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1.  Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring System. In vitro results and implications 
Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.
PMCID: PMC3979313  PMID: 24461293
Ring-expanded nucleosides; imidazo[4,5-e][1,3]diazepines; organic synthesis; antiviral compounds; in vitro screening; hepatitis C virus (HCV); human immunodeficiency virus (HIV); dual inhibitors of HCV and HIV; inhibition of HCV NTPase/helicase; inhibition of RNA helicase DDX3
2.  Efficacy of anti–tumor necrosis factor therapy for extra-articular manifestations in patients with ankylosing spondylitis: a meta–analysis 
We performed a meta-analysis to evaluate the effect of anti–tumor necrosis factor (TNF) therapy on the frequency of extra–articular manifestations (EAMs) in patients with ankylosing spondylitis (AS).
We searched with the terms ‘ankylosing spondylitis’, ‘infliximab’, ‘etanercept’, ‘adalimumab’, ‘golimumab’, ‘certolizumab’, ‘TNF inhibitor/blocker/antagonists’ or ‘anti-TNF’ on MEDLINE, EMBASE and Cochrane Library for randomized controlled trials (RCTs) of ≥12 weeks with parallel or crossover design of TNF inhibitor versus placebo to treat uveitis, inflammatory bowel disease (IBD) and/or psoriasis of AS, published before February 2014.
We found 8 RCTs that fit our criteria. Anti–TNF therapy was associated with less uveitis than placebo in patients with AS (OR: 0.35, 95% CI: 0.15–0.81, P = 0.01). Subgroup analysis showed receptor fusion proteins were more efficacious for uveitis than placebo (OR: 0.30, 95% CI: 0.09–0.94, P = 0.04), but monoclonal antibodies were not (OR: 0.43, 95% CI: 0.12–1.49, P = 0.18). Anti–TNF therapy and placebo group did not significantly differ in treating IBD in AS patients (OR: 0.75, 95% CI: 0.25–2.29, P = 0.61). In subgroup analysis, neither monoclonal antibodies (OR: 0.45, 95% CI: 0.10–1.92, P = 0.28) nor receptor fusion proteins (OR: 1.52, 95% CI: 0.25–9.25, P = 0.65) significantly differed from placebo in treating IBD. We found no suitable reports on psoriasis.
Anti–TNF therapy was preventive for flares or new onset of uveitis in AS patients, and might be an alternative for these patients. However, monoclonal anti–TNF antibodies and TNF receptor fusion proteins were not efficacious for IBD in AS patients.
PMCID: PMC4328050
Ankylosing spondylitis; Anti-TNF therapy; Extra–articular manifestations; Uveitis; Inflammatory bowel disease; Meta–analysis
3.  Predictors of Percutaneous Catheter Drainage (PCD) after Abdominal Paracentesis Drainage (APD) in Patients with Moderately Severe or Severe Acute Pancreatitis along with Fluid Collections 
PLoS ONE  2015;10(2):e0115348.
Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
PMCID: PMC4319763  PMID: 25659143
4.  Different types of androgen receptor mutations in patients with complete androgen insensitivity syndrome 
Mutations of androgen receptor (AR) are the most frequent cause of 46, XY disorders of sex development and associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome (CAIS)) to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). From 2009 to 2012, two young Chinese female individuals with CAIS from two families were referred to our hospital due to primary amenorrhea. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Physical examination revealed that the patients have normal female external genitalia, normal breast development, vellus hair in the axilla and on the arms and legs, but absence of pubic hair, and a blind-ending vagina. Two different types of AR mutations have been detected by sequencing of genomic DNA: Family A showed deletion of exon 2 in AR gene; Family B showed a single nucleotide C-to-T transition in exon 8 of AR gene resulting in a proline 893-to-leucine substitution (Pro893Leu). Testicular histology showed developmental immaturity of seminiferous tubules with the absence of spermatogenic cells or spermatozoa. No AR immunoreactivity was observed in either case. Three adult patients recovered well from bilateral orchiectomy. The juvenile patient of family B was followed up. Our present study on these two families revealed two different types of AR mutation. The definitive diagnosis of AIS was based on clinical examination and genetic investigations. Our findings verified the mechanism of CAIS and also enriched AR Gene Mutation Database.
