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1.  Treatment with a vascular disrupting agent does not increase recruitment of indium labelled human endothelial outgrowth cells in an experimental tumour model 
BMC Cancer  2014;14(1):903.
The effect of vascular disrupting agents in tumour therapy depends on both the immediate vascular shutdown, and on the following re-vascularization of the tumour. The aim of this study was to use a tumour model to investigate whether endothelial outgrowth cells (EOCs) influenced the short term treatment efficiency of combretastatin A-4 disodium phosphate (CA4P) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by increasing EOC tumour recruitment.
In order to visualize the recruitment of EOCs to the tumours, umbilical cord blood derived human EOCs were labelled with 111Indium-tropolone in a dose of 0.37 MBq pr 3×106 cells and were injected intravenously into mice carrying a C3H mammary carcinoma on their right rear foot. DMXAA and CA4P in different concentrations and at different exposure times were used to create a hypoxic environment in the C3H mammary carcinoma in the mice. Three different mice strains with various degrees of functional immune system were used to study the homing capability of EOCs.
Our data showed that approximately 4% of the total injected radioactive dose per gram of tissue was found in the tumour after treatment with CA4P and DMXAA. Regardless of the concentration and the treatment duration, CA4P did not increase EOC recruitment to the tumour in comparison to EOC recruitment in control tumours in any of the 3 mice strains studied.
Our data showed that regardless of the grade of the immune system, ranging from a fully working to a fully compromised immune system, treatment with CA4P did not increase recruitment of xenotransplanted EOCs to tumour tissue.
PMCID: PMC4265399  PMID: 25466422
Endothelial outgrowth cells; Vascular disrupting agents; CA4P; Tumour
2.  Cross-sectional study of the association of cognitive function and hippocampal volume among healthy elderly adults 
Shanghai Archives of Psychiatry  2014;26(5):280-287.
Cognitive impairment and dementia among elderly adults is a pressing public health issue in China but research on biomarkers of cognitive decline has been limited.
Explore the relationship between multiple domains of cognitive functioning and the volume of the left and right hippocampus in healthy elderly adults.
Structural MRI scanning was performed on 65 community-dwelling healthy participants 65 to 75 years of age using the Siemens 3.0 T Trio Tim with the MPRAGE sequence. The volumes of the left and right hippocampus were determined using Freesurfer software. Cognitive functioning was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Both unadjusted and adjusted associations between the hippocampal volumes and cognitive functioning were estimated.
Within this relatively narrow age range, age was significantly associated with most of the cognitive measures assessed in women but was not significantly associated with any of the cognitive measures in men. In both men and women right hippocampal volume was positively associated with delayed memory and left hippocampal volume was positively associated with both immediate memory and delayed memory (though the relationship with delayed memory in women was only at a trend level). After adjustment for age, gender, and years of formal education (the variable that was most strongly associated with all of the cognitive measures), both left hippocampal volume and right hippocampal volume were positively associated with delayed memory, but not with immediate memory. Interestingly, the difference in the volumes of the left and right hippocampi was negatively associated with the score of the RBANS attention subscale, a relationship that was stronger in women than in men.
This study confirms previous work about the relationship of hippocampal volume and memory, identifies a possible relationship between attention and the difference in size of the two hippocampi, and suggests that there may be some differences in these relationships by gender.
PMCID: PMC4248260  PMID: 25477721
elderly adults; executive function; AMSTAR; hippocampal volume; China
3.  The Long Noncoding RNA Expression Profile of Hepatocellular Carcinoma Identified by Microarray Analysis 
PLoS ONE  2014;9(7):e101707.
Thousands of long noncoding RNAs (lncRNAs) have been reported in mammalian genomes. These RNAs represent an important subset of pervasive genes involved in a broad range of biological functions. Aberrant expression of lncRNAs is associated with many types of cancers. Here, in order to explore the potential lncRNAs involved in hepatocellular carcinoma (HCC) oncogenesis, we performed lncRNA gene expression profile analysis in 3 pairs of human HCC and adjacent non-tumor (NT) tissues by microarray.
