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1.  On-line monitoring of oxygen in Tubespin, a novel, small-scale disposable bioreactor 
Cytotechnology  2011;63(4):345-350.
A novel, optical sensor was fixed in a new type of disposable bioreactor, Tubespin, for the on-line (real-time) monitoring of dissolved oxygen concentrations during cell culture. The cell density, viability and volumetric mass transfer coefficient were also determined to further characterize the bioreactors. The kLa value of the Tubespin at standard conditions was 24.3 h−1, while that of a spinner flask was only 2.7 h−1. The maximum cell density in the Tubespin bioreactor reached 6 × 106 cells mL−1, which was two times higher than the cell density in a spinner flask. Furthermore, the dynamic dissolved oxygen level was maintained above 90% air-saturation in the Tubespin, while the value was only 1.9% in a spinner flask. These results demonstrate the competitive advantage of using the Tubespin system over spinner flasks for process optimization and scale-down studies of oxygen transfer and cell growth.
PMCID: PMC3140833  PMID: 21574065
Tubespin; Spinner flask; Dissolved oxygen; kLa
2.  The Mechanism of Poly-Galloyl-Glucoses Preventing Influenza A Virus Entry into Host Cells 
PLoS ONE  2014;9(4):e94392.
Hemagglutinin (HA) is essential for Influenza A virus infection, but its diversity of subtypes presents an obstacle to developing broad-spectrum HA inhibitors. In this study, we investigated the molecular mechanisms by which poly-galloyl glucose (pGG) analogs inhibit influenza hemagglutinin (HA) in vitro and in silico. We found that (1) star-shaped pGG analogs exhibit HA-inhibition activity by interacting with the conserved structural elements of the receptor binding domain (RBD); (2) HA inhibition depends on the number of galloyl substituents in a pGG analog; the best number is four; and when PGG binds with two HA trimers at their conserved receptor binding domains (loop 130, loop 220, and 190-α-helix), PGG acts as a molecular glue by aggregating viral particles so as to prevent viral entry into host cells (this was revealed via an in silico simulation on the binding of penta-galloyl-glucose (PGG) with HA). pGGs are also effective on a broad-spectrum influenza A subtypes (including H1, H3, H5, H7); this suggests that pGG analogs can be applied to most influenza A subtypes as a prophylactic against influenza viral infections.
PMCID: PMC3981784  PMID: 24718639
3.  Prevalence and gender difference of lumbar disc space narrowing in elderly Chinese men and women: Mr. OS (Hong Kong) and Ms. OS (Hong Kong) studies 
Arthritis and rheumatism  2013;65(4):1004-1010.
Mr. OS (Hong Kong) and Ms. OS (Hong Kong) represent the first large scale prospective population based studies conducted on bone health in elderly (≥65 yrs) Chinese men (n=2000) and women (n=2000). The current study investigated the prevalence of lumbar disc space narrowing (DSN) in these subjects, and identified the potential relationship between DSN and gender, bone mineral density (BMD), and other demographic and clinical data.
On lumbar lateral radiographs, L1/L2-L4/L5 disc space was classified to 4 categories: 0= normal; 1= mild narrowing; 2= moderate narrowing; 3= severe narrowing. Demographic and clinical data between subjects with and without sum of DSN score ≥ 3 were compared.
DSN was more common in elderly women than in men. The average DSN score for the four discs was 2.71±2.21 for men, and 3.08±2.50 for women (P<0.0001). For the three age groups of 65~69, 70~79, ≥80 (yrs), average DSN score increased with increasing age in both men and women, and to a greater degree in women than men. Average DSN score difference between women and men was 0.12, 0.40, and 0.90 respectively in the three age groups. For both men and women, DSN ≥ 3 was associated with older age, higher spine and hip BMD, low back pain, and restricted leg mobility.
Prevalence and severity of DSN is higher in elderly women than elderly men. With increasing age, DSN progresses at a greater rate in females than males. DSN ≥ 3 is associated with higher spine and hip BMD.
PMCID: PMC3618501  PMID: 23335175
lumbar; disc; gender; elderly; bone mineral density
4.  Development of a Gene Knockout System Using Mobile Group II Introns (Targetron) and Genetic Disruption of Acid Production Pathways in Clostridium beijerinckii 
Applied and Environmental Microbiology  2013;79(19):5853-5863.
