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1.  Novel Three-Component Rieske Non-Heme Iron Oxygenase System Catalyzing the N-Dealkylation of Chloroacetanilide Herbicides in Sphingomonads DC-6 and DC-2 
Applied and Environmental Microbiology  2014;80(16):5078-5085.
Sphingomonads DC-6 and DC-2 degrade the chloroacetanilide herbicides alachlor, acetochlor, and butachlor via N-dealkylation. In this study, we report a three-component Rieske non-heme iron oxygenase (RHO) system catalyzing the N-dealkylation of these herbicides. The oxygenase component gene cndA is located in a transposable element that is highly conserved in the two strains. CndA shares 24 to 42% amino acid sequence identities with the oxygenase components of some RHOs that catalyze N- or O-demethylation. Two putative [2Fe-2S] ferredoxin genes and one glutathione reductase (GR)-type reductase gene were retrieved from the genome of each strain. These genes were not located in the immediate vicinity of cndA. The four ferredoxins share 64 to 72% amino acid sequence identities to the ferredoxin component of dicamba O-demethylase (DMO), and the two reductases share 62 to 65% amino acid sequence identities to the reductase component of DMO. cndA, the four ferredoxin genes, and the two reductases genes were expressed in Escherichia coli, and the recombinant proteins were purified using Ni-affinity chromatography. The individual components or the components in pairs displayed no activity; the enzyme mixture showed N-dealkylase activities toward alachlor, acetochlor, and butachlor only when CndA-His6 was combined with one of the four ferredoxins and one of the two reductases, suggesting that the enzyme consists of three components, a homo-oligomer oxygenase, a [2Fe-2S] ferredoxin, and a GR-type reductase, and CndA has a low specificity for the electron transport component (ETC). The N-dealkylase utilizes NADH, but not NADPH, as the electron donor.
PMCID: PMC4135782  PMID: 24928877
2.  Nanofibers Support Oligodendrocyte Precursor Cell Growth and Function as a Neuron-Free Model for Myelination Study 
Biomacromolecules  2013;15(1):319-326.
Nanofiber-based scaffolds may simultaneously provide immediate contact guidance for neural regeneration and act as a vehicle for therapeutic cell delivery to enhance axonal myelination. Additionally, nanofibers can serve as a neuron-free model to study myelination of oligodendrocytes. In this study, we fabricated nanofibers using a polycaprolactone and gelatin co-polymer. The ratio of the gelatin component in the fibers was confirmed by energy dispersive x-ray spectroscopy. The addition of gelatin to the polycaprolactone (PCL) for nanofiber fabrication decreased the contact angle of the electrospun fibers. We showed that both polycaprolactone nanofibers as well as polycaprolactone and gelatin co-polymer nanofibers can support oligodendrocyte precursor cell (OPC) growth and differentiation. OPCs maintained their phenotype and viability on nanofibers and were induced to differentiate into oligodendrocytes. The differentiated oligodendrocytes extend their processes along the nanofibers and ensheathed the nanofibers. Oligodendrocytes formed significantly more myelinated segments on the PCL and gelatin co3polymer nanofibers than those on PCL nanofibers alone.
PMCID: PMC3909489  PMID: 24304204
Oligodendrocyte precursor cells; nanofibers; myelination; differentiation
3.  Regional covariance patterns of gray matter alterations in Alzheimer’s disease and its replicability evaluation 
Journal of magnetic resonance imaging : JMRI  2013;39(1):10.1002/jmri.24143.
To identify regional network covariance patterns of gray matter associated with Alzheimer’s disease (AD) and to further evaluate its replicability and stability.
Materials and Methods
This study applied a multivariate analytic approach based on scaled subprofile modeling (SSM) to structural MRI data from 19 patients with AD and 19 healthy controls (HC). We further applied the derived covariance patterns to examine the replicability and stability of AD-associated covariance patterns in an independent dataset [13 AD and 14 HC] acquired with a different scanner.
The AD-associated covariance patterns identified from SSM combined principal components mainly involved the temporal lobe and parietal lobe. The expression of covariance patterns was significantly higher in AD patients than HC (t(36) = 5.84, p= 5.75E–7) and predicted the AD/HC group membership (84% sensitivity and 90% specificity). In replicability evaluation, the expression of the forward applied covariance patterns was still statistically significant and had acceptable discriminability (69% sensitivity and 71% specificity).
AD patients showed regional gray matter alterations in a reliable covariance manner. The results suggest that SSM has utility for characterizing covariant features, therefore, can assist us with further understanding covariance patterns of gray matter in AD based on the view of the network.
PMCID: PMC3732807  PMID: 23589138
multivariate analysis; scaled subprofile model; Alzheimer’s disease; structural MRI; voxel-based morphometry
4.  Validation of copy number variants associated with prostate cancer risk and prognosis 
Urologic oncology  2013;32(1):44.e15-44.e20.
