll-like pattern recognition receptor, predominately expressed on dendritic cells (DCs). Activation of DCs through dectin-1 signaling can lead to the maturation of DC, thus inducing both innate and adaptive immune responses against tumor development and microbial infection. In our study, we found that FCPS could effectively stimulate DCs, partially through the dectin-1/Syk pathway, and promote their maturation, as shown by the up-regulation of CD40, CD80, CD86, and major histocompatibility complex II (MHCII). FCPS also enhanced the production of cytokines by DCs, including IL-12, IFN-γ, IL-6, and IL-23. Moreover, FCPS-treated DCs showed an enhanced capability to stimulate T cells and promote T cell proliferation. Altogether, these results demonstrate that FCPS are able to activate and maturate DCs, thereby up-regulating the immunostimulatory capacity of DCs, which leads to enhanced T cell responses.
PMCID: PMC4139854  PMID: 25026176
polysaccharide; dendritic cells; dectin-1; Syk; immunomodulators
11.  Exploring the Patterns of Acupuncture on Mild Cognitive Impairment Patients Using Regional Homogeneity 
PLoS ONE  2014;9(6):e99335.
To investigate the different responses to acupuncture in MCI patients and age-matched healthy subjects reflected by the Regional Homogeneity (ReHo) indices.
The experiment was performed at the acupoint KI3 in 12 MCI patients and 12 healthy controls, respectively. A novel non-repeated event-related (NRER) fMRI design paradigm was applied to separately detect neural activities related to different stages of acupuncture (pre-acupuncture resting state, needling manipulation and post-acupuncture resting state). ReHo values were calculated for MCI patients and healthy controls in pre- and post-acupuncture resting state. Then, a two-way ANCOVA with repeated measures with post-hoc two sample t-tests was performed to explore the different responses to acupuncture in the two groups.
The ANCOVA revealed a significant main effect of group, but no significant main effect of acupuncture and interactions between group and acupuncture. During the pre-acupuncture resting state, ReHo values increased in the precentral gyrus (PCG), superior frontal gyrus (SFG), and insula (INS) and decreased mainly in middle temporal gyrus (MTG), parahippocampal (PHIP) and cingulate cortex in MCI patients compared with healthy controls. Furthermore, we found that the regions including precuneus (PCUN), and cingulate cortex showed increased ReHo values for MCI patients following acupuncture. For healthy controls, the medial frontal gyrus, PCG, anterior cingulate cortex (ACC) and INS showed enhanced ReHo values following acupuncture. During the post-acupuncture resting state, MCI patients showed increased ReHo values mainly in the MTG, superior parietal lobule (SPL), middle frontal gyrus (MFG), supramarginal (SMG), and PCG, and decreased ReHo values mainly in the frontal regions, PHIP, and posterior cingulated cortex (PCC) compared to healthy controls.
Though we found some ReHo changes between MCI patients and healthy controls, the two-way ANCOVA results showed no significant effects after multiple corrections. Further study is needed to reveal the real acupuncture effects on MCI patients.
PMCID: PMC4072601  PMID: 24968124
12.  Probability method for Cerenkov luminescence tomography based on conformance error minimization 
Biomedical Optics Express  2014;5(7):2091-2112.
Cerenkov luminescence tomography (CLT) was developed to reconstruct a three-dimensional (3D) distribution of radioactive probes inside a living animal. Reconstruction methods are generally performed within a unique framework by searching for the optimum solution. However, the ill-posed aspect of the inverse problem usually results in the reconstruction being non-robust. In addition, the reconstructed result may not match reality since the difference between the highest and lowest uptakes of the resulting radiotracers may be considerably large, therefore the biological significance is lost. In this paper, based on the minimization of a conformance error, a probability method is proposed that consists of qualitative and quantitative modules. The proposed method first pinpoints the organ that contains the light source. Next, we developed a 0-1 linear optimization subject to a space constraint to model the CLT inverse problem, which was transformed into a forward problem by employing a region growing method to solve the optimization. After running through all of the elements used to grow the sources, a source sequence was obtained. Finally, the probability of each discrete node being the light source inside the organ was reconstructed. One numerical study and two in vivo experiments were conducted to verify the performance of the proposed algorithm, and comparisons were carried out using the hp-finite element method (hp-FEM). The results suggested that our proposed probability method was more robust and reasonable than hp-FEM.