Clostridium beijerinckii is a well-known solvent-producing microorganism with great potential for biofuel and biochemical production. To better understand and improve the biochemical pathway to solvents, the development of genetic tools for engineering C. beijerinckii is highly desired. Based on mobile group II intron technology, a targetron gene knockout system was developed for C. beijerinckii in this study. This system was successfully employed to disrupt acid production pathways in C. beijerinckii, leading to pta (encoding phosphotransacetylase)- and buk (encoding butyrate kinase)-negative mutants. In addition to experimental characterization, the mutant phenotypes were analyzed in the context of our C. beijerinckii genome-scale model. Compared to those of the parental strain (C. beijerinckii 8052), acetate production in the pta mutant was substantially reduced and butyrate production was remarkably increased, while solvent production was dependent on the growth medium. The pta mutant also produced much higher levels of lactate, suggesting that disrupting pta influenced the energy generation and electron flow pathways. In contrast, acetate and butyrate production in the buk mutant was generally similar to that of the wild type, but solvent production was consistently 20 to 30% higher and glucose consumption was more rapid and complete. Our results suggest that the acid and solvent production of C. beijerinckii can be effectively altered by disrupting the acid production pathways. As the gene disruption method developed in this study does not leave any antibiotic marker in a disrupted allele, multiple and high-throughput gene disruption is feasible for elucidating genotype and phenotype relationships in C. beijerinckii.
PMCID: PMC3811342  PMID: 23872562
5.  Predictive Value of Imaging Markers at Multiple Sclerosis Disease Onset Based on Gadolinium- and USPIO-Enhanced MRI and Machine Learning 
PLoS ONE  2014;9(4):e93024.
A novel characterization of Clinically Isolated Syndrome (CIS) patients according to lesion patterns is proposed. More specifically, patients are classified according to the nature of inflammatory lesions patterns. It is expected that this characterization can infer new prospective figures from the earliest imaging signs of Multiple Sclerosis (MS), since it can provide a classification of different types of lesions across patients.
The method is based on a two-tiered classification. Initially, the spatio-temporal lesion patterns are classified. The discovered lesion patterns are then used to characterize groups of patients. The patient groups are validated using statistical measures and by correlations at 24-month follow-up with hypointense lesion loads.
The methodology identified 3 statistically significantly different clusters of lesion patterns showing p-values smaller than 0.01. Moreover, these patterns defined at baseline correlated with chronic hypointense lesion volumes by follow-up with an score of .
The proposed methodology is capable of identifying three major different lesion patterns that are heterogeneously present in patients, allowing a patient classification using only two MRI scans. This finding may lead to more accurate prognosis and thus to more suitable treatments at early stage of MS.
PMCID: PMC3972197  PMID: 24691080
6.  CXCL12 Enhances Human Neural Progenitor Cell Survival through a CXCR7- and CXCR4- mediated Endocytotic Signaling Pathway 
Stem cells (Dayton, Ohio)  2012;30(11):2571-2583.
Chemokine CXCL12 is widely expressed in the central nervous system (CNS) and essential for the proper functions of human neural progenitor cells (hNPCs). Although CXCL12 is known to function through its receptor CXCR4, recent data have suggested that CXCL12 binds to chemokine receptor CXCR7 with higher affinity than to CXCR4. However, little is known about the function of CXCR7 in hNPCs. Using a primary hNPC culture system, we demonstrated that CXCL12 promotes hNPC survival in the events of camptothecin-induced apoptosis or growth factor deprivation, and that this effect requires both CXCR7 and CXCR4. Through FACS analysis and immunocytochemistry, we determined that CXCR7 is mainly localized in the early endosome, while CXCR4 is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the pro-survival function of CXCL12. Using dual-color Total Internal Reflection Fluorescence microscopy and immunoprecipitation, we demonstrated that CXCR7 quickly trafficks to plasma membrane in mediating CXCL12 endocytosis and colocalizes with CXCR4 after CXCL12 treatment. Investigating the molecular mechanisms, we found that ERK1/2 endocytotic signaling pathway is essential for hNPC survival upon apoptotic challenges. Consistent with these findings, a significantly higher number of apoptotic NPCs were found in the developing brain of CXCR7 knockout mice. In conclusion, CXCL12 protects hNPCs from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7 may become a new therapeutic target to properly regulate critical processes of brain development.
