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1.  Label-Free Characterization of Emerging Human Neuronal Networks 
Scientific Reports  2014;4:4434.
The emergent self-organization of a neuronal network in a developing nervous system is the result of a remarkably orchestrated process involving a multitude of chemical, mechanical and electrical signals. Little is known about the dynamic behavior of a developing network (especially in a human model) primarily due to a lack of practical and non-invasive methods to measure and quantify the process. Here we demonstrate that by using a novel optical interferometric technique, we can non-invasively measure several fundamental properties of neural networks from the sub-cellular to the cell population level. We applied this method to quantify network formation in human stem cell derived neurons and show for the first time, correlations between trends in the growth, transport, and spatial organization of such a system. Quantifying the fundamental behavior of such cell lines without compromising their viability may provide an important new tool in future longitudinal studies.
PMCID: PMC3963031  PMID: 24658536
2.  Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men – the role of gut microbiota composition: study protocol for the AELC randomized controlled trial 
BMC Public Health  2014;14:48.
Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects.
A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50–65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3–5 times/week and 30–60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview.
Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases.
Trial registration
Current Controlled Trials: ISRCTN42622771.
PMCID: PMC3897962  PMID: 24438438
Liver fat content; Glucose metabolism; Lipid metabolism; Gut microbiota; Metabonomics; Human; Clinical setting
3.  Microarray Gene Expression Analysis of Tumorigenesis and Regional Lymph Node Metastasis in Laryngeal Squamous Cell Carcinoma 
PLoS ONE  2013;8(12):e84854.
Laryngeal squamous cell carcinoma (LSCC) is the most common type in head and neck squamous cell carcinoma (HNSCC), and the development and progression of LSCC are multistep processes accompanied by changes of molecular biology.
The purpose of this study was to investigate the molecular basis of tumorigenesis and regional lymph node metastasis in LSCC, and provide a set of genes that may be useful for the development of novel diagnostic markers and/or more effective therapeutic strategies.
A total number of 10 patients who underwent surgery for primary laryngeal squamous cell carcinoma were recruited for microarray analysis. LSCC tissues compared with corresponding adjacent non-neoplastic tissues were analysed by Illumina mRNA microarrays, and LSCC tissues with regional lymph node metastasis and LSCC tissues without regional lymph node metastasis were analyzed in the same manner. The most frequently differently expressed genes screened by microarrays were also validated by qRT-PCR in another 42 patients diagnosed for LSCC.
Analysed by Illumina mRNA microarrays, there were 361 genes significantly related to tumorigenesis while 246 genes significantly related to regional lymph node metastasis in LSCC. We found that the six genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4) were most frequently differently expressed functional genes related to tumorigenesis while eIF3a and RPN2 were most frequently differently expressed functional genes related to regional lymph node metastasis in LSCC. The expressions of these genes were also validated by qRT-PCR.
The research revealed a gene expression signature of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. The result will contribute to the understanding of the molecular basis of LSCC and help to improve diagnosis and treatment.
PMCID: PMC3873425  PMID: 24386425
4.  Does Serum 25-Hydroxyvitamin D Influence Muscle Development during Puberty in Girls? - A 7-Year Longitudinal Study 
PLoS ONE  2013;8(12):e82124.
Vitamin D is well known for its regulatory role in calcium and phosphate homeostasis, but its role in muscle mass and strength during growth remains inconclusive. We explored the association of serum 25-hydroxyvitamin D (25(OH)D) with muscle development in girls from 11 to 18-years old. Whole body lean tissue mass (LMWB), appendicular lean mass (aLM), muscle cross-sectional area at the lower leg (mCSA), maximal voluntary contraction of elbow flexors (MVCelbow) and knee extensors (MVCknee) were assessed in 217 girls aged 10–13 years (at baseline), 215 in 2-year and 226 in 7.5-year follow-up. Serum concentration of 25(OH)D and intact parathyroid hormone (PTH) were analyzed retrospectively and girls were categorized according to their 25(OH)D levels (consistently insufficient 25(OH)D GLL <50 nmol/l and consistently sufficient GHH >50 nmol/l from baseline to 7-year follow-up). We found that 25(OH)D level declined until menarche (p<0.05) while LMWB, aLM, mCSA, MVCelbow and MVCknee continued to increase (p<0.001 for all) post menarche. At pre-menarche, the GLL (n = 34) had higher LMWB and aLM than the GHH (n = 21, p<0.05), while post-menarche the GHH (n = 15) had a greater catch-up gain in LMWB (p = 0.004), aLM (p = 0.001) and mCSA (p = 0.027) compared to the GLL (n = 65) over the first 2-year period. At the age of 18, no differences in muscle mass/strength between the low (n = 151) and high (n = 77) levels of 25(OH)D groups were found. This finding was independent of vitamin D receptor genotype and other confounders. In conclusion, our results showed that levels of 25(OH)D have no significant negative influence on the development of muscle mass and strength during pubertal growth both with longitudinal and cross-sectional comparison. On the contrary, our results suggest that the temporary negative association between 25(OH)D and muscle mass arises as a consequence of fast growth prior to menarche, and this negative association is diminished through catch-up growth after menarche.