Differentially expressed lncRNAs and mRNAs were detected by human lncRNA microarray containing 33,045 lncRNAs and 30,215 coding transcripts. Bioinformatic analyses (gene ontology, pathway and network analysis) were applied for further study of these differentially expressed mRNAs. By qRT-PCR analysis in nineteen pairs of HCC and adjacent normal tissues, we found that eight lncRNAs were aberrantly expressed in HCC compared with adjacent NT tissues, which is consistent with microarray data.
We identified 214 lncRNAs and 338 mRNAs abnormally expressed in all three HCC tissues (Fold Change ≥2.0, P<0.05 and FDR <0.05) with the genome-wide lncRNAs and mRNAs expression profile analysis. The lncRNA-mRNA co-expression network was constructed, which may be used for predicting target genes of lncRNAs. Furthermore, we demonstrated for the first time that BC017743, ENST00000395084, NR_026591, NR_015378 and NR_024284 were up-regulated, whereas NR_027151, AK056988 and uc003yqb.1 were down-regulated in nineteen pairs of HCC samples compared with adjacent NT samples. Expression of seven lncRNAs was significantly correlated to their nearby coding genes. In conclusion, our results indicated that the lncRNA expression profile in HCC was significantly changed, and we identified a series of new hepatocarcinoma associated lncRNAs. These results provide important insights about the lncRNAs in HCC pathogenesis.
PMCID: PMC4099127  PMID: 25025236
4.  Erectile Dysfunction and Risk of End Stage Renal Disease Requiring Dialysis: A Nationwide Population-Based Study 
PLoS ONE  2014;9(7):e102055.
Previous studies have suggested that erectile dysfunction (ED) is an independent risk factor for macrovascular disease. Very few studies have evaluated the relationship between ED and risk of end stage renal disease (ESRD) requiring dialysis.
A random sample of 1,000,000 individuals from Taiwan's National Health Insurance database was collected. We selected the control group by matching the subjects and controls by age, diabetes, hypertension, coronary heart disease, hyperlipidemia, area of residence, monthly income and index date. We identified 3985 patients with newly-diagnosed ED between 2000 and 2008 and compared them with a matched cohort of 23910 patients without ED. All patients were tracked from the index date to identify which patients subsequently developed a need for dialysis.
The incidence rates of dialysis in the ED cohort and comparison groups were 10.85 and 9.06 per 10000 person-years, respectively. Stratified by age, the incidence rate ratio for dialysis was greater in ED patients aged <50 years (3.16, 95% CI: 1.62–6.19, p = 0.0008) but not in aged 50–64 (0.94, 95% CI: 0.52–1.69, p = 0.8397) and those aged ≧65 (0.69, 95% CI: 0.32–1.52, p = 0.3594). After adjustment for patient characteristics and medial comorbidities, the adjusted HR for dialysis remained greater in ED patients aged <50 years (adjusted HR: 2.08, 95% CI: 1.05–4.11, p<0.05). The log-rank test revealed that ED patients <50-years-old had significantly higher cumulative incidence rates of dialysis than those without (p = 0.0004).
Patients with ED, especially younger patients, are at an increased risk for ESRD requiring dialysis later in life.
PMCID: PMC4094485  PMID: 25013905
5.  Elevated Plasma Total Cholesterol Level Is Associated with the Risk of Asymptomatic Intracranial Arterial Stenosis 
PLoS ONE  2014;9(7):e101232.
Intracranial arterial stenosis (ICAS) is one of the most common causes of stroke, and dyslipidemia was one of the most common risk factors related to ICAS. However, the correlation between the plasma total cholesterol level (PTC) and ICAS, especially asymptomatic ICAS (AICAS) is not clear.
Materials and Methods
5,300 participants were enrolled in this study. The diagnosis of AICAS was made by transcranial Doppler ultrasonography. The participants were then divided into 5 essentially equal-sized groups based on their PTC levels. The multivariate logistic regression was used to analyze the correlation between the PTC level and the prevalence of AICAS.
13.0% of the participants were diagnosed with AICAS. The prevalence of AICAS gradually increased with the increasing PTC level. After adjusted by the possible confounding factors, the Odds Ratios (OR) of the AICAS prevalence between the 1st quintile group and the other 4 groups were 1.13, 1.23, 1.63 and 1.75 with 95% confident intervals (CI) of 0.84–1.52, 0.91–1.66, 1.20–2.22 and 1.23–2.47, respectively. The further subgroup analysis revealed that the PTC level was stronger for males (OR 1.42 95%CI 1.23–1.64), regarding the prevalence of AICAS.
