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1.  A pharmacodynamic model of portal hypertension in isolated perfused rat liver 
AIM: To develop a pharmacodynamic model of portal hypertension from chronic hepatitis.
METHODS: Pathological changes and collagen depositions were analyzed using morphometry to confirm CCl4-induced chronic hepatitis. At d0, d28, d56 and d84 of the process, the portal perfused velocities (μL/min) in isolated rat livers were exactly controlled with a quantified pump. The pressure (mmHg) was monitored with a Physiological System. The geometric concentrations of phenylephrine or acetylcholine were added to a fixed volume (300 mL) of the circulating perfusate. The equation, the median effective concentration and its 95% confidence intervals of phenylephrine or acetylcholine were regressed with Prism-4 software in non-linear fit and various slopes. In the isolated perfused rat livers with chronic hepatitis, both median effective concentrations were defined as the pharmacodynamic model of portal hypertension.
RESULTS: At d0, d28, d56 and d84, the equations of portal pressure potency from the concentrations of phenylephrine used to constrict the portal vein in isolated perfused rat livers were Y = 0.1732 + 0.3970/[1 + 10(-4.3061-0.4407 X)], Y = -0.004934 + 0.12113/[1 + 10(-3.1247-0.3262 X)], Y = 0.0104 + 0.2643/[1 + 10(-8.8462-0.9579 X)], and Y = 0.01603 + 0.12107/[1 + 10(-5.1134-0.563 X)]; the median effective concentrations were 1.69 × 10-10 mol/L, 2.64 × 10-10 mol/L, 5.82 × 10-10 mol/L, and 8.24 × 10-10 mol/L, respectively. The equations from the concentrations of acetylcholine used to relax the portal vein were Y = -0.4548 + 0.3274/[1 + 10(6.1538 + 0.5554 X)], Y = -0.05391 + 0.06424/[1 + 10(3.8541 + 0.3469 X)], Y = -0.2733 + 0.22978/[1 + 10(3.0472 + 0.3008 X)], and Y = -0.0559 + 0.053178/[1 + 10(5.6336 + 0.5883 X)]; the median effective concentrations were 8.40 × 10-10 mol/L, 7.73 × 10-12 mol/L, 5.98 × 10-11 mol/L, and 2.66 × 10-10 mol/L, respectively.
CONCLUSION: A pharmacodynamic model of portal hypertension in isolated perfused rat livers with chronic hepatitis was defined as the median effective concentrations of phenylephrine and acetylcholine.
PMCID: PMC3270509  PMID: 22346254
Chronic hepatitis; Isolated portal perfused rat liver; Pharmacodynamic model; Portal hypertension
2.  Association between cholesterol intake and pancreatic cancer risk: Evidence from a meta-analysis 
Scientific Reports  2015;5:8243.
Quantification of the association between the intake of cholesterol and risk of pancreatic cancer is still conflicting. We therefore conducted a meta-analysis to summarize the evidence from epidemiological studies of cholesterol intake and the risk of pancreatic cancer. Pertinent studies were delivered by PubMed and Web of Knowledge issued through April of 2014. A random effects model was used to process the data for analysis. Sensitivity analysis and publication bias were conducted. Dose-response relationship was assessed by restricted cubic spline and variance-weighted least squares regression analysis. With 4513 pancreatic cases exemplified, 16 articles were applied in the meta-analysis. Pooled results suggest that cholesterol intake level was significantly associated with the risk of pancreatic cancer [summary relative risk (RR) = 1.371, 95%CI = 1.155–1.627, I2 = 58.2%], especially in America [summary RR = 1.302, 95%CI = 1.090–1.556]. A linear dose-response relation was attested that the risk of pancreatic cancer rises by 8% with 100 mg/day of cholesterol intake. [summary RR = 1.08, 95% CI = 1.04–1.13]. In conclusion, our analysis suggests that a high intake of cholesterol might increase the risk of pancreatic cancer, especially in America.
PMCID: PMC4316166  PMID: 25649888
3.  Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa 
BioMed Research International  2015;2015:485709.
Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure.
PMCID: PMC4331166
4.  Stigma against HIV/AIDS among female sex workers and general migrant women in eastern China 
BMC Women's Health  2015;15:2.
HIV related stigma is a recognized barrier to early detection of HIV and causes great suffering for those affected. However, data regarding HIV related stigma among female sex workers (FSW) in China was limited, with none for comparison between FSW and general migrant women (GMW). Therefore, the aim of this study was to examine HIV related stigma among FSW and GMW in Shanghai, China.
A community based cross-sectional study with face-to-face interviews was conducted in Shanghai (September 2011 through December 2012), using a structured questionnaire.HIV related stigma scores were examined graphically using boxplot. A logistic regression analysis with the proportional odds model was employed to identify factors affecting HIV related stigma scores.
A total of 1,396 subjects, including 721 FSW and 675 GMW, were recruited in the present study. Both groups had substantial misconceptions about HIV/AIDS, although FSW had slightly higher scores on average. Both groups showed a medium level of HIV related stigma (38.34 ± 6.21 and 38.35 ± 6.86 for FSW and GMW, respectively). For the FSW, higher levels of stigma were observed for those who were in the older age groups (age 26-35 years, OR, 2.06, 95% CI 1.06-4.01), those who were married (OR, 1.62, 95% CI 1.03-2.54), and those who were working at lower-level sex service sites (OR, 1.60, 95% CI 1.06-2.43). Conversely, HIV knowledge was inversely associated with the level of HIV related stigma (OR, 0.93, 95% CI 0.87-0.98).Among GMW participating in the study, those age in the 26-35 years were more likely to show higher level of stigma (OR, 2.61, 95% CI 1.03-2.54), and HIV knowledge was found to be inversely associated with the HIV related stigma level as well (OR, 0.89, 95% CI 0.84-0.95).
The present study suggests that there is an urgent need for the development of appropriate education strategies to reduce HIV related stigma among FSW and GMW in Shanghai, China. In particular, older women, less educated women, and women that have lived in Shanghai a relatively long time should be targeted in future stigma reduction programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12905-014-0160-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4316807  PMID: 25608866
5.  miR-136 Modulates TGF-β1-Induced Proliferation Arrest by Targeting PPP2R2A in Keratinocytes 
BioMed Research International  2015;2015:453518.
Keratinocytes proliferation is critical for the capacity to heal wounds and accumulating evidences have proved that dysregulation of microRNAs is involved in proliferation of keratinocytes. However, the molecular mechanisms remain to be completely elucidated. Here, we show that miR-136 was significantly decreased by TGF-β1 treatment in HaCaT cells and normal human epidermal keratinocytes (NHEK), and it was a Smad3-dependent manner. By cell proliferation assay and cell cycle analysis, we found that reintroduction of miR-136 by transfection, as well as PPP2R2A silencing, counteracted TGF-β-induced proliferation arrest in HaCaT cells. Further, PPP2R2A was verified as a direct target of miR-136 by dual-luciferase reporter assays and Western blotting. These data suggest that miR-136 may play an important role during TGF-β1-induced proliferation arrest by targeting PPP2R2A in keratinocytes, which might represent a potential target for improving skin wound healing.
PMCID: PMC4310454  PMID: 25654102
6.  Rapid Synthesis of Monodisperse Au Nanospheres through a Laser Irradiation -Induced Shape Conversion, Self-Assembly and Their Electromagnetic Coupling SERS Enhancement 
Scientific Reports  2015;5:7686.
We develop a facile and effective strategy to prepare monodispersed Au spherical nanoparticles by two steps. Large-scale monocrystalline Au nanooctahedra with uniform size were synthesized by a polyol-route and subsequently Au nanoparticles were transformed from octahedron to spherical shape in a liquid under ambient atmosphere by non-focused laser irradiation in very short time. High monodipersed, ultra-smooth gold nanospheres can be obtained by simply optimizing the laser fluence and irradiation time. Photothermal melting-evaporation model was employed to get a better understanding of the morphology transformation for the system of nanosecond pulsed-laser excitation. These Au nanoparticles were fabricated into periodic monolayer arrays by self-assembly utilizing their high monodispersity and perfect spherical shape. Importantly, such Au nanospheres arrays demonstrated very good SERS enhancement related to their periodic structure due to existence of many SERS hot spots between neighboring Au nanospheres caused by the electromagnetic coupling in an array. These gold nanospheres and their self-assembled arrays possess distinct physical and chemical properties. It will make them as an excellent and promising candidate for applying in sensing and spectroscopic enhancement, catalysis, energy, and biology.