PMCID: PMC3864869  PMID: 24358145
5.  Assessment of left ventricular dyssynchrony and cardiac function in patients with different pacing modes using real-time three-dimensional echocardiography: Comparison with tissue Doppler imaging 
The aim of this study was to evaluate the left ventricular mechanical dyssynchrony (LVMD) and left ventricular dysfunction of patients in AAI, DDD and VVI pacing modes using real-time three-dimensional echocardiography (RT3DE) and tissue Doppler imaging (TDI). The results from the RT3DE and TDI were subsequently compared. Twenty patients with sick sinus syndrome (SSS) who had undergone the implantation of a dual-chamber pacemaker were enrolled in this study and the pacemakers were programmed to AAI, DDD and VVI modes, sequentially. The RT3DE and TDI parameters were obtained following pacing for 24 h in each mode. With RT3DE, we measured the systolic dyssynchrony indices, including Tmsv16-SD%, Tmsv12-SD%, Tmsv6-SD%, Tmsv16-Dif%, Tmsv12-Dif% and Tmsv6-Dif%, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF), respectively. With TDI, we measured the standard deviation and the maximal difference in time from the QRS onset to the peak systolic velocity for 12 left ventricular myocardial segments, i.e. Ts-SD and Ts-Dif, respectively. The results showed that the Tmsv16-SD% and Ts-SD in the AAI mode were significantly lower than those in the DDD and VVI modes (P<0.05); however, there were no significant differences between the DDD and VVI modes (P>0.05). The LVEF in the AAI, DDD and VVI modes was 63.1±8.9, 58.6±11.2 and 57.9±7.6%, respectively (P>0.05). There were negative correlations between the LVEF and Tmsv16-SD% (r, −0.651; P<0.001) and Ts-SD (r, −0.649; P<0.0001). A moderate correlation (r, 0.698; P<0.0001) was observed between Tmsv16-SD% and Ts-SD. The concordance rate between Tmsv16-SD% and Ts-SD for detecting LVMD was 76%. This study showed that DDD and VVI pacing modes induced significant LVMD and a reduction in LVEF, unlike the AAI pacing mode. RT3DE and TDI were capable of objectively evaluating LVMD; however, each method had certain faults. At present, there is a lack of a uniform standard for assessing LVMD; therefore, the use of a variety of techniques and indices is necessary in order to comprehensively evaluate LVMD in patients with different cardiac pacing modes.
PMCID: PMC3820759  PMID: 24223646
real-time three-dimensional echocardiography; tissue Doppler imaging; cardiac pacing; left ventricular dyssynchrony
6.  Students’ awareness of malaria at the beginning of national malaria elimination programme in China 
Malaria Journal  2013;12:237.
In the battle against malaria in China, the rate of elementary and high school students’ awareness on malaria knowledge is an important index for malaria elimination, but only rare data is available. This study aimed to investigate the level of malaria awareness in students at elementary and high schools in malaria endemic areas of China, and to provide the baseline information for the malaria elimination.
This cross-sectional survey was conducted in 20 different malaria-endemic provinces in the first year of China’s National Malaria Elimination Programme (NMEP). A structured questionnaire was administrated to students at elementary and high schools enrolled. A total of 44,519 questionnaires were effective while 1,220 were excluded because of incomplete survey responses.
More than 60% of students were aware of malaria, but only 9,013 of them answered correctly to all five questions, and there were still 1,862 students unaware of malaria. There were significant differences of the awareness of malaria among different age groups, between male and female, between two different education levels.