In this large community-based study, the prevalence of AICAS is 13.0%, subjects with higher PTC levels showed a mild increase in the prevalence of AICAS. The PTC level is an independent risk factor of AICAS. Males seem to be significantly more vulnerable to the risk of AICAS.
PMCID: PMC4081648  PMID: 24992466
6.  Equity in use of maternal health services in Western Rural China: a survey from Shaanxi province 
The 20th century was marked by a significant improvement in worldwide human health and access to healthcare. However, these improvements were not completely or uniformly distributed among, or even within, nations. This study was designed to assess the use of maternal health services by pregnant women in China, with a focus on the inequity related to family income level.
Two population-based cross-sectional surveys were carried out in the Zhenan and Lantian counties in March 2007 and from December 2008 to March 2009. A total of 2562 women completed the questionnaires, including 948 who were pregnant in 2006 and 1614 from 2008–2009. The concentration index (CI) was calculated and used to analyze the parameters of maternal health care in the two counties surveyed.
The responses in both 2006 and 2008–2009 indicated a bias towards higher (rich) economic statuses for the use of maternal and child health services. The CI of ‘delivery at health facility’ was 0.0206 (95% confidence interval between 0.0114 and 0.0299) for 2006 and 0.0053 (95% confidence interval between 0.0015 and 0.0091) for 2008, which represented a statistically significant inequity for women of lower (poor) economic statuses. Similar CI was observed in ‘receiving antenatal care within 12 weeks’ for 2006 (CI2006 = 0.0956, 95% confidence interval between 0.0516 and 0.1396). The CIs of ‘postnatal visit’ and ‘postnatal visit >3-times’ was positive (except for 2006), indicating that the poor used postnatal care less than the non-poor. In 2008, poor women had C-sections more often than non-poor women (CI2008 = −0.0629, 95% confidence interval between-0.1165 and −0.0093), but such a difference was not observed in 2006.
In 2006 and 2008, the use of maternal health services in western rural China was significantly unequal between pregnant women of poor and non-poor economic statuses. Financial support that enables poorer pregnant women to use health services will be beneficial. Utilization of maternal healthcare services can be improved if out-of-pocket expenses can be minimized.
PMCID: PMC3985545  PMID: 24708641
Equity; Maternal and child health service; Economic situation
7.  Analyzing and modeling rheological behavior of liver fibrosis in rats using shear viscoelastic moduli*  
The process of liver fibrosis changes the rheological properties of liver tissue. This study characterizes and compares liver fibrosis stages from F0 to F4 in rats in terms of shear viscoelastic moduli. Here two viscoelastic models, the Zener model and Voigt model, were applied to experimental data of rheometer tests and then values of elasticity and viscosity were estimated for each fibrosis stage. The results demonstrate that moderate fibrosis (≤F2) has a good correlation with liver viscoelasticity. The mean Zener elasticity E 1 increases from (0.452±0.094) kPa (F0) to (1.311±0.717) kPa (F2), while the mean Voigt elasticity E increases from (0.618±0.089) kPa (F0) to (1.701±0.844) kPa (F2). The mean Zener viscosity increases from (3.499±0.186) Pa·s (F0) to (4.947±1.811) Pa·s (F2) and the mean Voigt viscosity increases from (3.379±0.316) Pa·s (F0) to (4.625±1.296) Pa·s (F2). Compared with viscosity, the elasticity shows smaller variations at stages F1 and F2 no matter what viscoelastic model is used. Therefore, the estimated elasticity is more effective than viscosity for differentiating the fibrosis stages from F0 to F2.
PMCID: PMC3989156  PMID: 24711358
Biological mechanics; Rheological properties; Liver fibrosis; Viscoelasticity; Shear modulus; Elasticity; Viscosity; Zener model; Voigt model
8.  Spatial–temporal modelling of fMRI data through spatially regularized mixture of hidden process models 
Neuroimage  2014;84:657-671.