PMCID: PMC4286736  PMID: 25566872
7.  Pathophysilogical Mechanism and Treatment Strategies for Leber Congenital Amaurosis 
Mutations in retinoid isomerase, RPE65, or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat−/−, a murine model for LCA, to investigate the mechanism of rapid cone degeneration. We found that mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat−/− cones before the onset of massive ventral/central cone degeneration. Since the ventral and central retina expresses higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65−/− and Lrat−/− LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in LCA patients. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an ER stress pathway as demonstrated in both the Lrat−/− retina and transfected cells. Based on this mechanism, we designed a new therapy of LCA by reducing ER stress. We found that systemic injection of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat−/− mice.
PMCID: PMC4080891  PMID: 24664772
aggregation; RPE65; LRAT; Leber congenital amaurosis (LCA); Short-wavelength sensitive opsins (SWS); Medium/long-wavelength sensitive opsins (M/LWS); Cone degeneration
8.  MicroRNA-301a promotes migration and invasion by targeting TGFBR2 in human colorectal cancer 
MicroRNAs (miRNAs) have been reported to play crucial roles in regulating a variety of genes pivotal for tumor metastasis. MicroRNA-301a (miR-301a) is overexpressed and displays oncogenic activity in many cancers. However, little is known about the potential roles of miR-301a in colorectal cancer (CRC).
Taqman probe stem-loop real-time PCR was used to quantitatively measure the expression level of miR-301a in 48 cases of CRC tissues and the matched adjacent non-tumor mucosa as well as in CRC cell lines. miR-301a mimics and inhibitors were used to up-regulate and down-regulate miR-301a in CRC cells, respectively; lentivirus was used to construct miR-301a stably up- and down-regulated CRC cell lines. Metastasis ability was evaluated by transwell and wound healing assays while invasion was measured by transwell coated with matrix gel in vitro; in vivo metastasis was performed on nude mice model. The target of miR-301a was predicted by TargetScan software and validated by qRT-PCR, immunohistochemistry, western blot and luciferase reporter gene assay.
The expression of miR-301a was significantly higher in lymph node metastasis positive CRC samples compared with negative ones. Downregulation of miR-301a significantly inhibited the migration and invasion both in vitro and in vivo while forced up-regulation of miR-301a promoted migration and invasion. TGFBR2 was identified to be the downstream target of miR-301a. Knockdown of TGFBR2 in cells treated by miR-301a inhibitor elevated the previously abrogated migration and invasion.
Our data indicated that miR-301a correlated with the metastatic and invasive ability in human colorectal cancers and miR-301a exerted its role as oncogene by targeting TGFBR2.
PMCID: PMC4304202  PMID: 25551793
CRC; miRNA-301a; Metastasis; Invasion; TGFBR2
9.  Comparative biophysical properties of tenofovir-loaded, thiolated and nonthiolated chitosan nanoparticles intended for HIV prevention 
Nanomedicine (London, England)  2014;9(11):1595-1612.
This study is designed to test the hypothesis that tenofovir-loaded (an anti-HIV microbicide) chitosan–thioglycolic acid-conjugated (CS–TGA) nanoparticles (NPs) exhibit superior biophysical properties for mucoadhesion compared with those of native CS NPs.
Materials & methods
The NPs are prepared by ionotropic gelation. The particle mean diameter, encapsulation efficiency and release profile are analyzed by dynamic light scattering and UV spectroscopy, respectively. The cytotoxicity, cellular uptake and uptake mechanism are assessed on VK2/E6E7 and End1/E6E7 cell lines by colorimetry/fluorimetry, and percentage mucoadhesion is assessed using porcine vaginal tissue.