PMCID: PMC3969741  PMID: 22987307
7.  Current Status of Pediatric Labeling in China and the near Future Efforts Needed for the Country 
Background: Children are recognized as “therapeutic orphan” in many parts of the world, one expression of this is the lack of adequate pediatric labeling information. Some research studies have been done to investigate the pediatric labeling condition in the U.S. and other countries, but no national studies had been carried out in China. This survey was conducted aiming to inquire the current situation of pediatric labeling in China.
Methods: We investigated 6020 child-applied medicines from 15 representative Chinese hospitals, and analyzed the information according to the dosage forms, therapeutic category, and label information integrity.
Results: Among all these medicines, only 238 (3.95%) are pediatric products, the rest are adult formulations with an extended use in children. The major pediatric formulations were injection (45.95%), tablet (23.69%), and capsule (4.93%), respectively. Alimentary tract/metabolism medicine (24.70%) and infections medicines (20.60%) had the most species. In prescription drugs, only 210 of 5187 (4%) medicines had adequate pediatric labeling information. The main cause of this deficiency was lack of evidence derived from pediatric clinical trials.
Conclusion: The dilemma of “therapeutic orphan” requires significant attention. Inadequate labeling information and lack of pediatric clinical trials were two prominent issues in China. It calls for more efforts from pharmaceutical industries, regulatory agencies, and legislature in China to collaborate and find solution to improve the situation.
PMCID: PMC3972450  PMID: 24724075
pediatric; label; information; integrity; China
8.  Asexuality Development among Middle Aged and Older Men 
PLoS ONE  2014;9(3):e92794.
To assess erectile function in middle-aged and older men with asexuality status and further analyze their specific reasons for this condition.
Subjects and Methods
Men who had regular sexual intercourse attempts (sex frequency≥1 time per month) were classified into mild erectile dysfunction (ED), moderate to severe ED and non-ED according to International Index of Erectile Function-5, and men having no sexual intercourse attempts for at least 6 months were defined as having an asexuality status. The risk factors associated with ED were collected in a sample of 1,531 Chinese men aged 40 to 80 years, and the self-report reasons for asexuality were recorded in asexual cohort individually. Comparative analyses and multivariate regression models were conducted among these groups.
The prevalence rates of ED and asexuality status were 49.9% and 37.2%. The asexuality status group had higher risk factors than the moderate to severe ED group in terms of old age (age≥65, adjusted odds ratio (OR) 17.69 versus (Vs.) 7.19), diabetes (crude OR: 2.40 Vs. 2.36) and hypertension (crude OR: 1.78 Vs. 1.72). The specific reasons for the asexuality status were “erectile difficulty” (52.9%), “do not care about sexuality” (53.5%)”, “no longer necessary to have sexuality at this age” (47.7%), “severe stress” (44.4%), “severe fatigue” (26.3%) and “masturbation” (26.9%).
Men with an asexual status suffer from higher risk factors for ED than men with moderate to severe ED. The majority of this asexual status could be attributed to a full ED, although the reasons for this transient asexuality also involved sexual attitudes and interests, sexual partners and masturbation.
PMCID: PMC3965446  PMID: 24667838
9.  Time-Efficient Myocardial Contrast Partition Coefficient Measurement from Early Enhancement with Magnetic Resonance Imaging 
PLoS ONE  2014;9(3):e93124.
Our purpose was to validate an early enhancement time point for accurately measuring the myocardial contrast partition coefficient (lambda) using dynamic-equilibrium magnetic resonance imaging.
Materials and Methods
The pre- and post-contrast longitudinal relaxation rates (reciprocal of T1) of the interventricular septum (R1m) and blood pool (R1b) were obtained from fifteen healthy volunteers and three diabetic patients with hypertension using two optimized T1 mapping sequences (modified Look-Locker inversion recovery) on a 3-Tesla magnetic resonance scanner. Reference lambda values were calculated as the slope of the regression line of R1m versus R1b at dynamic equilibrium (multi-point regression method). The simplified pre-/post-enhancement two-acquisition method (two-point method) was used to calculate lambda by relating the change in R1m and R1b using different protocols according to the acquisition stage of the post-enhancement data point. The agreement with the referential method was tested by calculating Pearson's correlation coefficient and the intra-class correlation coefficient.