PMCID: PMC4102351  PMID: 25071951
(100.3190) Inverse problems; (110.6960) Tomography; (170.3010) Image reconstruction techniques; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6280) Spectroscopy, fluorescence and luminescence
13.  Altered functional brain networks in Prader–Willi syndrome 
NMR in biomedicine  2013;26(6):10.1002/nbm.2900.
Prader–Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.
PMCID: PMC3776442  PMID: 23335390
Prader; Willi syndrome; eating disorder; obesity; amplitude of low-frequency fluctuation; resting-state networks; functional MRI
14.  Incorporating MRI structural information into bioluminescence tomography: system, heterogeneous reconstruction and in vivo quantification 
Biomedical Optics Express  2014;5(6):1861-1876.
Combining two or more imaging modalities to provide complementary information has become commonplace in clinical practice and in preclinical and basic biomedical research. By incorporating the structural information provided by computed tomography (CT) or magnetic resonance imaging (MRI), the ill poseness nature of bioluminescence tomography (BLT) can be reduced significantly, thus improve the accuracies of reconstruction and in vivo quantification. In this paper, we present a small animal imaging system combining multi-view and multi-spectral BLT with MRI. The independent MRI-compatible optical device is placed at the end of the clinical MRI scanner. The small animal is transferred between the light tight chamber of the optical device and the animal coil of MRI via a guide rail during the experiment. After the optical imaging and MRI scanning procedures are finished, the optical images are mapped onto the MRI surface by interactive registration between boundary of optical images and silhouette of MRI. Then, incorporating the MRI structural information, a heterogeneous reconstruction algorithm based on finite element method (FEM) with L 1 normalization is used to reconstruct the position, power and region of the light source. In order to validate the feasibility of the system, we conducted experiments of nude mice model implanted with artificial light source and quantitative analysis of tumor inoculation model with MDA-231-GFP-luc. Preliminary results suggest the feasibility and effectiveness of the prototype system.
PMCID: PMC4052915  PMID: 24940545
(110.0110) Imaging systems; (170.3880) Medical and biological imaging; (110.6955) Tomographic imaging
15.  Adipose Tissue Dendritic Cells Enhances Inflammation by Prompting the Generation of Th17 Cells 
PLoS ONE  2014;9(3):e92450.
Obesity has become a global challenge for public health. It has been reported that obesity is associated with chronic inflammation. However, the mechanism for the chronic inflammation contributes to obesity remains elusive.
Methodology/Principal Findings
In our study, we found a novel CD11c+ dendritic cell subset existed in murine adipose tissues which was immature phenotype. Moreover, as compared to the lean controls, the number of CD11c+ DCs and CD4+IL-17+T cells were higher in adipose tissue of high fat diet (HFD) mice. Adipose tissues derived dendritic cells (ATDCs) displayed lower levels of CD40, CD80, CD86, MHCI and MHCII expression than splenic DCs (SPDCs). However, ATDCs showed higher levels of IL-6, TGF-β and IL-23 secretion. Moreover, our in vitro experiments demonstrated that ATDCs were capable of promoting Th17 cell generation.
Our results indicate the existence of CD11c+ DCs in adipose tissues, which displays an immature phenotype but possessing pro-inflammatory function.
PMCID: PMC3958510  PMID: 24642966
16.  Islet-1 promotes the cardiac-specific differentiation of mesenchymal stem cells through the regulation of histone acetylation 
The aim of the present study was to investigate the effects of Islet-1 on the process of mesenchymal stem cell (MSC) differentiation into cardiomyocyte-like cells and to elucidate the possible mechanisms involved. Lentiviral vectors expressing Islet-1 (Lenti-Islet-1) were constructed and used for C3H10T1/2 cell transfection. Cell morphology was observed. Cardiac-related genes and proteins were detected by qPCR and western blot analysis. Epigallocatechin gallate (EGCG) was used as an inhibitor of acetylated histone H3 (AcH3). AcH3 was detected by chromatin immunoprecipitation. Cells overexpressing Islet-1 tended to change into fibroblast-like cells and were arranged in the same direction. The enhanced expression of GATA binding protein 4 (Gata4), NK2 homeobox 5 (Nkx2.5), myocyte enhancer factor 2C (Mef2c) and cardiac troponin T (cTnT) was observed in the cells overexpressing Islet-1 following transfection with Lenti-Islet-1. However, the expression of hepatocyte-, bone- and neuronal-specific markers was not affected by Islet-1. The AcH3 relative amount increased following transfection with Lenti-Islet-1, which was associated with the enhanced expression of Gata4, Nkx2.5 and Mef2c in these cells. The expression of Gata4, Nkx2.5 and Mef2c in the C3H10T1/2 cells transfected with Lenti-Islet-1 and treated with EGCG was reduced following treatment with EGCG. The data presented in this study indicate that Islet-1 specifically induces the differentiation of C3H10T1/2 cells into cardiomyocyte-like cells, and one of the mechanisms involved is the regulation of histone acetylation.