The study reveals that students at elementary and high school levels did not have adequate knowledge of malaria about biology, pathogenicity, transmitting vectors and preventive methods and so on at the beginning of NMEP in China. Further emphasis should be paid on health education campaigns in China to increase students’ public awareness of malaria about vector control, treatment, prevention.
PMCID: PMC3723966  PMID: 23844969
Awareness; Malaria; Students; China
7.  A potential threat to malaria elimination: extensive deltamethrin and DDT resistance to Anopheles sinensis from the malaria-endemic areas in China 
Malaria Journal  2013;12:164.
Insecticide resistance in malaria vectors is a growing concern in many countries and requires immediate attention because of the limited chemical arsenal available for vector control. There is lack of systematic and standard monitoring data of malaria vector resistance in the endemic areas, which is essential for the ambitious goal of malaria elimination programme of China.
In 2010, eight provinces from different malaria endemic region were selected for study areas. Bioassays were performed on F1 progeny of Anopheles sinensis reared from wild-caught females using the standard WHO susceptibility test with diagnostic concentrations of 0.25% deltamethrin and 4% DDT.
For An. sinensis, the results indicated that exposure to 0.25% deltamethrin of F1 families with mortalities ranging from 5.96% to 64.54% and less than 80% mortality to DDT at the diagnostic concentration of 4% across the study areas.
Anopheles sinensis was completely resistant to both deltamethrin and DDT, and resistance to pyrethroid has risen strikingly compared to that recorded during 1990s. The results highlight the importance of longitudinal insecticide resistance monitoring and the urgent need for a better understanding of the status of insecticide resistance in this region.
PMCID: PMC3668211  PMID: 23683359
Insecticide resistance; An. sinensis; Malaria-endemic areas
8.  An Update on Antitumor Activity of Naturally Occurring Chalcones 
Chalcones, which have characteristic 1,3-diaryl-2-propen-1-one skeleton, are mainly produced in roots, rhizomes, heartwood, leaves, and seeds of genera Angelica, Sophora, Glycyrrhiza, Humulus, Scutellaria, Parartocarpus, Ficus, Dorstenia, Morus, Artocarpus, and so forth. They have become of interest in the research and development of natural antitumor agents over the past decades due to their broad range of mechanisms including anti-initiation, induction of apoptosis, antiproliferation, antimetastasis, antiangiogenesis, and so forth. This review summarizes the studies on the antitumor activity of naturally occurring chalcones and their underlying mechanisms in detail during the past decades.
PMCID: PMC3652162  PMID: 23690855
9.  Cardiomyocyte Imaging Using Real-Time Spatial Light Interference Microscopy (SLIM) 
PLoS ONE  2013;8(2):e56930.
Spatial light interference microscopy (SLIM) is a highly sensitive quantitative phase imaging method, which is capable of unprecedented structure studies in biology and beyond. In addition to the π/2 shift introduced in phase contrast between the scattered and unscattered light from the sample, 4 phase shifts are generated in SLIM, by increments of π/2 using a reflective liquid crystal phase modulator (LCPM). As 4 phase shifted images are required to produce a quantitative phase image, the switching speed of the LCPM and the acquisition rate of the camera limit the acquisition rate and, thus, SLIM's applicability to highly dynamic samples. In this paper we present a fast SLIM setup which can image at a maximum rate of 50 frames per second and provide in real-time quantitative phase images at 50/4 = 12.5 frames per second. We use a fast LCPM for phase shifting and a fast scientific-grade complementary metal oxide semiconductor (sCMOS) camera (Andor) for imaging. We present the dispersion relation, i.e. decay rate vs. spatial mode, associated with dynamic beating cardiomyocyte cells from the quantitative phase images obtained with the real-time SLIM system.