Two recent studies have reported novel heritable copy number variants (CNVs) on chromosomes 2p, 15q, and 12q to be associated with prostate cancer risk in non Hispanic Caucasians. The goal of the current study was to determine whether these findings could be independently confirmed in the Caucasian population from the South Texas area.
Methods and Materials
The study subjects consisted of participants of the San Antonio Biomarkers Of Risk for prostate cancer (SABOR) cohort and additional cases ascertained in the same metropolitan area. We genotyped all 7 of the reported copy number variants using real time quantitative PCR in 1536 (317 cases, 1219 controls) non Hispanic Caucasian men, and additionally genotyped 632 (191 cases, 441 controls) Hispanic Caucasian men for one of these variants, a deletion on 2p24.3.
Association of the deletion on 2p24.3 with overall prostate cancer risk did not meet our significance criteria but was consistent with previous reports [odds ratio (OR), 1.40; 95% confidence interval (95% CI), 0.99 2.00; P = 0.06]. Among Hispanic Caucasians, this deletion is much less prevalent (MAF of 0.059 and 0.024 in non Hispanic and Hispanic Caucasians respectively) and did not show evidence of association with risk for prostate cancer. Interestingly, among non Hispanic Caucasians, carrying a homozygous deletion of 2p24.3 was significantly associated with high grade prostate cancer as defined by a Gleason sum ≥8 [OR, 27.99; 95% CI, 1.99 392.6; P = 0.007 (Fischer's Exact)]. The remaining six copy number variable regions were either not polymorphic in our cohort of non Hispanic Caucasians, or showed no evidence of association.
Our findings are consistent with the reported observation that a heritable deletion on 2p24.3 is associated with prostate cancer risk in non Hispanic Caucasians. Additionally, our observations indicate that the 2p24.3 variant is associated with risk for high grade prostate cancer in a recessive manner. We were unable to replicate any association with prostate cancer for the variants on chromosomes 15q and 12q which may be explained by regional population differences in low frequency variants and disease heterogeneity.
PMCID: PMC4105226  PMID: 24054869
Prostate; cancer; risk; deletion; prognosis
5.  How is water-use efficiency of terrestrial ecosystems distributed and changing on Earth? 
Scientific Reports  2014;4:7483.
A better understanding of ecosystem water-use efficiency (WUE) will help us improve ecosystem management for mitigation as well as adaption to global hydrological change. Here, long-term flux tower observations of productivity and evapotranspiration allow us to detect a consistent latitudinal trend in WUE, rising from the subtropics to the northern high-latitudes. The trend peaks at approximately 51°N, and then declines toward higher latitudes. These ground-based observations are consistent with global-scale estimates of WUE. Global analysis of WUE reveals existence of strong regional variations that correspond to global climate patterns. The latitudinal trends of global WUE for Earth's major plant functional types reveal two peaks in the Northern Hemisphere not detected by ground-based measurements. One peak is located at 20° ~ 30°N and the other extends a little farther north than 51°N. Finally, long-term spatiotemporal trend analysis using satellite-based remote sensing data reveals that land-cover and land-use change in recent years has led to a decline in global WUE. Our study provides a new framework for global research on the interactions between carbon and water cycles as well as responses to natural and human impacts.
PMCID: PMC4265788  PMID: 25500908
6.  Development of synthetic of peptide-functionalized liposome for enhanced targeted ovarian carcinoma therapy 
In this study, we report an active targeting liposomal formulation directed by a novel peptide (T7) that specifically binds to the transferrin receptor (TfR) overexpressed on ovarian carcinoma cells. The objectives of this study were to evaluate the in vitro and in vivo tumor drug targeting delivery of T7-anchored liposomes on A2780 cells. T7 conjugated to the distal end of DSPE-PEG2000-maleimide was incorporated into the liposomes via a post-insertion method, the liposome could keep stability in 50% FBS for more than 24 h. The uptake efficiency of T7-LP was 3.7 times higher than that of LP on A2780 cells. The anti-proliferative activity of T7-LP-PTX against A2780 cells was much stronger compared to that of LP-PTX and free PTX, respectively. The homing specificity and anticancer efficacy of T7-LP-PTX were also evaluated on the tumor spheroids, which revealed that T7-LP-PTX was more efficaciously internalized into tumor cells than LP. Compared to LP, T7-LP-PTX showed the highest accumulation capability into tumor spheroids, and the greatest tumor growth inhibitory effect in vitro. In the in vivo study, the T7-LP-PTX showed the best inhibition effect of the tumor growth for the A2780-bearing mice and tumor accumulation. In brief, the T7-LP may be an efficient targeting drug delivery system for ovarian carcinoma.
PMCID: PMC4307424  PMID: 25663977
Ovarian carcinoma; transferrin receptor; liposome; tumor targeting
7.  Resistant mutants induced by adefovir dipivoxil in hepatitis B virus isolates 
World Journal of Gastroenterology : WJG  2014;20(45):17100-17106.