PMCID: PMC4322596
Complete androgen insensitivity syndrome; androgen receptor; disorder of sex development; AR domains; deletion and transition
5.  Synthesis and evaluation of a nanoglobular dendrimer 5-aminosalicylic acid conjugate with a hydrolyzable Schiff base spacer for treating retinal degeneration 
ACS nano  2013;8(1):153-161.
Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolysable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4−/−Rdh8−/− mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.
PMCID: PMC4060971  PMID: 24350906
dendrimer; 5-aminosalicylic acid; Schiff base; drug delivery; controlled release
6.  Incomplete Radiofrequency Ablation Enhances Invasiveness and Metastasis of Residual Cancer of Hepatocellular Carcinoma Cell HCCLM3 via Activating β-Catenin Signaling 
PLoS ONE  2014;9(12):e115949.
Radiofrequency ablation (RFA) is one of the curative therapies for hepatocellular carcinoma (HCC), however, accelerated progression of residual HCC after incomplete RFA has been reported more frequently. The underlying molecular mechanism of this phenomenon remains to be elucidated. In this study, we used an incomplete RFA orthotopic HCC nude mouse model to study the invasive and metastatic potential of residual cancer as well as the correlated mechanism.
The incomplete RFA orthotopic nude mouse models were established using high metastatic potential HCC cell line HCCLM3 and low metastatic potential HCC cell line HepG2, respectively. The changes in cellular morphology, motility, metastasis and epithelial–mesenchymal transition (EMT), and HCC cell molecular markers after in vitro and in vivo incomplete RFA intervention were observed.
Pulmonary and intraperitoneal metastasis were observed in an in vivo study. The underlying pro-invasive mechanism of incomplete RFA appeared to be associated with promoting EMT, including down-regulation of E-cadherin and up-regulation of N-cadherin and vimentin. These results were in accordance with the in vitro response of HCC cells to heat intervention. Further studies demonstrated that β-catenin was a pivotal factor during this course and blocking β-catenin reduced metastasis and EMT phenotype changes in heat-treated HCCLM3 cells in vitro.
Incomplete RFA enhanced the invasive and metastatic potential of residual cancer, accompanying with EMT-like phenotype changes by activating β-catenin signaling in HCCLM3 cells.
PMCID: PMC4277411  PMID: 25542041
7.  Asn563Ser polymorphism of CD31/PECAM-1 is associated with atherosclerotic cerebral infarction in a southern Han population 
CD31, also called platelet endothelial cell adhesion molecule-1 (PECAM-1), is thought to play a role in the pathological mechanisms of atherosclerosis. Leu125Val polymorphism and elevated plasma levels of soluble PECAM-1 (sPECAM-1) were found to be associated with cerebral infarction. Our aim was to investigate the association between the Asn563Ser polymorphism of CD31/PECAM-1, plasma level of sPECAM-1, and the risk of atherosclerotic cerebral infarction (ACI) in the southern Han population of the People’s Republic of China.
Subjects and methods
A total of 147 subjects with ACI and 114 controls were enrolled in the study. The Asn563Ser CD31/PECAM-1 polymorphism was detected using the polymerase chain reaction–restriction fragment length polymorphism method. The plasma spECAM-1 level was measured using the enzyme-linked immunosorbent assay method.
In this study, statistically significant differences in Asn563Ser genotype and allele distribution were found between the cases and controls (P<0.05). Furthermore, logistic regression analysis showed that the GG genotype is associated with increase in ACI risk (odds ratio =4.862, P<0.001). The plasma level of sPECAM-1 was associated with ACI (odds ratio =1.431, P=0.038). In both the ACI and the control groups, the plasma sPECAM-1 level in subjects with the GG genotype was higher than that in subjects carrying the AA or GA genotype (P<0.05).
Our study showed that the Asn563Ser polymorphism of CD31/PECAM-1 gene and elevated plasma sPECAM-1 level are related to ACI risk in the southern Han population of People’s Republic of China.