PMCID: PMC3574023  PMID: 23457641
10.  Association between C1019T polymorphism of the connexin37 gene and coronary heart disease in patients with in-stent restenosis 
Studies have shown that a C1019T polymorphism of the gene encoding the gap junction protein connexin37 is associated with coronary artery disease (CAD). The aim of the present study was to explore the association between the C1019T polymorphism in the connexin37 gene and CAD patients with in-stent restenosis (ISR). A total of 532 patients who had undergone coronary stenting and coronary angiography at least three months after the procedure were divided according to a clinical diagnosis standard into two groups which were ISR (n=67) and no in-stent restenosis (NISR; n=465) groups. A further 501 healthy individuals were controls. The subjects were genotyped by DNA sequencing. The results demonstrated the following: i) connexin37 gene 1019 sites in the population were distributed by polymorphism into three genetic types (CC, TC and TT types). The distribution frequency of the healthy control, ISR and NISR groups conformed to the Hardy-Weinberg genetic balance rule; ii) in comparison with the healthy controls, the frequency of the connexin37 C allele was higher in the CAD patients (57.05% vs. 41.32%; OR, 1.89; 95% CI, 1.58–2.25; P<0.01). The frequency of the C carriers (CC+TC) was 65.47% in the healthy controls, vs. 79.32% in CAD patients (P<0.01). The CAD risk was significantly increased in the carriers of the C allele (CC+TC) compared with TT homozygotes (OR, 2.03; 95% CI, 1.53–2.80; P<0.01). Stratified analysis demonstrated that a significant difference existed in the frequency of C carriers between the male CAD patients and healthy controls (79.63% vs. 72.45%; OR, 1.48; 95% CI, 1.06–2.09, P=0.02), as well as in the female CAD patients (78.00% vs. 51.50%; OR, 3.34; 95% CI, 1.90–5.86; P<0.01). In the female and male CAD patients, the frequency of the connexin37 C allele was higher than in the healthy controls (male: χ2=12.67, P<0.01; female: χ2=50.20, P<0.01); iii) compared with the NISR group, the frequencies of the connexin37 C allele and C carriers (CC+TC) were significantly higher in the ISR group (frequency of C allele: 72.39% vs. 54.84%; P<0.01; frequency of C carriers: 89.55% vs. 77.85%; P=0.03). Compared with TT homozygotes, the restenosis risk was significantly increased in the carriers of the C allele (CC+TC; OR, 2.44; 95% CI, 1.08–5.50). Subsequent stratified analysis revealed that the frequency of the C allele was significantly higher in the male ISR group than in the male NISR group (78.57% vs. 52.66%; OR, 3.30; 95% CI, 2.05–5.29; P<0.01). The restenosis risk was ∼four-fold higher in the C carriers (CC+TC) than in the TT homozygotes (OR, 3.74; 95% CI, 1.32–10.64). However in the female population, there was no difference in the ISR risk between the carriers of the C allele (CC+TC) and the TT homozygotes (P=0.70). In summary, the C allele of the connexin37 gene is not only is associated with the susceptibility to CAD, but also associated with restenosis following coronary stenting in the population studied herein, particularly the male population.
PMCID: PMC3570167  PMID: 23403905
coronary heart disease; in-stent restenosis; connexin37; gene polymorphism
12.  Dispersion-relation phase spectroscopy of intracellular transport 
Optics Express  2011;19(21):20571-20579.
We used quantitative phase imaging to measure the dispersion relation, i.e. decay rate vs. spatial mode, associated with mass transport in live cells. This approach applies equally well to both discrete and continuous mass distributions without the need for particle tracking. From the quadratic experimental curve specific to diffusion, we extracted the diffusion coefficient as the only fitting parameter. The linear portion of the dispersion relation reveals the deterministic component of the intracellular transport. Our data show a universal behavior where the intracellular transport is diffusive at small scales and deterministic at large scales. Measurements by our method and particle tracking show that, on average, the mass transport in the nucleus is slower than in the cytoplasm.
PMCID: PMC3495870  PMID: 21997064
(180.0180) Microscopy; (170.0170) Medical optics and biotechnology; (000.2700) General science
13.  One-dimensional deterministic transport in neurons measured by dispersion-relation phase spectroscopy 
We studied the active transport of intracellular components along neuron processes with a new method developed in our laboratory, dispersion-relation phase spectroscopy. This method is able to quantitatively map spatially the heterogeneous dynamics of the concentration field of the cargos at submicron resolution without the need for tracking individual components. The results in terms of density correlation function reveal that the decay rate is linear in wavenumber, which is consistent with a narrow Lorentzian distribution of cargo velocity.