AIM: To investigate the loci of adefovir dipivoxil (ADV)-induced resistance in hepatitis B virus (HBV) isolates and optimize the management of ADV-treated patients.
METHODS: Between June 2008 and August 2010, a cross-sectional control study was conducted comprising 79 patients with chronic HBV infection-related liver disease who had been administered ADV monotherapy. Patients underwent liver imaging. Serum DNA extracts were analyzed for HBV DNA levels, genotypes, and serology markers, and deep sequencing of the HBV P gene was performed.
RESULTS: ADV-resistant patients were found either with a single mutated locus, or with coexisting mutated loci. The most prevalent mutations were rtA181T, rtV214A, and rtN236T. Twenty-six patients had more than two mutated loci. The mutants were distributed among the patients without any significant affinity for gender, age, end-stage of liver disease, complications of non-alcoholic fatty liver disease, or HBV DNA levels. Patients with the rtA181T mutant were primarily infected with genotype C and e-antigen negative HBV, while patients with the rtN236T mutant were primarily infected by genotype B HBV (χ2 = 6.004, 7.159; P = 0.023, 0.007). The duration of treatment with ADV was shorter in the single mutant group compared with the multi-mutant group (t = 2.426, P = 0.018).
CONCLUSION: Drug-resistant HBV mutants are complex and diverse. Patients should receive the standard and first-line antiviral treatment, strictly comply with medication dosage, and avoid short-term withdrawal.
PMCID: PMC4258578  PMID: 25493022
Hepatitis B virus; Adefovir dipivoxil; Drug-resistant mutant; Gene sequencing
8.  Recent trends in SELEX technique and its application to food safety monitoring 
Mikrochimica acta  2014;181(5-6):479-491.
The method referred to as “systemic evolution of ligands by exponential enrichment” (SELEX) was introduced in 1990 and ever since has become an important tool for the identification and screening of aptamers. Such nucleic acids can recognize and bind to their corresponding targets (analytes) with high selectivity and affinity, and aptamers therefore have become attractive alternatives to traditional antibodies not the least because they are much more stable. Meanwhile, they have found numerous applications in different fields including food quality and safety monitoring. This review first gives an introduction into the selection process and to the evolution of SELEX, then covers applications of aptamers in the surveillance of food safety (with subsections on absorptiometric, electrochemical, fluorescent and other methods), and then gives conclusions and perspectives. The SELEX method excels by its features of in vitro, high throughput and ease of operation. This review contains 86 references.
PMCID: PMC4239545  PMID: 25419005
SELEX; Aptamer; Food safety; Rapid detection; Biosensor
9.  PDCD5 transfection increases cisplatin sensitivity and decreases invasion in hepatic cancer cells 
Oncology Letters  2014;9(1):411-417.
Low expression levels of the programmed cell death 5 (PDCD5) gene have been reported in numerous human cancers, however, PDCD5 expression has not been investigated in hepatic cancer. The present study aims to investigate the biological behavior of PDCD5 overexpression in hepatocellular carcinoma (HCC) cells. The PDCD5 gene was stably transfected into the HepG2 HCC cell line (HepG2-PDCD5), and the expression levels of PDCD5 were examined by quantitative polymerase chain reaction and western blotting. An MTT assay was used to assess the cellular proliferating ability, and propidium iodide (PI) staining was used to evaluate the cell cycle by flow cytometry. The cells were incubated with 2 ng/ml transforming growth factor (TGF)-β for 7 days in order to induce invasion and epithelial-mesenchymal transition (EMT). Apoptosis was measured by Annexin V-fluorescein isothiocyanate and PI double labeling. A Boyden chamber invasion assay was carried out to detect tumor invasion. Western blotting was performed to detect the protein expression levels of PDCD5, insulin-like growth factor (IGF)-1 and the EMT marker, Snail. The results showed that the HepG2-PDCD5 cells exhibited slower proliferation rates and high G2/M cell numbers compared with those of the HepG2 and HepG2-Neo controls (P<0.05). The PDCD5 transfected cells showed higher sensitivity to cisplatin treatment than the HepG2-Neo cells, with a higher p53 protein expression level. PDCD5 overexpression can attenuate tumor invasion, EMT and the level of IGF-1 protein induced by TGF-β treatment. In conclusion, stable transfection of the PDCD5 gene can inhibit growth and induce cell cycle arrest in HepG2 cells, and its also notably improves the apoptosis-inducing effects of cisplatin, and reverses invasion and EMT induced by TGF-β. The use of PDCD5 is a novel strategy for improving the chemotherapeutic effects on HCC.
PMCID: PMC4246700  PMID: 25436001
hepatocellular carcinoma; PDCD5; cisplatin; apoptosis; p53; epithelial-mesenchymal transition
10.  The Utility of Gadoxetic Acid-Enhanced MR Imaging to Characterize Atypical Cirrhotic Nodules Detected on Dynamic CT Images 
PLoS ONE  2014;9(10):e107869.