PMCID: PMC4274145  PMID: 25565847
genetic polymorphism; CD31; platelet endothelial cell adhesion molecule-1 (PECAM-1)
8.  Spinocerebellar ataxia type 3/Machado-Joseph disease manifested as spastic paraplegia: A clinical and genetic study 
The aim of the present study was to conduct a familial investigation and provide a genetic diagnosis to a family presenting with spastic paraplegia and clinically diagnosed with hereditary spastic paraplegia (HSP). Blood samples were obtained from the family, and mutations in the gene causing spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD), known as MJD1, were analyzed using the polymerase chain reaction, 8% denaturing polyacrylamide gel electrophoresis, and T-vector ligation and sequencing. The trinucleotide repeat number of the mutant allele was 80, leading to a genetic diagnosis of SCA3/MJD. This suggests that patients with SCA3/MJD characteristically present with typical spastic paraplegia without evident manifestations of ataxia. For those families with HSP involving the nervous system and showing genetic anticipation, an MJD1 genetic diagnosis should be considered to assist in clinical diagnosis of HSP.
PMCID: PMC4280951  PMID: 25574208
spastic paraplegia; hereditary spinocerebellar ataxia type 3; Machado-Joseph disease gene; mutation analysis; genetic anticipation; CAG trinucleotide repeats
9.  Role of cancer stem cell marker CD44 in gastric cancer: a meta-analysis 
Cluster of differentiation 44 (CD44), a principal cell surface receptor for hyaluronic acid, has been implicated in tumorigenesis and metastasis. However, the relationship between CD44 expression and the patients with gastric cancer remains controversial. A meta-analysis was performed to quantitatively review the correlation of CD44 expression with the clinicopathological data of the patients with gastric cancer. We conducted a final analysis of the patients from 18 studies. Combined odds ratios (OR) suggested that CD44 expression was related with stage, tumor size, and LN metastasis of gastric cancer, and CD44v6 was related with LN metastasis, lymphatic invasion, and venous invasion. Our results suggested that CD44 and CD44v6 expression could be used to predict the metastasis of gastric cancer.
PMCID: PMC4307452  PMID: 25664005
CD44; gastric cancer; metastasis; tumorigenesis; invasion
10.  Leu125Val polymorphism of platelet endothelial cell adhesion molecule-1 is associated with atherosclerotic cerebral infarction in Chinese Han population 
A total of 142 Atherosclerotic cerebral infarction (ACI) patients and 116 controls were enrolled in our study. The Leu125Val polymorphism of PECAM-1 was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The plasma sPECAM-1 level was measured by enzyme-linked immunosorbent assay (ELISA) method. We found a statistically significant difference in Leu125Val genotypic distribution between cases and controls (P < 0.05). The frequencies of the Val allele between ACI group and controls were significantly different (P < 0.05). Logistic regression analysis showed that the genotype Val/Val was associated with increased ACI risk (OR = 2.355, 95% CI = 1.153-4.809, P = 0.019). In both the ACI group and the control group, the plasma PECAM-1 levels of carriers of the Val/Val genotype were higher than those carrying Leu/Leu and Leu/Val genotypes. The plasma sPECAM-1 level is associated with ACI. Our study showed that Leu125Val polymorphism of PECAM-1 may be associated with ACI risk. Carrying the Val/Val genotype showed increased risk for ACI. The Leu125Val polymorphism of PECAM-1 may be associated with the plasma sPECAM-1 level, which is associated with Chinese ACI also. In conclusions, The Leu125Val polymorphism of the PECAM-1 gene is likely to be related to ACI, and the Val/Val genotype may be an independent risk factor for ACI. The plasma sPECAM-1 level may be associated with ACI risk.
PMCID: PMC4307558  PMID: 25664111
Platelet-endothelial cell adhesion molecule-1 (PECAM-1); polymorphism; atherosclerotic cerebral infarction (ACI); restriction fragment length polymorphism (RFLP)
11.  Formation of Well-defined Embryoid Bodies from Dissociated Human Induced Pluripotent Stem Cells using Microfabricated Cell-repellent Microwell Arrays 
Scientific Reports  2014;4:7402.