The lambda values measured by the two-point method increased (from 0.479±0.041 to 0.534±0.043) over time from 6 to 45 minutes after contrast and exhibited good correlation with the reference at each time point (r≥0.875, p<0.05). The intra-class correlation coefficient on absolute agreement with the reference lambda was 0.946, 0.929 and 0.922 at the 6th, 7th and 8th minutes and dropped from 0.878 to 0.403 from the 9th minute on.
The time-efficient two-point method at 6–8 minutes after the Gd-DTPA bolus injection exhibited good agreement with the multi-point regression method and can be applied for accurate lambda measurement in normal myocardium.
PMCID: PMC3965516  PMID: 24667489
10.  Polymorphism of rs873308 near the transmembrane protein 57 gene is associated with serum lipid levels 
Bioscience Reports  2014;34(2):e00095.
SNP (single-nucleotide polymorphism) of rs10903129 near the TMEM (transmembrane protein) 57 locus has been associated with TC (total cholesterol) in a previous GWAS (genome-wide association study), but the association of TMEM57 rs873308 SNP and serum lipid levels has not been previously reported. The current study was undertaken to detect the association of the TMEM57 rs873308 SNP and several environmental factors with serum lipid profiles in the Han Chinese and Mulao populations. The genotypes of the TMEM57 rs873308 SNP in 865 individuals of Han Chinese and 902 participants of Mulao nationality were determined by PCR and RFLP (restriction-fragment-length polymorphism) combined with gel electrophoresis and then confirmed by direct sequencing. The T allele frequency of TMEM57 rs873308 SNP was not different between Han and Mulao (23.18% versus 25.72%, P>0.05), but different between males and females in the two ethnic groups (P<0.05). The T allele carriers had lower serum TC, Apo (apolipoprotein) B, HDL-C (high-density lipoprotein cholesterol) levels, ApoA1/ApoB ratio in Han; and lower TAG (triacylglycerol), LDL-C (low-density lipoprotein cholesterol), ApoA1 levels and the ApoA1/ApoB ratio and higher HDL-C levels in Mulao than the T allele non-carriers. There was also different association of the TMEM57 rs873308 SNP and serum lipid profiles between males and females in the both ethnic groups. Serum lipid parameters in the two ethnic groups were also associated with several environmental factors. The association of the TMEM57 rs873308 SNP and serum lipid levels was different in the Han Chinese and Mulao populations and between males and females in the both ethnic groups. There may be a sex-specific association of the TMEM57 rs873308 SNP and serum lipid levels in our study populations.
PMCID: PMC3953947  PMID: 24517463
environmental factors; lipids; single-nucleotide polymorphism; transmembrane protein 57; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; GWAS, genome-wide association study; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; RFLP, restriction-fragment-length polymorphism; SNP, single-nucleotide polymorphism; TC, total cholesterol; TAG, triacylglycerol; TMEM, transmembrane protein
11.  Differential expressed genes of change in glucose metabolism in the liver of GCK knockout mice 
Gene  2013;516(2):248-254.
To investigate the role of liver-specific expression of GCK in the pathogenesis of hyperglycemia and identify candidate genes involved in the mechanisms for onset and progression of MODY2, we examined the differentially expression of genes in the liver of liver-specific glucokinase (GCK) knockout mice (gckw/−) model at 2 and 26 weeks by suppression subtractive hybridization (SSH). The expression levels of the ACAT2 and PEPCK genes identified by SSH, glycogen Synthase (GS) and glycogen phosphorylase (GP) genes were further examined at different ages by Real time PCR. In addition, we also characterized the expression of mouse GCK mRNA at different ages as well as the fasting blood glucose, serum insulin, GCK activity, total cholesterol (TC), triglyceride(TG) and glycogen content. The results show that, except for 2-week-old gckw/− mice, the fasting blood glucose levels are significantly higher for gckw/− mice (P<0.01)and the GCK activity of gckw/− mice lower about 50% than for GCK wild type(gckw/w )mice(P<0.05). The glycogen content of 4-week old and 40-week old gckw/− mice was lower than that of 4-week old and 40-week old gckw/w mice. The GP mRNA levels decrease at 40-week old gckw/− mice compared to age-matched gckw/w mice. PEPCK mRNA decreases at 2-week old gckw/− mice, but increases at 4-week old gckw/− mice(P<0.05). Changes in the expression of PEPCK genes, delayed development of GCK and impaired hepatic glycogen synthesis in liver potentially lead to onset and progression of maturity onset diabetes of the young, type 2 (MODY-2).