To evaluate whether gadoxetic acid (Gd-EOB-DTPA)-enhanced MR images of tumors taken during the hepatocyte-specific phase can aid in the differentiation between hepatocellular carcinoma (HCC) and dysplastic nodules (DNs) in patients with atypical cirrhotic nodules detected on dynamic CT images.
Materials and Methods
Seventy-one patients with 112 nodules showing atypical dynamic enhancement on CT images underwent gadoxetic acid-enhanced MR imaging (MRI) studies. Using a reference standard, we determined that 33 of the nodules were DNs and that 79 were true HCCs. Tumor size, signal intensity on precontrast T1-weighted images (T1WI) and T2WI, and the pattern of dynamic enhancement on MR images taken in the hepatocyte-phase were determined.
There were significant differences in tumor size, hyperintensity on T2WI, hypointensity on T1WI, typical HCC enhancement pattern on dynamic MR images, or hypointensity on hepatocyte-phase images between DNs and HCC. The sensitivity and specificity were 60.8% and 87.9% for T2WI, 38.0% and 87.9% for T1WI, 17.7% and 100% for dynamic MR imaging, 83.5% and 84.9% for hepatocyte-phase imaging, and 60.8% and 87.9% for tumor size (threshold of 1.7 cm).
Gd-EOB-DTPA-enhanced hepatocyte-phase imaging is recommended for patients at high risk of HCC who present with atypical lesions on dynamic CT images.
PMCID: PMC4195587  PMID: 25310817
11.  Development and application of an AllGlo probe-based qPCR assay for detecting knockdown resistance (kdr) mutations in Anopheles sinensis 
Malaria Journal  2014;13(1):379.
Anopheles sinensis is one of the most important malaria vectors in China and other Southeast Asian countries. High levels of resistance have been reported in this species due to the long-term use of insecticides, especially pyrethroids, for public health and agricultural purposes. Knockdown resistance (kdr) caused by a single base pair mutation in the gene encoding the sodium channel is strongly associated with pyrethroid insecticide resistance in many Anopheles mosquitoes. There are few methods currently available for detecting kdr mutations in An. sinensis.
A novel AllGlo probe-based qPCR (AllGlo-qPCR) method was developed to screen for the predominant kdr mutations in An. sinensis mosquitoes from the Jiangsu Province. The results from AllGlo-qPCR, allele-specific PCR (AS-PCR), and TaqMan-MGB probe-based qPCR (TaqMan-qPCR) were compared. A comparative analysis of the equipment required, ease of use and cost of the available methods was also performed. Finally, the AllGlo-qPCR method was used to detect the frequencies of kdr mutations from the other four provinces in central China.
Six kdr genotypes were detected in An. sinensis from the Jiangsu Province by DNA sequencing. The AllGlo-qPCR method detected all of the kdr genotypes with a high level of accuracy (97% sensitivity and 98% specificity). AllGlo-qPCR correctly determined the kdr genotypes of 98.73% of 158 An. sinensis samples, whereas TaqMan-qPCR and AS-PCR correctly identified 96.84% and 88.61% of mutations, respectively. Furthermore, the AllGlo-qPCR method is simpler to perform, requires less equipment, and exhibits a moderate expense cost comparing with the other tested methods of kdr mutation detection. Samples collected from four of the other provinces in central China showed a high frequency of kdr mutation in An. sinensis, as detected by the established AllGlo-qPCR method.
The novel AllGlo-qPCR method developed for kdr mutation detection in An. sinensis exhibits greater specificity and sensitivity than currently available methods and is more cost-effective; therefore, it represents a useful tool for entomological surveillance.
PMCID: PMC4182860  PMID: 25245258
Anopheles sinensis; Knockdown resistance (kdr); AllGlo probe; qPCR
12.  BurnCalc assessment study of computer-aided individual three-dimensional burn area calculation 
Accurate estimation of a burned area is crucial to decisions about fluid resuscitation, surgical options, nutritional support, and prognosis. Widely used clinical methods to estimate a burn area are two-dimensional. They do not consider age, sex, body mass, physical deformities, or other relevant factors. Computer-aided methods have improved the accuracy of estimating burned areas by including data analysis and reducing subjective differences. Three-dimensional (3D) scanning allows us to determine body dimensions rapidly and reproducibly. We describe an individualized, cost-efficient, portable 3D scanning system, BurnCalc, that can create an individual 3D model and then calculate body surface area (BSA) and the burn area accurately and quickly.