Previous work investigated a range of spatio-temporal constraints for fMRI data analysis to provide robust detection of neural activation. We present a mixture-based method for the spatio-temporal modelling of fMRI data. This approach assumes that fMRI time series are generated by a probabilistic superposition of a small set of spatio-temporal prototypes (mixture components). Each prototype comprises a temporal model that explains fMRI signals on a single voxel and the model's “region of influence” through a spatial prior over the voxel space. As the key ingredient of our temporal model, the Hidden Process Model (HPM) framework proposed in Hutchinson et al. (2009) is adopted to infer the overlapping cognitive processes triggered by stimuli. Unlike the original HPM framework, we use a parametric model of Haemodynamic Response Function (HRF) so that biological constraints are naturally incorporated in the HRF estimation. The spatial priors are defined in terms of a parameterised distribution. Thus, the total number of parameters in the model does not depend on the number of voxels. The resulting model provides a conceptually principled and computationally efficient approach to identify spatio-temporal patterns of neural activation from fMRI data, in contrast to most conventional approaches in the literature focusing on the detection of spatial patterns. We first verify the proposed model in a controlled experimental setting using synthetic data. The model is further validated on real fMRI data obtained from a rapid event-related visual recognition experiment (Mayhew et al., 2012). Our model enables us to evaluate in a principled manner the variability of neural activations within individual regions of interest (ROIs). The results strongly suggest that, compared with occipitotemporal regions, the frontal ones are less homogeneous, requiring two HPM prototypes per region. Despite the rapid event-related experimental design, the model is capable of disentangling the perceptual judgement and motor response processes that are both activated in the frontal ROIs. Spatio-temporal heterogeneity in the frontal regions seems to be associated with diverse dynamic localizations of the two hidden processes in different subregions of frontal ROIs.
•We present a “spatio-temporal prototype”-based approach to fMRI data analysis.•Our model is capable of disentangling overlapping mental processes evoked by stimuli.•We found frontal ROIs were functionally less homogeneous than occipitotemporal ones.•We detected spatio-temporal heterogeneity of mental processes in the frontal regions.
PMCID: PMC4066951  PMID: 24041873
ROI-based fMRI analysis; Generative fMRI models; Clustering fMRI time series
9.  Over-expression of histone H3K4 demethylase gene JMJ15 enhances salt tolerance in Arabidopsis 
Histone H3 lysine 4 trimethylation (H3K4me3) has been shown to be involved in stress-responsive gene expression and gene priming in plants. However, the role of H3K4me3 resetting in the processes is not clear. In this work we studied the expression and function of Arabidopsis H3K4 demethylase gene JMJ15. We show that the expression of JMJ15 was relatively low and was limited to a number of tissues during vegetative growth but was higher in young floral organs. Over-expression of the gene in gain-of-function mutants reduced the plant height with accumulation of lignin in stems, while the loss-of-function mutation did not produce any visible phenotype. The gain-of-function mutants showed enhanced salt tolerance, whereas the loss-of-function mutant was more sensitive to salt compared to the wild type. Transcriptomic analysis revealed that over-expression of JMJ15 down-regulated many genes which are preferentially marked by H3K4me3 and H3K4me2. Many of the down-regulated genes encode transcription regulators involved in stress responses. The data suggest that increased JMJ15 levels may regulate the gene expression program that enhances stress tolerance.
PMCID: PMC4068201  PMID: 25009544
histone methylation; jumonji demethylase; JMJ15; abiotic stress tolerance gene; epigenetic regulation; H3K4me3; chromatin modification
10.  Using the Chinese version of Memorial Delirium Assessment Scale to describe postoperative delirium after hip surgery 
Objective: Memorial Delirium Assessment Scale (MDAS) assesses severity of delirium. However, whether the MDAS can be used in a Chinese population is unknown. Moreover, the optimal postoperative MDAS cutoff point for describing postoperative delirium in Chinese remains largely to be determined. We therefore performed a pilot study to validate MDAS in the Chinese language and to determine the optimal postoperative MDAS cutoff point for delirium.
Methods: Eighty-two patients (80 ± 6 years, 21.9% male), who had hip surgery under general anesthesia, were enrolled. The Confusion Assessment Method (CAM) and Mini-Mental State Examination (MMSE) were administered to the patients before surgery. The CAM and MDAS were performed on the patients on the first, second and fourth postoperative days. The reliability and validity of the MDAS were determined. A receiver operating characteristic (ROC) curve was used to determine the optimal Chinese version MDAS cutoff point for the identification of delirium.