A simple, scalable, and reproducible technology that allows direct formation of large numbers of homogeneous and synchronized embryoid bodies (EBs) of defined sizes from dissociated human induced pluripotent stem cells (hiPSCs) was developed. Non-cell-adhesive hydrogels were used to create round-bottom microwells to host dissociated hiPSCs. No Rho-associated kinase inhibitor (ROCK-i), or centrifugation was needed and the side effects of ROCK-i can be avoided. The key requirement for the successful EB formation in addition to the non-cell-adhesive round-bottom microwells is the input cell density per microwell. Too few or too many cells loaded into the microwells will compromise the EB formation process. In parallel, we have tested our microwell-based system for homogeneous hEB formation from dissociated human embryonic stem cells (hESCs). Successful production of homogeneous hEBs from dissociated hESCs in the absence of ROCK-i and centrifugation was achieved within an optimal range of input cell density per microwell. Both the hiPSC- and hESC-derived hEBs expressed key proteins characteristic of all the three developmental germ layers, confirming their EB identity. This novel EB production technology may represent a versatile platform for the production of homogeneous EBs from dissociated human pluripotent stem cells (hPSCs).
PMCID: PMC4261164  PMID: 25492588
12.  Functional Study of One Nucleotide Mutation in Pri-MiR-125a Coding Region which Related to Recurrent Pregnancy Loss 
PLoS ONE  2014;9(12):e114781.
MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3′UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.
PMCID: PMC4257728  PMID: 25479352
13.  Assessment of trabecular bone yield and post-yield behavior from high-resolution MRI-based nonlinear finite-element analysis at the distal radius of pre- and postmenopausal women susceptible to osteoporosis 
Academic radiology  2013;20(12):10.1016/j.acra.2013.09.005.
Rationale and Objectives
To assess the performance of a nonlinear micro-finite element model on predicting trabecular bone (TB) yield and post-yield behavior based on high-resolution in-vivo MR images via the serial reproducibility.
Materials and Methods
The nonlinear model captures material nonlinearity by iteratively adjusting tissue-level modulus based on tissue-level effective strain. It enables simulations of TB yield and post-yield behavior from micro-MR images at in-vivo resolution by solving a series of nonlinear systems via an iterative algorithm on a desktop computer. Measures of mechanical competence (yield strain/strength, ultimate strain/strength, modulus of resilience and toughness) were estimated at the distal radius of pre- and postmenopausal women (N=20; age 50–75) in whom osteoporotic fractures typically occur. Each subject underwent three scans (20.2±14.5 days). Serial reproducibility was evaluated via coefficients of variation (CV) and intra-class correlation coefficient (ICC).
Nonlinear simulations were completed in an average of 14 minutes per 3D image data set involving analysis of 61 strain levels. The predicted yield strain/strength, ultimate strain/strength, modulus of resilience and toughness had a mean value of 0.78%, 3.09 MPa, 1.35%, 3.48 MPa, 14.30 kPa and 32.66 kPa, respectively, covering a substantial range by a factor of up to four. ICC ranged from 0.986 to 0.994 (average 0.991); CV ranged from 1.01% to 5.62% (average 3.6%), with yield strain and toughness having the lowest and highest CV values, respectively.
The data suggest that the yield and post-yield parameters have adequate reproducibility to evaluate treatment effects in interventional studies within short follow-up periods.
PMCID: PMC3842221  PMID: 24200486
Finite element analysis; Trabecular bone mechanics; MRI; reproducibility and reliability
14.  Trastuzumab-Related Cardiotoxicity Among Older Patients With Breast Cancer 
Journal of Clinical Oncology  2013;31(33):4222-4228.
The use of trastuzumab in the adjuvant setting improves outcomes but is associated with cardiotoxicity manifested as congestive heart failure (CHF). The rates and risk factors associated with trastuzumab-related CHF among older patients are unknown.