PMCID: PMC4020474  PMID: 24604334
mesenchymal stem cells; cardiomyocyte; differentiation; histone acetylation
17.  Automated Delineation of Lung Tumors from CT Images Using a Single Click Ensemble Segmentation Approach 
Pattern recognition  2013;46(3):692-702.
A single click ensemble segmentation (SCES) approach based on an existing “Click&Grow” algorithm is presented. The SCES approach requires only one operator selected seed point as compared with multiple operator inputs, which are typically needed. This facilitates processing large numbers of cases. Evaluation on a set of 129 CT lung tumor images using a similarity index (SI) was done. The average SI is above 93% using 20 different start seeds, showing stability. The average SI for 2 different readers was 79.53%. We then compared the SCES algorithm with the two readers, the level set algorithm and the skeleton graph cut algorithm obtaining an average SI of 78.29%, 77.72%, 63.77% and 63.76% respectively. We can conclude that the newly developed automatic lung lesion segmentation algorithm is stable, accurate and automated.
PMCID: PMC3580869  PMID: 23459617
Image Features; Delineation; Lung Tumor; Lesion; CT; Region growing; Ensemble Segmentation
18.  Estimates of Forest Biomass Carbon Storage in Liaoning Province of Northeast China: A Review and Assessment 
PLoS ONE  2014;9(2):e89572.
Accurate estimates of forest carbon storage and changes in storage capacity are critical for scientific assessment of the effects of forest management on the role of forests as carbon sinks. Up to now, several studies reported forest biomass carbon (FBC) in Liaoning Province based on data from China's Continuous Forest Inventory, however, their accuracy were still not known. This study compared estimates of FBC in Liaoning Province derived from different methods. We found substantial variation in estimates of FBC storage for young and middle-age forests. For provincial forests with high proportions in these age classes, the continuous biomass expansion factor method (CBM) by forest type with age class is more accurate and therefore more appropriate for estimating forest biomass. Based on the above approach designed for this study, forests in Liaoning Province were found to be a carbon sink, with carbon stocks increasing from 63.0 TgC in 1980 to 120.9 TgC in 2010, reflecting an annual increase of 1.9 TgC. The average carbon density of forest biomass in the province has increased from 26.2 Mg ha−1 in 1980 to 31.0 Mg ha−1 in 2010. While the largest FBC occurred in middle-age forests, the average carbon density decreased in this age class during these three decades. The increase in forest carbon density resulted primarily from the increased area and carbon storage of mature forests. The relatively long age interval in each age class for slow-growing forest types increased the uncertainty of FBC estimates by CBM-forest type with age class, and further studies should devote more attention to the time span of age classes in establishing biomass expansion factors for use in CBM calculations.
PMCID: PMC3934887  PMID: 24586881
19.  CITED2 Mutation and methylation in children with congenital heart disease 
The occurrence of Congenital Heart Disease (CHD) is resulted from either genetic or environmental factors or the both. The CITED2 gene deletion or mutation is associated with the development of cardiac malformations. In this study, we have investigated the role of CITED2 gene mutation and methylation in the development of Congenital Heart Disease in pediatric patients in China.
We have screened 120 pediatric patients with congenital heart disease. Among these patients, 4 cases were detected to carry various CITED2 gene heterozygous mutations (c.550G > A, c.574A > G, c.573-578del6) leading correspondingly to the alterations of amino acid sequences in Gly184Ser, Ser192Gly, and Ser192fs, respectively. No CITED2 gene mutations were detected in the control group. At the same time, we found that CITED2 mutations could inhibit TFAP2c expression. In addition, we have demonstrated that abnormal CITED2 gene methylation was detected in most of the tested pediatric patients with CHD, which leads to a decrease of CITED2 transcription activities.