The BurnCalc system was validated by verifying the accuracy and stability of BSA calculation. We measured 10 regular objects in experiment 1, using Student’s t-test and the intraclass correlation coefficient (ICC) in the analysis. In experiment 2, artificial paper patches of known dimensions were attached to various parts of the body of 40 volunteers. Their sizes were then calculated using BurnCalc. The BurnCalc data were compared to actually measured values to verify accuracy and stability. Total BSAs of these 40 volunteers were also calculated by BurnCalc and compared to those derived from an accepted formula. In experiment 3, four experts using Chinese Rule-of-Nines or Rule-of-Palms methods calculated the percentages of the total BSA in 17 volunteers. Student’s t-test and ICC, respectively, were used to compare the results obtained with the BurnCalc technique.
Statistically, in experiment 1, p = 0.834 and ICC = 0.999, demonstrating that there was no difference between the BurnCalc and real measurements. Also, the hypothesis of null difference among measures (experiment 2) was true because p > 0.05 and ICC = 0.999, indicating that calculations of the total BSA and the burn area were more accurate using the BurnCalc technology. The reliability of the BurnCalc program was 99.9%. In experiment 3, only the BurnCalc method exhibited values of p > 0.05 (p = 0.774) and ICC = 0.999.
BurnCalc technology produced stable, accurate readings, suggesting that BurnCalc could be regarded as a new standard clinical method.
PMCID: PMC4173062  PMID: 25204349
Three-dimensional scanning; Individualized body model; Burn area estimation
13.  Association between ERCC1 and TS mRNA levels and disease free survival in colorectal cancer patients receiving oxaliplatin and fluorouracil (5-FU) adjuvant chemotherapy 
BMC Gastroenterology  2014;14(1):154.
Aim was to explore the association of ERCC1 and TS mRNA levels with the disease free survival (DFS) in Chinese colorectal cancer (CRC) patients receiving oxaliplatin and 5-FU based adjuvant chemotherapy.
Total 112 Chinese stage II-III CRC patients were respectively treated by four different chemotherapy regimens after curative operation. The TS and ERCC1 mRNA levels in primary tumor were measured by real-time RT-PCR. Kaplan–Meier curves and log-rank tests were used for DFS analysis. The Cox proportional hazards model was used for prognostic analysis.
In univariate analysis, the hazard ratio (HR) for the mRNA expression levels of TS and ERCC1 (logTS: HR = 0.820, 95% CI = 0.600 - 1.117, P = 0.210; logERCC1: HR = 1.054, 95% CI = 0.852 - 1.304, P = 0.638) indicated no significant association of DFS with the TS and ERCC1 mRNA levels. In multivariate analyses, tumor stage (IIIc: reference, P = 0.083; IIb: HR = 0.240, 95% CI = 0.080 - 0.724, P = 0.011; IIc: HR < 0.0001, P = 0.977; IIIa: HR = 0.179, 95% CI = 0.012 - 2.593, P = 0.207) was confirmed to be the independent prognostic factor for DFS. Moreover, the Kaplan-Meier DFS curves showed that TS and ERCC1 mRNA levels were not significantly associated with the DFS (TS: P = 0.264; ERCC1: P = 0.484).
The mRNA expression of ERCC1 and TS were not applicable to predict the DFS of Chinese stage II-III CRC patients receiving 5-FU and oxaliplatin based adjuvant chemotherapy.
PMCID: PMC4156636  PMID: 25175730
Colorectal cancer; ERCC1; TS; Real-time PCR; Adjuvant chemotherapy
14.  VEGF Genetic Polymorphisms May Contribute to the Risk of Diabetic Nephropathy in Patients with Diabetes Mellitus: A Meta-Analysis 
The Scientific World Journal  2014;2014:624573.
Objective. This meta-analysis aimed to investigate a comprehensive and reliable conclusion on the correlations of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) gene with the risk of diabetic nephropathy (DN) in patients with diabetes mellitus (DM). Methods. We screened PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases for those relevant studies that investigated the association of 14,945 subjects with clinicopathological parameters in gastric cancer. Results. Eleven case-control studies that met all inclusion criteria were included in this meta-analysis. A total of 14,945 subjects were involved, including 3,049 DN patients and 11,896 DM patients. Our meta-analysis results revealed that VEGF rs2010963 and rs3025039 polymorphisms might contribute to the risk of DN in DM patients. Ethnicity-stratified analysis suggested that VEGF genetic polymorphisms were associated with an increased risk of DN among Asians. However, we found no correlations of VEGF genetic polymorphisms with susceptibility to DN among Caucasians. Conclusion. Our findings suggest that VEGF rs2010963 and rs3025039 polymorphisms may contribute to the risk of DN in DM patients, especially among Asians. Thus, VEGF genetic polymorphisms could be useful biomarkers for early diagnosis of DN in DM patients.