PMCID: PMC3642073  PMID: 23291412 CAMSID: cams2937
glucokinase; MODY2; differentially expressed genes
12.  The Apoptotic Effect of D Rhamnose β-Hederin, a Novel Oleanane-Type Triterpenoid Saponin on Breast Cancer Cells 
PLoS ONE  2014;9(3):e90848.
There is growing interest in development of natural products as anti-cancer and chemopreventive agents. Many triterpenoids have been proved as potential agents for chemoprevention and therapy of breast cancer. Ginsenosides from ginseng, which mostly belong to dammarane-type triterpenoids, have gained great attention for their anti-breast cancer activity with diverse mechanisms. However, studies of other kinds of triterpenoid saponins on breast cancer are limited. Previously, we purified and identified a novel oleanane-type triterpene saponin named D Rhamnose β-hederin (DRβ-H) from Clematis ganpiniana, a Chinese traditional anti-tumor herb. In the present study, DRβ-H showed strong inhibitory activity on the growth of various breast cancer cells and induced apoptosis in these cells. DRβ-H inhibited PI3K/AKT and activated ERK signaling pathway. PI3K inhibitor LY294002 synergistically enhanced DRβ-H-induced apoptosis whereas MEK inhibitor U0126 reduced the apoptosis rate. Moreover, DRβ-H regulated the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family proteins. Furthermore, DRβ-H induced depolarization of mitochondrial membrane potential which released Apaf-1 and Cytochrome C from the inter membrane space into the cytosol, where they promoted caspase-9 and caspase-3 activation. This is the first report on the pro-apoptotic effects of DRβ-H, a novel oleanane-type triterpenoid saponin, on breast cancer cells and its comprehensive apoptosis pathways. It implied that oleanane-type triterpenoid saponin DRβ-H could be a promising candidate for chemotherapy of breast cancer.
PMCID: PMC3946269  PMID: 24603880
13.  Fine-Mapping of Immunodominant Linear B-Cell Epitopes of the Staphylococcus Aureus SEB Antigen Using Short Overlapping Peptides 
PLoS ONE  2014;9(3):e90445.
Staphylococcal enterotoxin B (SEB) is one of the most potent Staphylococcus aureus exotoxins (SEs). Due to its conserved sequence and stable structure, SEB might be a good candidate antigen for MRSA vaccines. Although cellular immune responses to SEB are well-characterized, much less is known regarding SEB-specific humoral immune responses, particularly regarding detailed epitope mapping. In this study, we utilized a recombinant nontoxic mutant of SEB (rSEB) and an AlPO4 adjuvant to immunize BALB/c mice and confirmed that rSEB can induce a high antibody level and effective immune protection against MRSA infection. Next, the antisera of immunized mice were collected, and linear B cell epitopes within SEB were finely mapped using a series of overlapping synthetic peptides. Three immunodominant B cell epitopes of SEB were screened by ELISA, including a novel epitope, SEB205-222, and two known epitopes, SEB97–114 and SEB247-261. Using truncated peptides, an ELISA was performed with peptide-KLH antisera, and the core sequence of the three immunodominant B cell epitopes were verified as SEB97-112, SEB207-222, and SEB247-257. In vitro, all of the immunodominant epitope-specific antisera (anti-SEB97-112, anti-SEB207-222 and anti-SEB247-257) were observed to inhibit SEB-induced T cell mitogenesis and cytokine production from splenic lymphocytes of BALB/c mice. The homology analysis indicated that SEB97–112 and SEB207-222 were well-conserved among different Staphylococcus aureus strains. The 3D crystal structure of SEB indicated that SEB97–112 was in the loop region inside SEB, whereas SEB207-222 and SEB247-257 were in the β-slice region outside SEB. In summary, the fine-mapping of linear B-cell epitopes of the SEB antigen in this study will be useful to understand anti-SEB immunity against MRSA infection further and will be helpful to optimize MRSA vaccine designs that are based on the SEB antigen.
PMCID: PMC3943954  PMID: 24599257
14.  A New Method for Computing Attention Network Scores and Relationships between Attention Networks 
PLoS ONE  2014;9(3):e89733.