Our study suggests that CITED2 gene mutations and methylation may play an important role in the development of pediatric congenital heart disease.
PMCID: PMC3917535  PMID: 24456003
CITED2; Mutation; Methylation; Congenital heart disease
20.  Comprehensive Evaluation of the Anti-Angiogenic and Anti-Neoplastic Effects of Endostar on Liver Cancer through Optical Molecular Imaging 
PLoS ONE  2014;9(1):e85559.
Molecular imaging enables non-invasive monitoring of tumor growth, progression, and drug treatment response, and it has become an important tool to promote biological studies in recent years. In this study, we comprehensively evaluated the in vivo anti-angiogenic and anti-neoplastic effects of Endostar on liver cancer based on the optical molecular imaging systems including micro-computer tomography (Micro-CT), bioluminescence molecular imaging (BLI) and fluorescence molecular tomography (FMT). Firefly luciferase (fLuc) and green fluorescent protein (GFP) dual labeled human hepatocellular carcinoma cells (HCC-LM3-fLuc-GFP cells) were used to establish the subcutaneous and orthotopic liver tumor model. After the tumor cells were implanted 14∼18 days, Endostar (5 mg/kg/day) was administered through an intravenous tail vein injection for continuous 14 days. The computer tomography angiography (CTA) and BLI were carried out for the subcutaneous tumor model. FMT was executed for the orthotopic tumor model. The CTA data showed that tumor vessel formation and the peritumoral vasculature of subcutaneous tumor in the Endostar treatment group was significantly inhibited compared to the control group. The BLI data exhibited the obvious tumor inhibition day 8 post-treatment. The FMT detected the tumor suppression effects of Endostar as early as day 4 post-treatment and measured the tumor location. The above data confirmed the effects of Endostar on anti-angiogenesis and tumor suppression on liver cancer. Our system combined CTA, BLI, and FMT to offer more comprehensive information about the effects of Endostar on the suppression of vessel and tumor formation. Optical molecular imaging system enabled the non-invasive and reliable assessment of anti-tumor drug efficacy on liver cancer.
PMCID: PMC3885728  PMID: 24416426
21.  Fast and robust reconstruction for fluorescence molecular tomography via a sparsity adaptive subspace pursuit method 
Biomedical Optics Express  2014;5(2):387-406.
Fluorescence molecular tomography (FMT), as a promising imaging modality, can three-dimensionally locate the specific tumor position in small animals. However, it remains challenging for effective and robust reconstruction of fluorescent probe distribution in animals. In this paper, we present a novel method based on sparsity adaptive subspace pursuit (SASP) for FMT reconstruction. Some innovative strategies including subspace projection, the bottom-up sparsity adaptive approach, and backtracking technique are associated with the SASP method, which guarantees the accuracy, efficiency, and robustness for FMT reconstruction. Three numerical experiments based on a mouse-mimicking heterogeneous phantom have been performed to validate the feasibility of the SASP method. The results show that the proposed SASP method can achieve satisfactory source localization with a bias less than 1mm; the efficiency of the method is much faster than mainstream reconstruction methods; and this approach is robust even under quite ill-posed condition. Furthermore, we have applied this method to an in vivo mouse model, and the results demonstrate the feasibility of the practical FMT application with the SASP method.
PMCID: PMC3920871  PMID: 24575335
(100.3010) Image reconstruction techniques; (100.3190) Inverse problems; (110.6955) Tomographic imaging; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (290.1990) Diffusion; (290.7050) Turbid media
22.  Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology 
Theranostics  2014;4(11):1072-1084.
Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.
PMCID: PMC4165775  PMID: 25250092
Optical molecular imaging; Intraoperative imaging-guided cancer surgery; Near-infrared fluorescence; Multi-modality Imaging; Indocyanine green.