PMCID: PMC3195397  PMID: 21862838
14.  Diagnostic Significance of Intracystic Nodules on MRI in Rathke's Cleft Cyst 
Background and Purpose. To explore strategies for the diagnosis and treatment of Rathke's cleft cyst (RCC). Methods. The medical records of 24 patients with sellar RCC were retrospectively reviewed. Two patients had concomitant pituitary adenoma, 2 underwent transcranial surgery, and 22 underwent transsphenoidal surgery. The clinical features, especially the findings of intracystic nodules on MRI, were evaluated and compared with the pathological findings. Results. Preoperatively, only 2 patients were diagnosed with RCC or suspected RCC. Pre- and postoperative MRI images revealed 10 intracystic nodules in 9 (37.5%) patients. Two nodules had bull's eyelike changes. The signal intensity of the intracystic nodules varied on T1- and T2-weighted images. Not all nodules on T2-weighted images were visualized. Postoperative MRI revealed recurrence or residual lesion in 5 patients; none had new symptoms and a second surgery was not required. Conclusions. Identifying intracystic nodules is important in patients with sellar cystic lesions. Bull's eyelike change in an intracystic nodule on MRI, which is reported here for the first time, potentially might have value for confirming the diagnosis.
PMCID: PMC3447369  PMID: 23008711
15.  Correction: BCAR1 Protein Plays Important Roles in Carcinogenesis and Predicts Poor Prognosis in Non-Small-Cell Lung Cancer 
PLoS ONE  2012;7(8):10.1371/annotation/384d93a8-eef6-406b-8903-c7009061b496.
PMCID: PMC3435421
16.  Formamido-Diterpenes from the South China Sea Sponge Acanthella cavernosa 
Marine Drugs  2012;10(7):1445-1458.
Seven new formamido-diterpenes, cavernenes A–D (1–4), kalihinenes E and F (5–6), and kalihipyran C (7), together with five known compounds (8–12), were isolated from the South China Sea sponge Acanthella cavernosa. Structures were established using IR, HRESIMS, 1D and 2D NMR, and single X-ray diffraction techniques. The isolated compounds were assessed for their cytotoxicity against a small panel of human cancer cell lines (HCT-116, A549, HeLa, QGY-7701, and MDA-MB-231) with IC50 values in the range of 6–18 μM. In addition, compound 9 showed weak antifungal activity against Trichophyton rubrum and Microsporum gypseum with MIC values of 8 and 32 μg/mL, respectively, compound 10 displayed weak antifungal activity against fungi Candida albicans, Cryptococcus neoformans, T. rubrum, and M. gypseum with MIC values of 8, 8, 4, and 8 μg/mL, respectively.
PMCID: PMC3407923  PMID: 22851918
Acanthella cavernosa; formamido-diterpenes; cytotoxicity; antifungal activity
17.  Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity 
Cardiovascular Research  2010;90(2):344-352.
n-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochrome P450 (CYP) metabolites of n-3 PUFAs remain virtually unexplored. In this study, we examined the effects of docosahexaenoic acid (DHA) on the regulation of large-conductance calcium-activated potassium (BK) channel activities in coronary arterial smooth muscle cells.
Methods and results
Using whole-cell patch-clamp techniques, we found that DHA is a potent activator of BK currents in rat coronary arterial smooth muscle cells with an EC50 of 0.23 ± 0.03 µM. This effect was abolished by pre-incubation with the CYP epoxygenase inhibitor, SKF525A (10 µM). The effects of DHA on the BK channels were reproduced by 16,17-epoxydocosapentaenoic acid (16,17-EpDPE) with an EC50 of 19.7 ± 2.8 nM. The physiological role of the CYP metabolites of DHA was confirmed by measuring DHA-mediated vasodilatation in isolated rat coronary arteries. DHA dilated pressurized isolated coronary arteries in a dose-dependent manner, and the DHA effects were abolished after pre-treatment with SKF525A (10 µM) or with iberiotoxin (100 nM). In addition, 16,17-EpDPE directly produced coronary vasodilatation that was iberiotoxin sensitive.
These results suggest that DHA-mediated vasodilatation is mediated through CYP epoxygenase metabolites by activation of vascular BK channels.
PMCID: PMC3078798  PMID: 21187320
Docosahexaenoic acid; Coronary arterial smooth muscle cell; BK channel; Cytochrome P450 epoxygenase; 16,17-Epoxydocosapentaenoic acid
18.  Urinary Hypoxia-Inducible Factor-1alpha Levels Are Associated with Histologic Chronicity Changes and Renal Function in Patients with Lupus Nephritis 
Yonsei Medical Journal  2012;53(3):587-592.