Results: The Chinese version of the MDAS had satisfactory internal consistency (α = 0.910). ROC analysis obtained an average optimal MDAS cutoff point of 7.5 in describing the CAM-defined postoperative delirium, with an area under the ROC of 0.990 (95% CI 0.977–1.000, P < 0.001).
Conclusions: The Chinese version of the MDAS had good reliability and validity. The patients whose postoperative Chinese version MDAS cutoff point score was 7.5 would likely have postoperative delirium. These results have established a system for a larger scale study in the future.
PMCID: PMC4220661  PMID: 25414664
memorial delirium assessment scale; confusion assessment method; postoperative delirium; hip surgery; Chinese
12.  Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity 
Science (New York, N.Y.)  2013;341(6143):275-278.
Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed Melanocortin 2 Receptor Accessory Protein 2 (MRAP2), we characterized mice with whole body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with Melanocortin 4 Receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic AMP, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.
PMCID: PMC3788688  PMID: 23869016
13.  Genome-Wide Identification of Molecular Pathways and Biomarkers in Response to Arsenic Exposure in Zebrafish Liver 
PLoS ONE  2013;8(7):e68737.
Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down-regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT-qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure.
PMCID: PMC3726666  PMID: 23922661
14.  HIF-1α knockdown by miRNA decreases survivin expression and inhibits A549 cell growth in vitro and in vivo 
The present study examined the downregulation of survivin expression by hypoxia-inducible factor-1α (HIF-1α) miRNA and its effect in the inhibition of A549 cell growth in vitro and in vivo. Survivin expression, apoptosis, proliferation and migration under normoxic and hypoxic conditions were assessed by standard methods. Cotransfection and chromatin immunoprecipitation were used to observe the effects of HIF-1α on survivin transcription. HIF-1α knockdown in A549 cells were injected into nude mice to examine survivin expression and suppression of tumorigenicity. Transfection of A549 cells with HIF-1α miRNA led to decreased expression of HIF-1α and survivin mRNA and protein. Survivin overexpression is mediated by HIF-1α by direct binding to a putative binding site in the survivin core promoter. HIF-1α-miRNA induced apoptosis and inhibited proliferation of A549 cells under hypoxic, but not normoxic, conditions, whereas transfection by survivin expression vectors partly rescued the apoptotic phenotype and revived cell proliferation under hypoxic conditions. However, cell migration was substantially suppressed by HIF-1α silencing under normoxic and hypoxic conditions. After A549 cells were xenografted in nude mice, survivin expression in mice treated with HIF-1α miRNA was downregulated, and tumor growth was significantly inhibited. Silenced HIF-1α gene expression induced apoptosis and suppressed growth of A549 cells by downregulating survivin expression in vitro and in vivo. Our results also provide a basis to target the HIF-1α pathway in lung cancer therapy.
PMCID: PMC3776716  PMID: 23732337
Hypoxia-inducible factor-1α; miRNA; survivin; lung cancer
15.  Type 2C protein phosphatase ABI1 is a negative regulator of strawberry fruit ripening 
Journal of Experimental Botany  2013;64(6):1677-1687.
Although a great deal of progress has been made toward understanding the role of abscisic acid (ABA) in fruit ripening, many components in the ABA signalling pathway remain to be elucidated. Here, a strawberry gene homologous to the Arabidopsis gene ABI1, named FaABI1, was isolated and characterized. The 1641bp cDNA includes an intact open reading frame that encodes a deduced protein of 546 amino acids, in which putative conserved domains were determined by homology analysis. Transcriptional analysis showed that the levels of FaABI1 mRNA expression declined rapidly during strawberry fruit development as evidenced by real-time PCR, semi-quantitative reverse transcription–PCR, and northern blotting analyses, suggesting that the Ser/Thr protein phosphatase PP2C1 encoded by FaABI1 may be involved in fruit ripening as a negative regulator. The results of Tobacco rattle virus-induced gene silencing and PBI121 vector-mediated overexpression suggested that the down- and up-regulation of FaABI1 mRNA expression levels in degreening strawberry fruit could promote and inhibit ripening, respectively. Furthermore, alteration of FaABI1 expression could differentially regulate the transcripts of a set of both ABA-responsive and ripening-related genes, including ABI3, ABI4, ABI5, SnRK2, ABRE1, CHS, PG1, PL, CHI, F3H, DFR, ANS, and UFGT. Taken together, the data provide new evidence for an important role for ABA in regulating strawberry fruit ripening in the processes of which the type 2C protein phosphatase ABI1 serves as a negative regulator. Finally, a possible core mechanism underlying ABA perception and signalling transduction in strawberry fruit ripening is discussed.