Patients and Methods
Breast cancer patients at least 66 years old with full Medicare coverage, diagnosed with stage I-III breast cancer between 2005 and 2009, and treated with chemotherapy were identified in the SEER-Medicare and in the Texas Cancer Registry–Medicare databases. The rates and risk factors associated with CHF were evaluated. Chemotherapy, trastuzumab use, comorbidities, and CHF were identified using International Classification of Diseases, version 9, and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics and Cox proportional hazards models.
In total, 9,535 patients were included, of whom 2,203 (23.1%) received trastuzumab. Median age of the entire cohort was 71 years old. Among trastuzumab users, the rate of CHF was 29.4% compared with 18.9% in nontrastuzumab users (P < .001). Trastuzumab users were more likely to develop CHF than nontrastuzumab users (hazard ratio [HR], 1.95; 95% CI, 1.75 to 2.17). Among trastuzumab-treated patients, older age (age > 80 years; HR, 1.53; 95% CI, 1.16 to 2.10), coronary artery disease (HR, 1.82; 95% CI, 1.34 to 2.48), hypertension (HR, 1.24; 95% CI, 1.02 to 1.50), and weekly trastuzumab administration (HR, 1.33; 95% CI, 1.05 to 1.68) increased the risk of CHF.
In this large cohort of older breast cancer patients, the rates of trastuzumb-related CHF are higher than those reported in clinical trials. Among patients treated with trastuzumab, those with cardiac comorbidities and older age may be at higher risk. Further studies need to confirm the role that the frequency of administration plays in the development of trastuzumab-related CHF.
PMCID: PMC3821011  PMID: 24127446
15.  Evaluation of spinal cord injury animal models 
Neural Regeneration Research  2014;9(22):2008-2012.
Because there is no curative treatment for spinal cord injury, establishing an ideal animal model is important to identify injury mechanisms and develop therapies for individuals suffering from spinal cord injuries. In this article, we systematically review and analyze various kinds of animal models of spinal cord injury and assess their advantages and disadvantages for further studies.
PMCID: PMC4283285  PMID: 25598784
nerve regeneration; spinal cord injury; animal model; establishment; evaluation; reviews; neural regeneration
16.  The Positive Regulatory Roles of the TIFY10 Proteins in Plant Responses to Alkaline Stress 
PLoS ONE  2014;9(11):e111984.
The TIFY family is a novel plant-specific protein family, and is characterized by a conserved TIFY motif (TIFF/YXG). Our previous studies indicated the potential roles of TIFY10/11 proteins in plant responses to alkaline stress. In the current study, we focused on the regulatory roles and possible physiological and molecular basis of the TIFY10 proteins in plant responses to alkaline stress. We demonstrated the positive function of TIFY10s in alkaline responses by using the AtTIFY10a and AtTIFY10b knockout Arabidopsis, as evidenced by the relatively lower germination rates of attify10a and attify10b mutant seeds under alkaline stress. We also revealed that ectopic expression of GsTIFY10a in Medicago sativa promoted plant growth, and increased the NADP-ME activity, citric acid content and free proline content but decreased the MDA content of transgenic plants under alkaline stress. Furthermore, expression levels of the stress responsive genes including NADP-ME, CS, H+-ppase and P5CS were also up-regulated in GsTIFY10a transgenic plants under alkaline stress. Interestingly, GsTIFY10a overexpression increased the jasmonate content of the transgenic alfalfa. In addition, we showed that neither GsTIFY10a nor GsTIFY10e exhibited transcriptional activity in yeast cells. However, through Y2H and BiFc assays, we demonstrated that GsTIFY10a, not GsTIFY10e, could form homodimers in yeast cells and in living plant cells. As expected, we also demonstrated that GsTIFY10a and GsTIFY10e could heterodimerize with each other in both yeast and plant cells. Taken together, our results provided direct evidence supporting the positive regulatory roles of the TIFY10 proteins in plant responses to alkaline stress.
PMCID: PMC4222965  PMID: 25375909
17.  ROCK Inhibitor Is Not Required for Embryoid Body Formation from Singularized Human Embryonic Stem Cells 
PLoS ONE  2014;9(11):e100742.