Tubulointerstitial hypoxia in the kidney is considered a hallmark of injury and a mediator of the progression of tubulointerstitial fibrosis. Hypoxia-inducible factor-1alpha (HIF-1alpha), a master transcription factor in cellular adaptation to hypoxia, regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. The present study set out to characterize urinary HIF-1alpha expressions in patients with lupus nephritis (LN) and to explore whether urinary HIF-1alpha expressions are associated with histologic chronicity changes and renal function.
Materials and Methods
Urinary HIF-1alpha levels were measured by enzyme-linked immunosorbent assays in 42 patients with LN and in 30 healthy controls. Activity and chronicity indexes as well as tubular HIF-1alpha expressions were analyzed for each specimen.
Urinary HIF-1alpha levels were higher in LN patients than in healthy controls (3.977±1.696 vs. 2.153±0.554 ng/mL, p<0.001) and were associated with histologic chronicity indexes (r=0.463, p<0.01) and eGFR (r=-0.324, p<0.05). However, urinary HIF-1alpha levels showed no correlation with histologic activity indexes, anti-dsDNA, ANA, complement 3 and 4 levels, proteinuria, systemic lupus erythematosis disease activity index, and WHO pathological classification (p>0.05).
Urinary HIF-1alpha levels were elevated in LN patients and were associated with histologic chronicity changes and renal function, indicating that HIF-1alpha might contribute to histologic chronicity in LN.
PMCID: PMC3343432  PMID: 22477004
Hypoxia-inducible factor-1alpha; lupus nephritis; histologic chronicity change; renal function
19.  BCAR1 Protein Plays Important Roles in Carcinogenesis and Predicts Poor Prognosis in Non-Small-Cell Lung Cancer 
PLoS ONE  2012;7(4):e36124.
Our previous study suggested the potential clinical implications of BCAR1 in non-small-cell lung cancer (NSCLC) (Mol Diagn Ther. 2011. 15(1): 31–40). Herein, we aim to evaluate the predictive power of BCAR1 as a marker for poor prognosis in NSCLC cases, verify the carcinogenic roles of BCAR1 in the A549 lung adenocarcinoma cell line, and testify to the BCAR1/phospho-p38 axis.
Between January 2006 and June 2010, there were a total of 182 patients with NSCLC (151 cases with available follow up data, and 31 cases lost to follow-up due to the invalid contact information). We inspected BCAR1, phospho-BCAR1(Tyr410), phospho-p38(Thr180/Tyr182) and p38 expression in NSCLC tissues and matched adjacent normal tissues by immunoblotting and IHC. After BCAR1 -RNA interference in A549 cells, we inspected the protein expression (BCAR1, phospho-BCAR1, phospho-p38 and p38) and performed cell biology experiments (cell growth, migration and cycle).
BCAR1 was overexpressed in NSCLC tissues (177/182) and cell lines (A549 and Calu-3). However, it was not detected in the normal adjacent tissue in 161 of the 182 cases. Higher BCAR1 levels were strongly associated with more poorly differentiated NSCLC and predicted poorer prognosis. BCAR1 knockdown caused cell growth arrest, cell migration inhibition and cell cycle arrest of A549 cells. Overexpression of BCAR1 was associated with activation of p38 in NSCLC cases, and BCAR1 knockdown caused reduction of phospho-p38 levels in A549 cells.
Overexpression of BCAR1 is a predictor of poor prognosis in NSCLC and plays important carcinogenic roles in carcinogenesis, probably via activation of p38 MAPK. However, further investigations are required immediately.
PMCID: PMC3338601  PMID: 22558353
20.  SNP set analysis for detecting disease association using exon sequence data 
BMC Proceedings  2011;5(Suppl 9):S91.
Rare variants are believed to play an important role in disease etiology. Recent advances in high-throughput sequencing technology enable investigators to systematically characterize the genetic effects of both common and rare variants. We introduce several approaches that simultaneously test the effects of common and rare variants within a single-nucleotide polymorphism (SNP) set based on logistic regression models and logistic kernel machine models. Gene-environment interactions and SNP-SNP interactions are also considered in some of these models. We illustrate the performance of these methods using the unrelated individuals data from Genetic Analysis Workshop 17. Three true disease genes (FLT1, PIK3C3, and KDR) were consistently selected using the proposed methods. In addition, compared to logistic regression models, the logistic kernel machine models were more powerful, presumably because they reduced the effective number of parameters through regularization. Our results also suggest that a screening step is effective in decreasing the number of false-positive findings, which is often a big concern for association studies.