The attention network test (ANT) is a reliable tool to detect the efficiency of alerting, orienting, and executive control networks. However, studies using the ANT obtained inconsistent relationships between attention networks due to two reasons: on the one hand, the inter-network relationships of attention subsystems were far from clear; on the other hand, ANT scores in previous studies were disturbed by possible inter-network interactions. Here we proposed a new computing method by dissecting cue-target conditions to estimate ANT scores and relationships between attention networks as pure as possible. The method was tested in 36 participants. Comparing to the original method, the new method showed a larger alerting score and a smaller executive control score, and revealed interactions between alerting and executive control and between orienting and executive control. More interestingly, the new method revealed unidirectional influences from alerting to executive control and from executive control to orienting. These findings provided useful information for better understanding attention networks and their relationships in the ANT. Finally, the relationships of attention networks should be considered with more experimental paradigms and techniques.
PMCID: PMC3940671  PMID: 24594693
15.  Methylmercury and elemental mercury differentially associate with blood pressure among dental professionals 
Methylmercury-associated effects on the cardiovascular system have been documented though discrepancies exist, and most studied populations experience elevated methylmercury exposures. No paper has investigated the impact of low-level elemental (inorganic) mercury exposure on cardiovascular risk in humans. The purpose of this study was to increase understanding of the association between mercury exposure (methylmercury and elemental mercury) and blood pressure measures in a cohort of dental professionals that experience background exposures to both mercury forms. Dental professionals were recruited during the 2010 Michigan Dental Association Annual Convention. Mercury levels in hair and urine samples were analyzed as biomarkers of methylmercury and elemental mercury exposure, respectively. Blood pressure (systolic, diastolic) was measured using an automated device. Distribution of mercury in hair (mean, range: 0.45, 0.02–5.18 μg/g) and urine (0.94, 0.03–5.54 μg/L) correspond well with the US National Health and Nutrition Examination Survey. Linear regression models revealed significant associations between diastolic blood pressure (adjusted for blood pressure medication use) and hair mercury (n = 262, p = 0.02). Urine mercury results opposed hair mercury in many ways. Notably, elemental mercury exposure was associated with a significant systolic blood pressure decrease (n = 262, p = 0.04) that was driven by the male population. Associations between blood pressure and two forms of mercury were found at exposure levels relevant to the general population, and associations varied according to type of mercury exposure and gender.
PMCID: PMC3727420  PMID: 22494934
Mercury; Blood pressure; Epidemiology; Gender difference; Environmental exposure
16.  Hepatic Sinusoidal Obstruction Syndrome Caused by Herbal Medicine: CT and MRI Features 
Korean Journal of Radiology  2014;15(2):218-225.
To describe the CT and MRI features of hepatic sinusoidal obstruction syndrome (HSOS) caused by herbal medicine Gynura segetum.
Materials and Methods
The CT and MRI features of 16 consecutive Gynura segetum induced HSOS cases (12 men, 4 women) were analyzed. Eight patients had CT; three patients had MRI, and the remaining five patients had both CT and MRI examinations. Based on their clinical presentations and outcomes, the patients were classified into three categories: mild, moderate, and severe. The severity of the disease was also evaluated radiologically based on the abnormal hepatic patchy enhancement in post-contrast CT or MRI images.
Ascites, patchy liver enhancement, and main right hepatic vein narrowing or occlusion were present in all 16 cases. Hepatomegaly and gallbladder wall thickening were present in 14 cases (87.5%, 14/16). Periportal high intensity on T2-weighted images was present in 6 cases (75%, 6/8). Normal liver parenchymal enhancement surrounding the main hepatic vein forming a clover-like sign was observed in 4 cases (25%, 4/16). The extent of patchy liver enhancement was statistically associated with clinical severity classification (kappa = 0.565).
Ascites, patchy liver enhancement, and the main hepatic veins narrowing were the most frequent signs of herbal medicine induced HSOS. The grade of abnormal patchy liver enhancement was associated with the clinical severity.
PMCID: PMC3955788  PMID: 24643319
Hepatic sinusoidal obstruction syndrome; Herbal medicine; Pyrrolizidine alkaloid; Computed tomography; Magnetic resonance imaging
17.  Development and regeneration of Sox2+ endoderm progenitors is regulated by a HDAC1/2-Bmp4/Rb1 regulatory pathway 
Developmental cell  2013;24(4):345-358.
The mechanisms that govern the maintenance and differentiation of tissue specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by de-repression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue specific progenitor activity during development and regeneration.