The mean diameter of the optimal NP formulations ranges from 240 to 252 nm, with a maximal encapsulation efficiency of 22.60%. Tenofovir release from CS and CS–TGA NPs follows first-order and Higuchi models, respectively. Both NPs are noncytotoxic in 48 h. The cellular uptake, which is time dependent, mainly occurs via the caveolin-mediated pathway. The percentage of mucoadhesion of CS–TGA NPs is fivefold higher than that of CS NPs, and reached up to 65% after 2 h.
Collectively, CS–TGA NPs exhibit superior biophysical properties and can potentially maximize the retention time of a topical microbicide, such as tenofovir, intended for the prevention of HIV transmission.
PMCID: PMC4278848  PMID: 24405490
HIV prevention; mucoadhesion; tenofovir; thiolated chitosan; nanoparticle; vaginal drug delivery
10.  Glucocerebrosidase Gene Mutations Associated with Parkinson's Disease: A Meta-Analysis in a Chinese population 
PLoS ONE  2014;9(12):e115747.
Mutations of glucocerebrosidase (GBA) confer susceptibility to Parkinson's disease in several ethnical populations, with a high incidence especially in the Ashkenazi Jewish population. Although there are several studies that have investigated a similar association in a Chinese population, small sample sizes and few positive outcomes have made it difficult to obtain conclusive results from these individual studies. Therefore, the present study used a meta-analysis approach, pooling the appropriate data from published studies to investigate the association of GBA mutations and Parkinson's disease in a Chinese population. Nine studies containing 6536 Chinese subjects (3438 cases and 3098 healthy controls) and examining the GBA mutations of L444P, N370S and several other mutations were included. Review Manager 5.2 software was applied to analyze the pooled odds ratios (ORs) and 95% confidence intervals (CIs). The results showed a significant association of Parkinson's disease risk with overall GBA mutations (OR = 6.34, 95% CI = 3.77–10.68, p<0.00001), and with the subgroup of L444P mutation (OR = 11.68, 95% CI = 5.23–26.06, p<0.00001). No such association was observed for the subgroup with N370S mutation or other mutations, in part because of the small sample size or rare events. Thus, for the rare occurrence of GBA mutations, studies with larger sample size are necessary to minimize the sampling error and to obtain convincing results.
PMCID: PMC4275276  PMID: 25535748
11.  Hyaluronidase-Sensitive Nanoparticle Templates for Triggered Release of HIV/AIDS Microbicide In Vitro 
The AAPS Journal  2013;16(2):181-193.
This study was designed to test the hypothesis that a triggered release of a topical microbicide (tenofovir) from hyaluronic acid nanoparticles (HA-NPs) can be achieved under the influence of hyaluronidase (HAase) enzyme. A fractional factorial experimental design was used to examine the factors [molar concentrations of adipic acid dihydrazide (X1) and 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (X2), volume of acetone (X3) and reaction time (X4)] influencing the responses, Y1; particle mean diameter: PMD (nanometers: nm), Y2; polydispersity index: PDI and Y3; zeta (ζ) potential: (millivolts). The amide bond formation between HA and ADH after cross-linking was confirmed by FT-IR and 13C-NMR analyses. These NPs were also characterized for cytotoxicity on a human vaginal epithelial cell line and L. crispatus. When formulated with factors X1; 2.49 mM, X2; 9.96 mM, X3; 60 mL, X4; 6 h, HA-NPs exhibited a spherical shape with PMD, PDI, ζ potential, encapsulation efficiency, and drug loading of 70.6 ± 4.1 nm, 0.07 ± 0.02, −38.2 ± 2.8 mV, 51.8 ± 2.4% w/w and 26.1 ± 1.2% w/w, respectively, (n = 3). Unlike for HA based gel, HAase significantly triggered the drug release and HA degradation from the NPs after 24 h (∼90% w/w and 65% w/w, respectively); whereas, in its absence, these values were ∼39% w/w and 26% w/w, respectively. The NPs were non-cytotoxic to human vaginal VK2/E6E7, End1/E6E7 cells and Lactobacillus crispatus. These data highlight the potential of HAase-sensitive HA-NPs templates for the controlled and vaginal delivery of anti-HIV/AIDS microbicides.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9546-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3933588  PMID: 24343770