We report a technology to form human embryoid bodies (hEBs) from singularized human embryonic stem cells (hESCs) without the use of the p160 rho-associated coiled-coil kinase inhibitor (ROCKi) or centrifugation (spin). hEB formation was tested under four conditions: +ROCKi/+spin, +ROCKi/-spin, -ROCKi/+spin, and -ROCKi/-spin. Cell suspensions of BG01V/hOG and H9 hESC lines were pipetted into non-adherent hydrogel substrates containing defined microwell arrays. hEBs of consistent size and spherical geometry can be formed in each of the four conditions, including the -ROCKi/-spin condition. The hEBs formed under the -ROCKi/-spin condition differentiated to develop the three embryonic germ layers and tissues derived from each of the germ layers. This simplified hEB production technique offers homogeneity in hEB size and shape to support synchronous differentiation, elimination of the ROCKi xeno-factor and rate-limiting centrifugation treatment, and low-cost scalability, which will directly support automated, large-scale production of hEBs and hESC-derived cells needed for clinical, research, or therapeutic applications.
PMCID: PMC4217711  PMID: 25365581
18.  How Do Different Types of Community Commitment Influence Brand Commitment? The Mediation of Brand Attachment 
Although previous research indicates that participation in a brand community may foster consumer loyalty to the brand in question, research has seldom examined the mediating effect of community commitment on brand commitment. Drawing from the typologies of organizational commitment, we divide community commitment into three components: continuance community commitment (continuance CC), affective community commitment (affective CC), and normative community commitment (normative CC). We then assess the mediating role of brand attachment in the relationship between these three components and brand commitment. We test the hypotheses using a sample of online mobile phone brand communities in China. The empirical results reveal that brand attachment exerts an indirect (but not mediated) effect on the relationship between continuance CC and brand commitment and on the relationship between normative CC and brand commitment. We also find that it exerts a partial mediating effect on the relationship between affective CC and brand commitment. The findings contribute to the branding literature and have important implications for brand community management.
PMCID: PMC3833461  PMID: 23768073
19.  Short Laminin Peptide for Improved Neural Stem Cell Growth 
The authors developed a novel peptide sequence with only 12 amino acids based on the Ile-Lys-Val-Ala-Val sequence. This novel short peptide shows great promise in artificial niche development for supporting human neural stem/progenitor cell culture in vitro and in vivo and for promoting human neural stem/progenitor cell transplantation in future clinical therapy.
Human neural stem/progenitor cells (hNSCs) are very difficult to culture and require human or animal source extracellular matrix molecules, such as laminin or collagen type IV, to support attachment and to regulate their survival and proliferation. These extracellular matrix molecules are difficult to purify from human or animal tissues, have high batch-to-batch variability, and may cause an immune response if used in clinical applications. Although several laminin- and collagen IV-derived peptides are commercially available, they do not support long-term hNSC attachment and growth. To solve this problem, we developed a novel peptide sequence with only 12 amino acids based on the Ile-Lys-Val-Ala-Val, or IKVAV, sequence: Ac-Cys-Cys-Arg-Arg-Ile-Lys-Val-Ala-Val-Trp-Leu-Cys. This short peptide sequence, similar to tissue-derived full laminin molecules, supported hNSCs to attach and proliferate to confluence for continuous passage and subculture. This short peptide also directed hNSCs to differentiate into neurons. When conjugated to poly(ethylene glycol) hydrogels, this short peptide benefited hNSC attachment and proliferation on the surface of hydrogels and promoted cell migration inside the hydrogels with maximum enhancement at a peptide density of 10 μM. This novel short peptide shows great promise in artificial niche development for supporting hNSC culture in vitro and in vivo and for promoting hNSC transplantation in future clinical therapy.
PMCID: PMC4006481  PMID: 24692587
Neural stem/progenitor cells; Peptide; Attachment; Migration; Hydrogel
20.  ID1 Is a Functional Marker for Intestinal Stem and Progenitor Cells Required for Normal Response to Injury 
Stem Cell Reports  2014;3(5):716-724.