PMCID: PMC3287933  PMID: 22373133
21.  Retrospective analysis for thirty-nine patients with solitary fibrous tumor of pleura and review of the literature 
Solitary fibrous tumor of the pleura (SFTP) is an uncommon neoplasm arising from mesenchymal cells. The aim of this study is to summarize the experience and the outcome of the surgical treatment for 39 cases of SFTP.
From January 2004 to December 2008, 39 patients underwent surgical resection of SFTP in our department. All patients had clinical follow-up by the same team of surgeons. The mean follow-up was 40.3 months.
A local removal of the neoplasm was accomplished by video-assisted thoracic surgery (VATS) in 9 patients (group A) and by thoracotomy in 30 patients (group B) respectively. Comparing with group B, operations in group A took significantly less operative time, blood loss and spent less time in the intensive care unit and hospital. All specimens were positive for CD34 and Bcl-2. One patient developed recurrence, and the remaining 38 patients are alive and disease free at the end of follow-up.
Malignant SFTP still had the potential recurrence. VATS represents the more acceptable choice for the selected patients with SFTP.
PMCID: PMC3214850  PMID: 22014289
Solitary fibrous tumor; Pleura; Surgical treatment; Prognosis
22.  Regulation of Coronary Arterial BK Channels by Caveolae-Mediated Angiotensin II Signaling in Diabetes Mellitus 
Circulation research  2010;106(6):1164-1173.
The large conductance Ca2+-activated K+ (BK) channel, a key determinant of vascular tone, is regulated by angiotensin II (Ang II) type 1 receptor (AT1R) signaling. Upregulation of Ang II functions and downregulation of BK channel activities have been reported in diabetic vessels. However, the molecular mechanisms underlying Ang II-mediated BK channel modulation, especially in diabetes mellitus, have not been thoroughly examined.
The aim in this study was to determine whether caveolae-targeting facilitates BK channel dysfunction in diabetic vessels.
We found that BK channels, AT1R, Gαq/11, non-phagocytic NAD(P)H oxidases (NOX-1) and c-Src kinases (c-Src) were co-localized in the caveolae of rat arterial smooth muscle cells (SMC) and the integrity of caveolae in SMC was critical for Ang II-mediated BK channel regulation. Most importantly, membrane microdomain targeting of these proteins was upregulated in the caveolae of streptozotocin (STZ)-induced rat diabetic vessels, leading to enhanced Ang II-induced redox-mediated BK channel modification and causing BK channel and coronary dysfunction. The absence of caveolae abolished the effects of Ang II on vascular BK channel activity and preserved BK channel function in diabetes.
These results identified a molecular scheme of receptor-enzyme-channel-caveolae microdomain complex, which facilitates the development of vascular BK channel dysfunction in diabetes.
PMCID: PMC2927991  PMID: 20167931
BK channel; caveolin-1; Angiotensin II; reactive oxygen species; coronary smooth muscle cells
23.  Effective 3D viscoelasticity of red blood cells measured by diffraction phase microscopy 
Biomedical Optics Express  2011;2(3):485-490.
We present optical measurements of nanoscale red blood cell fluctuations obtained by highly sensitive quantitative phase imaging. These spatio-temporal fluctuations are modeled in terms of the bulk viscoelastic response of the cell. Relating the displacement distribution to the storage and loss moduli of the bulk has the advantage of incorporating all geometric and cortical effects into a single effective medium behavior. The results on normal cells indicate that the viscous modulus is much larger than the elastic one throughout the entire frequency range covered by the measurement, indicating fluid behavior.
PMCID: PMC3047354  PMID: 21412454
(000.0000) General; (000.2700) General science
24.  NADPH Oxidase: a Target for the Modulation of the Excessive Oxidase Damage Induced by Overtraining in Rat Neutrophils 
Objective: The purpose of this study is to demonstrate that NADPH oxidase mediating the ROS production is the major pathway for ROS generation in neutrophils during exercise. NADPH oxidase, as a target can modulate oxidative damage induced by overtraining, which can be value to the prevention of exercise-induced immunosuppression.