PMCID: PMC4144390  PMID: 25184149
15.  Repair of injured spinal cord using biomaterial scaffolds and stem cells 
The loss of neurons and degeneration of axons after spinal cord injury result in the loss of sensory and motor functions. A bridging biomaterial construct that allows the axons to grow through has been investigated for the repair of injured spinal cord. Due to the hostility of the microenvironment in the lesion, multiple conditions need to be fulfilled to achieve improved functional recovery. A scaffold has been applied to bridge the gap of the lesion as contact guidance for axonal growth and to act as a vehicle to deliver stem cells in order to modify the microenvironment. Stem cells may improve functional recovery of the injured spinal cord by providing trophic support or directly replacing neurons and their support cells. Neural stem cells and mesenchymal stem cells have been seeded into biomaterial scaffolds and investigated for spinal cord regeneration. Both natural and synthetic biomaterials have increased stem cell survival in vivo by providing the cells with a controlled microenvironment in which cell growth and differentiation are facilitated. This optimal multi‒disciplinary approach of combining biomaterials, stem cells, and biomolecules offers a promising treatment for the injured spinal cord.
PMCID: PMC4282172  PMID: 25157690
16.  Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity 
Journal of medicinal chemistry  2013;56(14):10.1021/jm400467w.
We described a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations, and either agonize or antagonize ERα and ERβ. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ERα positive breast) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer) or Vero (non-cancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working towards a higher therapeutic index at the earliest stages of drug development.
PMCID: PMC3812312  PMID: 23786452
17.  Peer support for patients with type 2 diabetes in rural communities of China: protocol for a cluster randomized controlled trial 
BMC Public Health  2014;14(1):747.
The prevalence of diabetes has been growing rapidly in developing countries. This causes devastating economic burdens and increases demands on the health care system. Therefore, there is an urgent need to find a cost-effective and multi-faceted approach for diabetes care. Peer support models provide a potentially low-cost, flexible means which complements the current existing health care services. In this way, trained peer leaders can become qualified extensions to a formal healthcare system, capable of assisting education delivery and bolstering the efforts of professional staff. As such, creating a cultural specific peer support program and determining whether it is acceptable and cost-effective in rural communities of China is crucial. This study aims to implement and evaluate biophysical and psychosocial outcomes of peer support program for people with type 2 diabetes in rural communities, and to explore the program’s feasibility and sustainability in China.
This study is a cluster randomised controlled trial. All consenting patients will be randomised by community staff members to receive either peer support or the control care. The data collection and analysis including social demographics, health status, psychosocial status, economic status and biomedical measures will be collected at baseline, 6 months, and 12 months. The primary indicator measured is the change in HbA1c, whereas secondary indicators include biophysical, psychosocial functioning and other lifestyle factors. Finally, economic evaluations will determine whether the program is cost effective.
This protocol is a cluster randomized, controlled trial of group-based peer support for people with type 2 diabetes in the community settings of rural China. Results from this trial may provide evidence to the effectiveness of peer support; furthermore, they will provide valuable information concerning the acceptability and feasibility of a new approach to improve diabetes self-management among resource-constrained settings.
Trial registration Identifier: NCT02119572, April 18, 2014.
PMCID: PMC4132925  PMID: 25056813
Peer support; Diabetes; Self-management; Rural health
18.  Online Spatial Normalization for Real-Time fMRI 
PLoS ONE  2014;9(7):e103302.
Real-time functional magnetic resonance imaging (rtfMRI) is a recently emerged technique that demands fast data processing within a single repetition time (TR), such as a TR of 2 seconds. Data preprocessing in rtfMRI has rarely involved spatial normalization, which can not be accomplished in a short time period. However, spatial normalization may be critical for accurate functional localization in a stereotactic space and is an essential procedure for some emerging applications of rtfMRI. In this study, we introduced an online spatial normalization method that adopts a novel affine registration (AFR) procedure based on principal axes registration (PA) and Gauss-Newton optimization (GN) using the self-adaptive β parameter, termed PA-GN(β) AFR and nonlinear registration (NLR) based on discrete cosine transform (DCT). In AFR, PA provides an appropriate initial estimate of GN to induce the rapid convergence of GN. In addition, the β parameter, which relies on the change rate of cost function, is employed to self-adaptively adjust the iteration step of GN. The accuracy and performance of PA-GN(β) AFR were confirmed using both simulation and real data and compared with the traditional AFR. The appropriate cutoff frequency of the DCT basis function in NLR was determined to balance the accuracy and calculation load of the online spatial normalization. Finally, the validity of the online spatial normalization method was further demonstrated by brain activation in the rtfMRI data.
PMCID: PMC4106896  PMID: 25050799
19.  Endoscopic submucosal dissection of esophageal granular cell tumor 
Esophageal granular cell tumor (GCT) is a rare benign tumor with malignant potential. With wide application of endoscopic techniques, the esophageal GCT discovery rate and treatment strategy has changed. This study was to preliminarily evaluate outcomes of endoscopic diagnosis and treatment for esophageal GCT.
Fourteen patients (eight men, six women; median age, 48.5 years) with esophageal GCT diagnosed and treated by esophageal endoscopy. Esophagoscopy, endoscopic ultrasound (EUS), and endoscopic submucosal dissection (ESD) techniques were employed in diagnosis and resection.