23.  Influence of Acupuncture Stimulation on Cerebral Network in Functional Diarrhea 
Acupuncture is a commonly used therapy for treating functional diarrhea (FD), although there is limited knowledge on the mechanism. The objectives of this study were to investigate the differences in brain activities elicited by acupuncture between FD patients and healthy controls (HC) so as to explore the possible mechanism. Eighteen FD patients and eighteen HC received 10 sessions of acupuncture treatment at ST25 acupoints. Functional magnetic resonance imaging (fMRI) scans were, respectively, performed before and after acupuncture. The defecation frequency, Bristol stool form scale (SBFS), and MOS 36-item Short Healthy Survey (SF-36) were employed to evaluate the clinical efficacy. After acupuncture, the FD patients showed a significant decrease in defecation frequency and BSFS score. The regional homogeneity (ReHo) map showed a decrease in the paracentral lobule and postcentral gyrus, and an increase in the angular gyrus, insula, anterior cingulate cortex (ACC), and precuneus in the FD group. Moreover, the changes in ReHo values in the ACC were correlated with the reduction in defecation frequency. Decreasing functional connectivity among the ACC, insula, thalamus, and orbital frontal cortex only existed in the FD group. Conclusively, acupuncture alleviated defecation frequency and improved stool formation in FD patients. The efficacy might result from the regulation of the homeostasis afferent processing network.
PMCID: PMC3888684  PMID: 24459533
24.  Use of Indocyanine Green for Detecting the Sentinel Lymph Node in Breast Cancer Patients: From Preclinical Evaluation to Clinical Validation 
PLoS ONE  2013;8(12):e83927.
Assessment of the sentinel lymph node (SLN) in patients with early stage breast cancer is vital in selecting the appropriate surgical approach. However, the existing methods, including methylene blue and nuclides, possess low efficiency and effectiveness in mapping SLNs, and to a certain extent exert side effects during application. Indocyanine green (ICG), as a fluorescent dye, has been proved reliable usage in SLN detection by several other groups. In this paper, we introduce a novel surgical navigation system to detect SLN with ICG. This system contains two charge-coupled devices (CCD) to simultaneously capture real-time color and fluorescent video images through two different bands. During surgery, surgeons only need to follow the fluorescence display. In addition, the system saves data automatically during surgery enabling surgeons to find the registration point easily according to image recognition algorithms. To test our system, 5 mice and 10 rabbits were used for the preclinical setting and 22 breast cancer patients were utilized for the clinical evaluation in our experiments. The detection rate was 100% and an average of 2.7 SLNs was found in 22 patients. Our results show that the usage of our surgical navigation system with ICG to detect SLNs in breast cancer patients is technically feasible.
PMCID: PMC3865279  PMID: 24358319
25.  Transgenic Insulin-like Growth Factor-1 stimulates activation of COX-2 signaling in mammary glands 
Molecular carcinogenesis  2011;51(12):973-983.
Studies show that elevated IGF-1 levels are associated with an increased risk of breast cancer; however, mechanisms through which IGF-1 promotes mammary tumorigenesis in vivo have not been fully elucidated. To assess the possible involvement of COX-2 signaling in the protumorigenic effects of IGF-1 in mammary glands, we used the unique BK5.IGF-1 mouse model in which transgenic (Tg) mice have significantly increased incidence of spontaneous and DMBA–induced mammary cancer compared to wild type (WT) littermates. Studies revealed that COX-2 expression was significantly increased in Tg mammary glands and tumors, compared to age-matched WTs. Consistent with this, PGE2 levels were also increased in Tg mammary glands. Analysis of expression of the EP receptors that mediate the effects of PGE2 showed that among the four G-protein-coupled receptors, EP3 expression was elevated in Tg glands. Up-regulation of the COX-2/PGE2/EP3 pathway was accompanied by increased expression of VEGF and a striking enhancement of angiogenesis in IGF-1 Tg mammary glands. Treatment with celecoxib, a selective COX-2 inhibitor, caused a 45% reduction in mammary PGE2 levels, attenuated the influx of mast cells and reduced vascularization in Tg glands. These findings indicate that the COX-2/PGE2/EP3 signaling pathway is involved in IGF-1–stimulated mammary tumorigenesis and that COX-2–selective inhibitors may be useful in the prevention or treatment of breast cancer associated with elevated IGF-1 levels in humans.
PMCID: PMC3790642  PMID: 22006370
mammary cancer; IGF-1; COX-2; stroma; transgenic mouse

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