LGR5 and BMI1 mark intestinal stem cells in crypt base columnar cells and +4 position cells, respectively, but characterization of functional markers in these cell populations is limited. ID1 maintains the stem cell potential of embryonic, neural, and long-term repopulating hematopoietic stem cells. Here, we show in both human and mouse intestine that ID1 is expressed in cycling columnar cells, +4 position cells, and transit-amplifying cells in the crypt. Lineage tracing revealed ID1+ cells to be self-renewing, multipotent stem/progenitor cells that are responsible for the long-term renewal of the intestinal epithelium. Single ID1+ cells can generate long-lived organoids resembling mature intestinal epithelium. Complete knockout of Id1 or selective deletion of Id1 in intestinal epithelium or in LGR5+ stem cells sensitizes mice to chemical-induced colon injury. These experiments identify ID1 as a marker for intestinal stem/progenitor cells and demonstrate a role for ID1 in maintaining the potential for repair in response to colonic injury.
•ID1 is expressed in mouse and human intestinal and colonic stem and progenitor cells•ID1+ cells are long-lived and multipotent•Deletion of Id1 in stem and progenitor cells sensitizes mice to colon injury
In this article, Benezra, Dannenberg, and colleagues show that the dominant-negative transcription factor ID1 marks the stem and progenitor cells of the gut and is required in the colon for an optimal response to injury in a mouse model of colitis.
PMCID: PMC4235234  PMID: 25418719
21.  Predicting A-to-I RNA Editing by Feature Selection and Random Forest 
PLoS ONE  2014;9(10):e110607.
RNA editing is a post-transcriptional RNA process that provides RNA and protein complexity for regulating gene expression in eukaryotes. It is challenging to predict RNA editing by computational methods. In this study, we developed a novel method to predict RNA editing based on a random forest method. A careful feature selection procedure was performed based on the Maximum Relevance Minimum Redundancy (mRMR) and Incremental Feature Selection (IFS) algorithms. Eighteen optimal features were selected from the 77 features in our dataset and used to construct a final predictor. The accuracy and MCC (Matthews correlation coefficient) values for the training dataset were 0.866 and 0.742, respectively; for the testing dataset, the accuracy and MCC were 0.876 and 0.576, respectively. The performance was higher using 18 features than all 77, suggesting that a small feature set was sufficient to achieve accurate prediction. Analysis of the 18 features was performed and may shed light on the mechanism and dominant factors of RNA editing, providing a basis for future experimental validation.
PMCID: PMC4206426  PMID: 25338210
22.  Proliferation and migration of hepatoblastoma cells are mediated by IRS-4 via PI3K/Akt pathways 
Levels of IRS-4 (insulin receptor substrate-4) in hepatoblastoma cells from the patients, HepG2 and HuH-6 cell lines were measured by Western Blot analysis, and they were all found significantly higher than those of normal hepatic cells. When the HepG2 and HuH-6 cells cultivated in vitro were treated with IRS-4 and infected with recombinant adenovirus containing IRS-4 gene, the proliferation and migration of the cells were significantly improved. Meanwhile, the expressions of PI3K (phosphatidylinositol 3’-kinase), pS473 Akt (Protein Kinase B) and pThr308 Akt were positively regulated by IRS-4 overexpression. These results indicated that IRS-4 was very likely to be involved in PI3K/Akt path way, which was further confirmed by the fact that the PI3K/Akt blocker LY294002 attenuated the proliferation and migration of the hepatoblastoma cells. In conclusion, IRS-4 enhanced the proliferation and migration of the hepatoblastoma cells via PI3K/Akt pathways.
PMCID: PMC4238470  PMID: 25419430
Hepatoblastoma; insulin receptor substrate-4; PI3K/Akt pathway; proliferation; migration
23.  Cloning and Characterization of tesk1, a Novel Spermatogenesis-Related Gene, in the Tongue Sole (Cynoglossus semilaevis) 
PLoS ONE  2014;9(10):e107922.