Esophageal GCTs are tumors which arise from the submucosal layer, and vary in color but with a yellowish color on endoscopy being most common. On EUS, features were homogenous (ten cases) or mildly heterogeneous (four cases) hypoechoic solid pattern originating from the muscularis mucosa (six cases) or submucosal layer (eight cases) of the esophageal wall. Tumors ranged from 4 to 26 mm (mean 12.1 mm). ESD was performed in all patients without complication. Clinical diagnosis was confirmed by pathology and immunohistochemical examination (positive for S-100 and vimentin). The en bloc resection rate was 92.9% (13/14) pathologically. Operation time was 25 to 60 minutes, mean 38.2 ± 10.1 minutes. No recurrence was observed during a mean follow-up of 16.6 ± 12.7 (range, 4 to 40) months.
Esophagoscopy and EUS increased the esophageal GCT discovery rate, and its features were summarized. Minimally invasive ESD is feasible and safe for excisional biopsy, providing pathological diagnosis and treatment.
PMCID: PMC4126351  PMID: 25030028
Endoscopic submucosal dissection; Esophagus; Granular cell tumor; Minimally invasive; Abrikossoff tumor
20.  Transplantation of endothelial progenitor cells in treating rats with IgA nephropathy 
BMC Nephrology  2014;15:110.
Therapeutic options in IgAN are still limited. The aim of this study is to explore the feasibility of using endothelial progenitor cell to treat IgAN in rat model.
Rat bone marrow mononuclear cells (BM-MNCs) obtained with density gradient centrifugation were cultured in vitro, and induced into endothelial progenitor cells (EPCs). EPCs were identified by surface marker CD34, CD133 and VEGFR2 (FLK-1) and by Dil-Ac-LDL/FITC-UEA-1 double staining. EPCs were labeled with PKH26 prior to transplantation. Rat model of IgAN was established by oral administration of bovine serum albumin together with lipopolysaccharide via the caudal vein and subcutaneous injection of CCL4. Kidney paraffin sections were stained by H&E and PAS. Immunofluorescence was used to assess IgA deposition in the glomeruli. Peritubular capillary (PTC) density was determined by CD31 staining. Monocyte chemoattrant protein-1 (MCP-1), hypoxia-inducible factor-1α (HIF-1α) and CD105 were also measured by immunohistochemistry, western blotting and real-time fluorescent quantitative PCR.
The transplanted BM-EPCs were successfully located in IgAN rat kidney. After transplantation, Urinary red blood cell, urine protein, BUN, Scr and IgA serum level were significantly decreased, so were the areas of glomerular extracellular matrix and the IgA deposition in the glomeruli. In addition, PTC density was elevated. And the expression levels of HIF-1α and MCP-1 were significantly down-regulated, while the expression of CD105 was up-regulated. All these changes were not observed in control groups.
The BM-EPCs transplantation significantly decreases the expansion of glomerular extracellular matrix and the deposition of IgA in the glomeruli; lowers the expression of inflammatory factors; increases PTC density; improves ischemic-induced renal tissue hypoxia, all of which improves the renal function and slows the progress of IgA nephropathy.
PMCID: PMC4109798  PMID: 25012471
Endothelial progenitor cells; IgA nephropathy; Peritubular capillary; Transplantation
21.  The Receiver Operational Characteristic for Binary Classification with Multiple Indices and Its Application to the Neuroimaging Study of Alzheimer’s Disease 
Given a single index, the receiver operational characteristic (ROC) curve analysis is routinely utilized for characterizing performances in distinguishing two conditions/groups in terms of sensitivity and specificity. Given the availability of multiple data sources (referred to as multi-indices), such as multimodal neuroimaging data sets, cognitive tests, and clinical ratings and genomic data in Alzheimer’s disease (AD) studies, the single-index-based ROC underutilizes all available information. For a long time, a number of algorithmic/analytic approaches combining multiple indices have been widely used to simultaneously incorporate multiple sources. In this study, we propose an alternative for combining multiple indices using logical operations, such as “AND,” “OR,” and “at least n” (where n is an integer), to construct multivariate ROC (multiV-ROC) and characterize the sensitivity and specificity statistically associated with the use of multiple indices. With and without the “leave-one-out” cross-validation, we used two data sets from AD studies to showcase the potentially increased sensitivity/specificity of the multiV-ROC in comparison to the single-index ROC and linear discriminant analysis (an analytic way of combining multi-indices). We conclude that, for the data sets we investigated, the proposed multiV-ROC approach is capable of providing a natural and practical alternative with improved classification accuracy as compared to univariate ROC and linear discriminant analysis.
PMCID: PMC4085147  PMID: 23702553
Alzheimer’s dementia (AD); multiple indices; multiV-ROC; receiver operational characteristic (ROC)
22.  Hainanerectamines A–C, Alkaloids from the Hainan Sponge Hyrtios erecta 
Marine Drugs  2014;12(7):3982-3993.