PMCID: PMC3617833  PMID: 23404898
Abscisic acid (ABA); overexpression; strawberry fruit ripening; Tobacco rattle virus; type 2C protein phosphatase ABI1; virus-induced gene silencing (VIGS).
16.  The attenuation of retinal nerve fiber layer thickness and cognitive deterioration 
Thinner retinal nerve fiber layer (RNFL) has been reported in Alzheimer’s disease (AD) patient. However, whether changes in RNFL thickness can predict the cognitive deterioration remains unknown. We therefore set out a prospective clinical investigation to determine the potential association between the attenuation of RNFL thickness and the deterioration of cognitive function over a period of 25 months. We assessed cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status and measured RNFL thickness employing optical coherence tomography in 78 participants (mean age 72.31 ± 3.98 years, 52% men). The participants were categorized as stable participants whose cognitive status remained no change (N = 60) and converted participants whose cognitive status deteriorated (N = 18). We found that there was an association between the attenuation of superior quadrant RNFL thickness and the deterioration of cognitive function in the stable participants. In the converted participants, however, there was an inverse association between the reduction of inferior quadrant RNFL thickness and decline of cognitive functions [scores of list recall (R = -0.670, P = 0.002), adjusted (R = -0.493, P = 0.031)]. These data showed that less reduction in the inferior quadrant of RNFL thickness might indicate a higher risk for the patients to develop cognitive deterioration. These findings have established a system to embark a larger scale study to further test whether changes in RNFL thickness can serve as a biomarker of AD, and would lead to mechanistic studies to determine the cellular mechanisms of cognitive deterioration.
PMCID: PMC3777215  PMID: 24065883
biomarker; Alzheimer’s disease; mild cognitive impairment; dementia; retinal nerve fiber layer thickness; cognition
17.  Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation 
This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation.
Materials and Methods
Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin (Nereus Pharmaceuticals, San Diego, USA) injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging measurements were made with gadolinium-DTPA on a 7-tesla magnet. Treatment response was assessed using either a regrowth delay (C3H mammary carcinoma) or clonogenic survival (KHT sarcoma) assay, or histological estimates of necrosis for both models.
Plinabulin (7.5 mg/kg) significantly reduced both IAUC and Ktrans within 1-hour after drug injection, reaching a nadir at 3-hours, but returning to normal within 24-hours. A dose-dependent decrease in IAUC and Ktrans, was seen at 3-hours. No significant anti-tumour effects were seen in the C3H mammary carcinoma until doses of 12.5 mg/kg and above were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1-hour after injecting plinabulin enhanced response in both models.
Plinabulin induced a time and dose dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H mammary carcinoma to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.
PMCID: PMC3509771  PMID: 21815749
Plinabulin (NPI-2358); Vascular targeting; Radiation; C3H mammary carcinoma; KHT sarcoma; Magnetic Resonance Imaging
18.  Characterization of sck1, a Novel Castanea mollissima Mutant with the Extreme Short Catkins and Decreased Gibberellin 
PLoS ONE  2012;7(8):e43181.