Testis-specific protein kinase 1 (Tesk1) is a serine/threonine kinase with unique structural features. In the present study, we cloned and characterized the tesk1 gene of tongue sole, Cynoglossus semilaevis. The full-length tesk1 cDNA consists of 1,672 nucleotides, encoding a 331 amino acid polypeptide with a characteristic structure composed of an N-terminal kinase domain and a C-terminal proline-rich domain. The tesk1 genomic sequence contains eight exons and seven introns. Real-time quantitative PCR revealed that tesk1 mRNA is expressed predominantly in the testis, though the level of expression varied throughout development. We used in situ hybridization to show that tesk1 mRNA is expressed in the spermatids of males and pseudo-males, but not in triploid males. Our results suggest that tongue sole Tesk1 may play a role in spermatogenesis.
PMCID: PMC4182740  PMID: 25271995
24.  Study of the mechanism of sonodynamic therapy in a rat glioma model 
OncoTargets and therapy  2014;7:1801-1810.
The study reported here examined the effect of hematoporphyrin monomethyl ether (HMME)-mediated sonodynamic therapy (SDT) on C6 gliomas implanted in rat brains.
Two weeks after inoculation, glioma development was evaluated by measuring tumor volume using a 1.5 T magnetic resonance imager. Rats that had a well-developed C6 glioma (usually when the tumor diameter reached 3–5 mm) were used to test SDT, ultrasound-alone, and HMME-alone treatments. Rats both administered and not administered intravenous HMME 10 μg/mL were insonated by a 1 MHz ultrasound at a dose of 0.5 W/cm2.
SDT treatment could effectively inhibit the expansion of intracranial gliomas in vivo. The treatment with ultrasound alone could inhibit glioma growth within 1 week; however, 1 week later, the tumor started growing again. In contrast, the effect of SDT could last at least 2 weeks. Injection of HMME alone had no effects on inhibiting glioma growth, suggesting the sonosensitizer HMME has no antitumor effect. Both SDT and ultrasound-alone treatment could extend the survival of rats implanted with a C6 glioma. Pathological and electron microscopic examinations suggested SDT and ultrasound-alone treatment could induce glioma necrosis by way of triggering glioma-cell apoptosis, which was confirmed by immunohistological examination with cytochrome-c and caspase-3 antibodies. Most importantly, we found that the sonosensitizer HMME could enhance the ultrasound-induced antitumor effect by selectively assisting ultrasound targeting of glioma angiogenesis inhibition.
This study with a rat C6 glioma experimental model showed that SDT can potentially be useful in the treatment of deep-seated malignant gliomas.
PMCID: PMC4199795  PMID: 25336971
antitumor mechanism; ultrasound; hematoporphyrin monomethyl ether
25.  Polymorphism Ala54Thr of Fatty Acid-Binding Protein 2 Gene is Not Associated with Stroke Risk in Han Population of Hunan China 
It is still unclear which genetic factors have a role in stroke. Studies have found that Ala54Thr of Fatty Acid-Binding Protein 2 (FABP2) was associated with stroke risk. This study aimed to determine whether polymorphism Ala54Thr of FABP2 is associated with stroke risk in the Hunan Han population of China.
A total of 206 cerebral infarction (CI) patients, 185 cerebral hemorrhage (CH) patients, and 172 controls were enrolled in this study. Ala54Thr genotyping was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).
No significant difference was observed in genotypic distribution of FABP2 Ala54Thr between the stroke group (CI subgroup, CH subgroup included) and control group. In the stroke group, plasma triglycerides (TG) levels of subjects who carried Ala/Thr, Thr/Thr were significantly higher than those carrying Ala/Ala. In the control group, blood lipids were not significantly different among 3 genotypes of Ala54Thr. There was no significant difference in blood pressure and fasting blood sugar between the stroke group and controls.
Our study showed that Ala54Thr of FABP2 may be not associated with stroke risk but may be associated with plasma TG level of stroke patients from a Hunan Han population of China.
PMCID: PMC4188191  PMID: 25262933
Cerebral Hemorrhage; Cerebral Infarction; Fatty Acid-Binding Proteins; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Stroke

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