Two new indole alkaloids, hainanerectamines A (1) and B (2), and one new β-carboline alkaloids, hainanerectamines C (4), along with five known related alkaloids (3, 5–8), have been isolated from the Hainan marine sponge Hyrtios erecta. The structures of new compounds 1, 2 and 4 were determined by detailed analysis of their 1D and 2D NMR spectra and by comparison of their spectroscopic data with those of related model compounds. Compounds 2–4 exhibited moderate inhibitory activity against Aurora A, a member of serine/threonine kinase family involving in the regulation of cell division and a new target in cancer treatment, with IC50 values of 24.5, 13.6, and 18.6 μg/mL, respectively.
PMCID: PMC4113810  PMID: 24983641
sponge; Hyrtios erecta; Thorectidae; hainanerectamines; indole; β-carboline; Aurora A
23.  Dual-Acting Histone Deacetylase-Topoisomerase I Inhibitors 
Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.
PMCID: PMC3657756  PMID: 23622981
24.  Predisposing Risk Factors for Delirium in Living Donor Liver Transplantation Patients in Intensive Care Units 
PLoS ONE  2014;9(5):e96676.
Delirium is one of the main causes of increased length of intensive care unit (ICU) stay among patients who have undergone living donor liver transplantation (LDLT). We aimed to evaluate risk factors for delirium after LDLT as well as to investigate whether delirium impacts the length of ICU and hospital stay.
Seventy-eight patients who underwent LDLT during the period January 2010 to December 2012 at a single medical center were enrolled. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale was used to diagnose delirium. Preoperative, postoperative, and hematologic factors were included as potential risk factors for developing delirium.
During the study period, delirium was diagnosed in 37 (47.4%) patients after LDLT. The mean onset of symptoms occurred 7.0±5.5 days after surgery and the mean duration of symptoms was 5.0±2.6 days. The length of stay in the ICU for patients with delirium (39.8±28.1 days) was significantly longer than that for patients without delirium (29.3±19.0 days) (p<0.05). Risk factors associated with delirium included history of alcohol abuse [odds ratio (OR) = 6.40, 95% confidence interval (CI): 1.85–22.06], preoperative hepatic encephalopathy (OR = 4.45, 95% CI: 1.36–14.51), APACHE II score ≥16 (OR = 1.73, 95% CI: 1.71–2.56), and duration of endotracheal intubation ≥5 days (OR = 1.81, 95% CI: 1.52–2.23).
History of alcohol abuse, preoperative hepatic encephalopathy, APACHE II scores ≥16 and endotracheal intubation ≥5 days were predictive of developing delirium in the ICU following liver transplantation surgery and were associated with increased length of ICU and hospital stay.
PMCID: PMC4014540  PMID: 24811254
25.  Hyperoxia arrests pulmonary development in newborn rats via disruption of endothelial tight junctions and downregulation of Cx40 
Molecular Medicine Reports  2014;10(1):61-67.
This study investigated changes in vascular endothelial cell tight junction structure and the expression of the gene encoding connexin 40 (Cx40) at the early pneumonedema stage of hyperoxia-induced bronchopulmonary dysplasia (BPD) in a newborn rat model. A total of 96 newborn rats were randomly assigned to one of the following two groups, the hyperoxia group (n=48) and the control group (n=48). A hyperoxia-induced BPD model was established for the first group, while rats in the control group were maintained under normoxic conditions. Extravasation of Evans Blue (EB) was measured; the severity of lung injury was assessed; a transmission electron microscope (TEM) was used to examine the vascular endothelial cell tight junction structures, and immunohistochemical assay, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to evaluate the expression of Cx40 at the mRNA and protein level. Our findings showed that injuries due to BPD are progressively intensified during the time-course of exposure to hyperoxic conditions. Pulmonary vascular permeability in the hyperoxia group reached the highest level at day 5, and was significantly higher compared to the control group. TEM observations demonstrated tight junctions between endothelial cells were extremely tight. In the hyperoxia group, no marked changes in the tight junction structure were found at days 1 and 3; paracellular gaps were visible between endothelial cells at days 5 and 7. Immunohistochemical staining revealed that the Cx40 protein is mainly expressed in the vascular endothelial cells of lung tissue. Western blotting and RT-PCR assays showed a gradual decrease in Cx40 expression, depending on the exposure time to hyperoxic conditions. However, the Cx40 mRNA level reached a trough at 5 days. Overall, our study demonstrated that exposure to hyperoxia damages the tight junction structures between vascular endothelial cells and downregulates Cx40. We therefore conclude that hyperoxia may participate in the regulation of pulmonary vascular endothelial permeability.
PMCID: PMC4068730  PMID: 24789212
hyperoxia; tight junction; Cx40; permeability; newborn; bronchopulmonary dysplasia

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