A novel Chinese chestnut (Castanea mollissima Bl.) mutant with extreme short catkins, here was named sck1 and has been characterized in the present study. This sck1 caused 6-fold shorter than wild-type catkins. Endogenous gibberellic acids markedly decreased in the mutant, and application of exogenous GA3 could partially restore the sck1 phenotype to the wild-type phenotype. Paclobutrazol (PP333), an antagonist of GAs biosynthesis, could significantly inhibit the wild-type catkins growth, and lead to a short catkins phenotype similar to the sck1. In addition, compared to the wild-type catkins, the mRNA expression level of ent-kaurenoic acid oxidase (KAO), a gibberellin biosynthsis key gene, was significantly down-regulated (P<0.01) in the sck1. Importantly, transient over-expression of a normal CmKAO gene in short catkins also could partially restore the wild-type phenotype. Real-time PCR and semi-quantitative analysis showed that the mRNA expression level of KAO was significantly up-regulated. In addition, transient RNA interference of CmKAO in wild-type catkins led the mRNA expression level of KAO decrease significantly and inhibited the wild-type catkins elongation strongly. Taken together, our results suggest that the lower gibberellic acids content that is due to decreased CmKAO expression level may contribute to the generation of the extreme short male catkins, sck1.
PMCID: PMC3419647  PMID: 22905227
19.  The effects of multi-domain versus single-domain cognitive training in non-demented older people: a randomized controlled trial 
BMC Medicine  2012;10:30.
Whether healthy older people can benefit from cognitive training (CogTr) remains controversial. This study explored the benefits of CogTr in community dwelling, healthy, older adults and compared the effects of single-domain with multi-domain CogTr interventions.
A randomized, controlled, 3-month trial of CogTr with double-blind assessments at baseline and immediate, 6-month and 12-month follow-up after training completion was conducted. A total of 270 healthy Chinese older people, 65 to 75 years old, were recruited from the Ganquan-area community in Shanghai. Participants were randomly assigned to three groups: multi-domain CogTr, single-domain CogTr, and a wait-list control group. Twenty-four sessions of CogTr were administrated to the intervention groups over a three-month period. Six months later, three booster training sessions were offered to 60% of the initial training participants. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A), the Color Word Stroop test (CWST), the Visual Reasoning test and the Trail Making test (TMT) were used to assess cognitive function.
Multi-domain CogTr produced statistically significant training effects on RBANS, visual reasoning, and immediate and delayed memory, while single-domain CogTr showed training effects on RBANS, visual reasoning, word interference, and visuospatial/constructional score (all P < 0.05). At the 12-month posttest, the multi-domain CogTr showed training effects on RBANS, delayed memory and visual reasoning, while single-domain CogTr only showed effects on word interference. Booster training resulted in effects on RBANS, visual reasoning, time of trail making test, and visuospatial/constructional index score.
Cognitive training can improve memory, visual reasoning, visuospatial construction, attention and neuropsychological status in community-living older people and can help maintain their functioning over time. Multi-domain CogTr enhanced memory proficiency, while single-domain CogTr augmented visuospatial/constructional and attention abilities. Multi-domain CogTr had more advantages in training effect maintenance.
Clinical Trial Registration
Chinese Clinical Trial Registry. Registration number: ChiCTR-TRC-09000732.
PMCID: PMC3364144  PMID: 22453114
20.  Some essential considerations in the design and conduct of non-inferiority trials 
Suppose a standard therapy (Standard) has been established to provide a clinically important reduction in risk of irreversible morbidity or mortality. In that setting, the safety and efficacy of an experimental intervention likely would be assessed in a clinical trial providing a comparison with Standard rather than a placebo arm. Such a trial often is designed to assess whether the efficacy of the experimental intervention is not unacceptably worse than that of Standard, and is called a non-inferiority trial. Formally, the non-inferiority trial usually is designed to rule out a non-inferiority margin, defined as the minimum threshold for what would constitute an unacceptable loss of efficacy.
Even though the literature has many important articles identifying various approaches to the design and conduct of non-inferiority trials, confusion remains especially regarding key considerations for selecting the non-inferiority margin. The purpose of this article is to provide improved clarity regarding these considerations.
We present scientific insights into many factors that should be addressed in the design and conduct of non-inferiority trials to enhance their integrity and reliability, and provide motivation for key considerations that guide the selection of non-inferiority margins. We also provide illustrations and insights from recent experiences.
Two considerations are essential, and should be addressed in separate steps, in the formulation of the non-inferiority margin. First, the margin should be formulated using adjustments to account for bias or lack of reliability in the estimate of the effect of Standard in the non-inferiority trial setting. Second, the non-inferiority margin should be formulated to achieve preservation of an appropriate percentage of the effect of Standard.