PMCID: PMC3586315  PMID: 23449471
18.  Self-Gated Free-Breathing 3D Coronary CINE Imaging with Simultaneous Water and Fat Visualization 
PLoS ONE  2014;9(2):e89315.
The aim of this study was to develop a novel technique for acquiring 3-dimensional (3D) coronary CINE magnetic resonance images with both water and fat visualization during free breathing and without external respiratory or cardiac gating. The implemented multi-echo hybrid 3D radial balanced Steady-State Free Precession (SSFP) sequence has an efficient data acquisition and is robust against motion. The k-space center along the slice encoding direction was repeatedly acquired to derive both respiratory and cardiac self-gating signals without an increase in scan time, enabling a free-breathing acquisition. The multi-echo acquisition allowed image reconstruction with water-fat separation, providing improved visualization of the coronary artery lumen. Ten healthy subjects were imaged successfully at 1.5 T, achieving a spatial resolution of 1.0×1.0×3.0 mm3 and scan time of about 5 minutes. The proposed imaging technique provided coronary vessel depiction comparable to that obtained with conventional breath-hold imaging and navigator gated free-breathing imaging.
PMCID: PMC3930724  PMID: 24586682
19.  New Researches and Application Progress of Commonly Used Optical Molecular Imaging Technology 
BioMed Research International  2014;2014:429198.
Optical molecular imaging, a new medical imaging technique, is developed based on genomics, proteomics and modern optical imaging technique, characterized by non-invasiveness, non-radiativity, high cost-effectiveness, high resolution, high sensitivity and simple operation in comparison with conventional imaging modalities. Currently, it has become one of the most widely used molecular imaging techniques and has been applied in gene expression regulation and activity detection, biological development and cytological detection, drug research and development, pathogenesis research, pharmaceutical effect evaluation and therapeutic effect evaluation, and so forth, This paper will review the latest researches and application progresses of commonly used optical molecular imaging techniques such as bioluminescence imaging and fluorescence molecular imaging.
PMCID: PMC3947735
20.  Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells 
Cancer research  2012;73(4):1411-1419.
Trastuzumab (Herceptin®) is an effective targeted therapy in HER2 overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating PI3K and MAPK signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Further, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. Based on this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF-HER2 interaction might be a novel target for therapeutic management of breast cancer patients whose disease is resistant to trastuzumab.
PMCID: PMC3577983  PMID: 23248119
21.  Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy 
BioMed Research International  2014;2014:819324.
Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy.
PMCID: PMC3943245
22.  Synthesis of Ag Nanocubes 18–32 nm in Edge Length: The Effects of Polyol on Reduction Kinetics, Size Control, and Reproducibility 
This article describes a robust method for the facile synthesis of small Ag nanocubes with edge lengths controlled in the range of 18–32 nm. The success of this new method relies on the substitution of ethylene glycol (EG) -- the solvent most commonly used in a polyol synthesis -- with diethylene glycol (DEG). Owing to the increase in hydrocarbon chain length, DEG possesses a higher viscosity and a lower reducing power relative to EG. As a result, we were able to achieve a nucleation burst in the early stage to generate a large number of seeds and a relatively slow growth rate thereafter; both factors were critical to the formation of Ag nanocubes with small sizes and in high purity (>95%). The edge length of the Ag nanocubes could be easily tailored in the range of 18–32 nm by quenching the reaction at different time points. For the first time, we were able to produce uniform sub-20 nm Ag nanocubes in a hydrophilic medium and on a scale of ~20 mg per batch. It is also worth pointing out that the present protocol was remarkably robust, showing good reproducibility between different batches and even for DEGs obtained from different vendors. Our results suggest that the high sensitivity of synthesis outcomes to the trace amounts of impurities in a polyol, a major issue for reproducibility and scale up synthesis, did not exist in the present system.