Methods: Thirty male Wistar rats were randomly divided into three groups: a negative control group (C, n = 10), an overtraining group (E, n = 10) and an overtraining + DPI intervention group (D, n =10). Groups E and D were trained on a standard treadmill with progressive load for 11 weeks. After 36-40 h from the last training, eight rats were randomly selected from each group, and blood was sampled from the orbital vein. ELISAs were used to measure serum cytokine levels and lipid peroxidation in blood plasma. Flow cytometry with Annexin V / PI double staining was used to measure neutrophil apoptosis and necrosis. DNA damage in lymphocytes was tested using single cell gel electrophoresis (SCGE). The co-localization between gp91phox and p47phox of the NADPH-oxidase was detected using immunocytochemistry and confocal microscopy.
Results: 1) Compared with group C, the concentrations of IL-1β, IL-8, and TNF-α were significantly increased and MCP-1, and CINC were significantly decreased in blood plasma from group E (P < 0.01 and P < 0.05, respectively). Concentrations of IL-1β and MCP-1 were decreased (P < 0.05), and IL-8 and TNF-α were significantly increased (P <0.05) in blood plasma from group D. MDA and MPO were elevated in plasma from groups E and D (P < 0.01 and P < 0.05, respectively). 2) Compared with group C, the percentage of neutrophils apoptosis were significantly elevated (P < 0.01) in both groups E and D, and the percentage of cell death was raised in group E (P < 0.05). No significant change was observed in group D. 3) Compared with group C, the number of comet cells, an indicator of DNA damage, was significantly increased (P < 0.01), and the width and tail length of comet cells were notably increased in group E, while no significant increase was observed in group D. 4) The p47phox protein translocated to the cell membrane and co-localized with the gp91phox subunit of NADPH oxidase in neutrophils activated by overtraining.
Conclusion: 1) Excessive exercise led to an increased secretion of inflammatory cytokines and chemokines in peripheral blood, and it may have induced tissue inflammation 2) Overtraining can activate the NADPH oxidase-mediated overproduction of ROS, leading to increased lipid peroxidation. 3) NADPHoxidase in neutrophils as a target, was responsible for ROS, oxidative damage to phagocytes and lymphocytes and changes to inflammatory cytokines and immune regulatory factors all affect cellular immune functions and may be causative factors for exercise-induced immunosuppression.
PMCID: PMC3149282  PMID: 21814483
overtraining; NADPHoxidase; neutrophils; radical oxygen species (ROS); lymphocytes; Cytokine; DNA damage; intervention.
25.  Effect of 5-Aza-2’-deoxycytidine on immune-associated proteins in exosomes from hepatoma 
AIM: To study the effect of 5-Aza-2’-deoxycytidine (5-Aza-CdR) on heat shock protein 70 (HSP70), human leucocyte antigen-I (HLA-I) and NY-ESO-1 proteins in exosomes produced by hepatoma cells, HepG2 and Hep3B.
METHODS: Exosomes derived from HepG2 and Hep3B cells treated with or without 5-aza-CdR were isolated and purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. The number of exosomes was counted under electron microscope. Concentration of proteins in exosomes was measured by bicinchoninic acid protein assay. Expression of HSP70, HLA-I and NY-ESO-1 proteins in exosomes was detected by Western blotting and immunoelectron microscopy. mRNA expression of p53 gene was detected by reverse transcription polymerase chain reaction.
RESULTS: The mRNA expression of p53 gene was increased in both hepatoma cell lines after treatment with 5-Aza-CdR. The number of exosomes and the concentration of total proteins in exosomes were increased significantly after treatment with 5-aza-CdR (P < 0.05). After treatment with 5-Aza-CdR, immunoelectron microscopy and Western blotting showed that the HSP70, HLA-I and NY-ESO-1 proteins were increased in exosomes produced by both hepatoma cell lines.
CONCLUSION: 5-aza-CdR, an inhibitor of DNA methyltransferase, can increase exosomes produced by hepatoma cells and immune-associated protein component of exosomes, which may be mediated by p53 gene up-regulation and 5-Aza-CdR demethylation.
PMCID: PMC2874141  PMID: 20480522
5-Aza-2’-deoxycytidine; Exosome; Immunomolecule; Hepatoma cell

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