The considerations, in particular regarding the importance of preservation of effect, might not apply to settings where it would be ethical as well as clinically relevant to include both Standard and placebo arms in the trial for direct comparisons with the experimental intervention arm.
Non-inferiority trials with non-rigorous margins allow substantial risk for accepting inadequately effective experimental regimens, leading to the risk of erosion in quality of health care. The design and conduct of non-inferiority trials, including selection of non-inferiority margins, should account for many factors that can induce bias in the estimated effect of Standard in the non-inferiority trial and thus lead to bias in the estimated effect of the experimental treatment, for the need to ensure the experimental treatment preserves a clinically acceptable fraction of Standard's effect, and for the particular vulnerability of the integrity of a non-inferiority trial to the irregularities in trial conduct. Due to the inherent uncertainties in non-inferiority trials, alternative designs should be pursued whenever possible.
PMCID: PMC3312046  PMID: 21835862
21.  Quantitative analysis of culture using millions of digitized books 
Science (New York, N.y.)  2010;331(6014):176-182.
We constructed a corpus of digitized texts containing about 4% of all books ever printed. Analysis of this corpus enables us to investigate cultural trends quantitatively. We survey the vast terrain of ‘culturomics’, focusing on linguistic and cultural phenomena that were reflected in the English language between 1800 and 2000. We show how this approach can provide insights about fields as diverse as lexicography, the evolution of grammar, collective memory, the adoption of technology, the pursuit of fame, censorship, and historical epidemiology. ‘Culturomics’ extends the boundaries of rigorous quantitative inquiry to a wide array of new phenomena spanning the social sciences and the humanities.
PMCID: PMC3279742  PMID: 21163965
22.  The impact of educational status on the clinical features of major depressive disorder among Chinese women 
Journal of Affective Disorders  2012;136(3):988-992.
Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting.
Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD.
Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide.
Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample.
The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD.
PMCID: PMC3314924  PMID: 21824664
Major depressive disorder; Education; Socio-economic status; Symptom
23.  Resemblance of Symptoms for Major Depression Assessed at Interview versus from Hospital Record Review 
PLoS ONE  2012;7(1):e28734.
Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies.
Principal findings
We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4).
Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes.
PMCID: PMC3256142  PMID: 22247760
24.  U.S. Food and Drug Administration Approval: Rituximab in Combination with Fludarabine and Cyclophosphamide for the Treatment of Patients with Chronic Lymphocytic Leukemia 
The Oncologist  2011;16(1):97-104.
The purpose of this study was to describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.
Learning Objectives
After completing this course, the reader will be able to: Compare the survival benefits of rituximab in combination with fludarabine and cyclophosphamide to those of alemtuzumab, bendamustine, and ofatumumab in patients with CLL.Identify CLL patients for whom rituximab in combination with fludarabine and cyclophosphamide may be an appropriate first-line regimen.
This article is available for continuing medical education credit at
To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL).
Materials and Methods.
The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS).
The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL.
On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.
PMCID: PMC3228054  PMID: 21212432
FDA; Rituximab; Chronic lymphocytic leukemia; Fludarabine; Cyclophosphamide
25.  Light-harvesting chlorophyll a/b-binding proteins are required for stomatal response to abscisic acid in Arabidopsis 
Journal of Experimental Botany  2011;63(3):1095-1106.
The light-harvesting chlorophyll a/b binding proteins (LHCB) are perhaps the most abundant membrane proteins in nature. It is reported here that the down-regulation or disruption of any member of the LHCB family, LHCB1, LHCB2, LHCB3, LHCB4, LHCB5, or LHCB6, reduces responsiveness of stomatal movement to ABA, and therefore results in a decrease in plant tolerance to drought stress in Arabidopsis thaliana. By contrast, over-expression of a LHCB member, LHCB6, enhances stomatal sensitivity to ABA. In addition, the reactive oxygen species (ROS) homeostasis and a set of ABA-responsive genes are altered in the lhcb mutants. These data demonstrate that LHCBs play a positive role in guard cell signalling in response to ABA and suggest that they may be involved in ABA signalling partly by modulating ROS homeostasis.
PMCID: PMC3276081  PMID: 22143917
Abscisic acid signalling; Arabidopsis thaliana; light-harvesting chlorophyll a/b binding protein; reactive oxygen species; stomatal movement

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