PMCID: PMC3576731  PMID: 23317148
silver nanocubes; nanocrystals; polyol synthesis; size control
23.  Accuracy and Uncertainty of Asymmetric Magnetization Transfer Ratio Quantification for Amide Proton Transfer (APT) Imaging at 3T: A Monte Carlo Study 
Amide proton transfer (APT) imaging offers a novel and powerful MRI contrast mechanism for quantitative molecular imaging based on the principle of chemical exchange saturation transfer (CEST). Asymmetric magnetization transfer ratio (MTRasym) quantification is crucial for Z-spectrum analysis of APT imaging, but is still challenging, particularly at clinical field strength. This paper studies the accuracy and uncertainty in the quantification of MTRasym for APT imaging at 3T, by using high-order polynomial fitting of Z-spectrum through Monte Carlo simulation. Results show that polynomial fitting is a biased estimator that consistently underestimates MTRasym. For a fixed polynomial order, the accuracy of MTRasym is almost constant with regard to signal-to-noise ratio (SNR) while the uncertainty decreases exponentially with SNR. The higher order polynomial fitting increases both the accuracy and the uncertainty of MTRasym. For different APT signal intensity levels, the relative accuracy and the absolute uncertainty keep constant for a fixed polynomial order. These results indicate the limitations and pitfalls of polynomial fitting for MTRasym quantification so better quantification technique for MTRasym estimation is warranted.
PMCID: PMC3915244  PMID: 24110892
24.  A Microfluidic Device for Continuous-Flow Magnetically Controlled Capture and Isolation of Microparticles 
This paper presents a novel microfluidic device that exploits magnetic manipulation for integrated capture and isolation of microparticles in continuous flow. The device, which was fabricated from poly(dimethylsiloxane) (PDMS) by soft-lithography techniques, consists of an incubator and a separator integrated on a single chip. The incubator is based on a novel scheme termed target acquisition by repetitive traversal (TART), in which surface-functionalized magnetic beads repetitively traverse a sample to seek out and capture target particles. This is accomplished by a judicious combination of a serpentine microchannel geometry and a time-invariant magnetic field. Subsequently, in the separator, the captured target particles are isolated from nontarget particles via magnetically driven fractionation in the same magnetic field. Due to the TART incubation scheme that uses a corner-free serpentine channel, the device has no dead volume and allows minimization of undesired particle or magnetic-bead retention. Single-chip integration of the TART incubator with the magnetic-fractionation separator further allows automated continuous isolation and retrieval of specific microparticles in an integrated manner that is free of manual off-chip sample incubation, as often required by alternative approaches. Experiments are conducted to characterize the individual incubation and separation components, as well as the integrated device. The device is found to allow 90% of target particles in a sample to be captured and isolated and 99% of nontarget particles to be eliminated. With this high separation efficiency, along with excellent reliability and flexibility, the device is well suited to sorting, purification, enrichment, and detection of micro/nanoparticles and cells in lab-on-a-chip systems.
PMCID: PMC3916004  PMID: 24511214
Cell sorting; magnetic manipulation; micro-fluidics; on-chip incubation; particle separation
25.  3D Multi-parametric Breast MRI Segmentation using Hierarchical Support Vector Machine with Coil Sensitivity Correction 
Academic radiology  2012;20(2):137-147.
Rationale and Objectives
The goal of the study is to develop a technique to achieve accurate volumetric breast tissue segmentation using MRI data. This segmentation can be useful to aid in the diagnosis of breast cancers and to assess breast cancer risk based on breast density. Tissue segmentation is also essential for development of acoustic and thermal models used in magnetic resonance guided high-intensity focused ultrasound treatment of breast lesions.
Materials and Methods
In addition to commonly used T1-, T2- and proton density-weighted images, three-point Dixon water- and fat-only images were also included as part of the multi-parametric inputs to a tissue segmentation algorithm using a hierarchical support vector machine (SVM). The effectiveness of a variety of pre-processing schemes was evaluated through two in vivo datasets. The performance of the hierarchical SVM was investigated and compared to the conventional classification algorithms—conventional SVM and fuzzy C-mean (FCM).
The need for co-registration, zero filled interpolation, coil sensitivity correction and optimal SNR reconstruction before the final stage classification was demonstrated. The overlap ratios of the hierarchical SVM, conventional SVM and FCM were 93.25%–94.08%, 81.68– 92.28%, and 75.96%–91.02% respectively. Classification outputs from in vivo experiments showed that the presented methodology is consistent and outperforms other algorithms.
The presented hierarchical SVM-based technique showed promising results in automatically segmenting breast tissues into fat, fibroglandular tissue, skin and lesions. The results provide evidence that both the multi-parametric breast MRI inputs and the pre-processing procedures contribute to the high accuracy of tissue classification.
PMCID: PMC3567300  PMID: 23099241
breast MRI segmentation; support vector machine; coil sensitivity correction; multiparametric input

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