experimental design; hyaluronic acid; hyaluronidase; microbicide; nanoparticles
12.  Association between TGF-β1 +869C/T polymorphism and fracture risk: a meta-analysis 
The association between TGF-β1 +869C/T polymorphism and risk of fractures remained controversial. Therefore, we performed this meta-analysis to investigate this association. We searched PubMed, EMBASE, and Wangfang databases for studies before Aug 2014. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association. A total of ten studies were included in this meta-analysis. TGF-β1 +869C/T polymorphism was associated with a significantly increased risk of fracture (OR=1.41; 95% CI, 1.20-1.65; I2=0%). In the subgroup analysis according to gender, women was significantly associated with risk of fracture (OR=1.44; 95% CI, 1.20-1.73; I2=4%). In the subgroup analysis by race, Asians (OR=1.43; 95% CI, 1.06-1.92; I2=0%) and Caucasians (OR=1.44; 95% CI, 1.13-1.85; I2=15%) showed increased fracture risk. Our meta-analysis suggested that the TGF-β1 +869C/T polymorphism may be a risk factor for developing fracture.
PMCID: PMC4307461  PMID: 25664014
Fracture; TGF-β1; meta-analysis; polymorphism
13.  Oridonin Inhibits Tumor Growth and Metastasis through Anti-Angiogenesis by Blocking the Notch Signaling 
PLoS ONE  2014;9(12):e113830.
While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases.
PMCID: PMC4259472  PMID: 25485753
14.  Kinetics of Sulforaphane in Mice after Consumption of Sulforaphane-Enriched Broccoli Sprout Preparation 
Molecular nutrition & food research  2013;57(12):10.1002/mnfr.201300210.
Sulforaphane is a natural isothiocyanate in broccoli sprouts with cancer chemopreventive activity. This study is aimed to to use different methods to develop broccoli sprout preparations to compare their ability to deliver sulforaphane to the mice and to evaluate the kinetics and biodistribution of sulforaphane.
Methods and Results
The sulforaphane-enriched sprout preparation generated by two-step procedure (quick-steaming followed by myrosinase treatment) contained the highest level of sulforaphane, which was 11 and 5 times higher than the freeze-dried fresh broccoli sprouts and the quick-steamed, freeze-dried broccoli sprouts, respectively. After oral administration of 2.5 mg/g body weight of the broccoli sprout preparations, sulforaphane was quickly absorbed and distributed throughout the tissues. The sulforaphane-rich preparation resulted in the highest exposure, with peak plasma sulforaphane concentration of 337 ng/ml, which is 6.0 times and 2.6 times higher compared to the other two preparations. A whole body physiologically-based pharmacokinetic model (developed with ADAPT 5 software) suggests that distribution of sulforaphane is perfusion-limited in all organs.
This study provides a broccoli sprout preparation that can serve as a good source of sulforaphane, and the model can be utilized to guide the dose design for the use of broccoli sprout preparation in chemoprevention.
PMCID: PMC3855579  PMID: 23929742
Broccoli Sprout; Cancer Chemoprevention; Kinetics; Mouse; Sulforaphane
15.  Human Infection with Influenza Virus A(H10N8) from Live Poultry Markets, China, 2014 
Emerging Infectious Diseases  2014;20(12):2076-2079.
Human infection with avian influenza virus A(H10N8) was initially reported in China in December 2013. We characterized H10N8 strains from a human patient and from poultry in live markets that infected persons had visited. Results of genome sequencing and virus characterization suggest that the virus strains that infected humans originated from these markets.
PMCID: PMC4257803  PMID: 25425075
avian influenza; H10N8; live poultry markets; phylogenetic analysis; human infection; influenza; viruses; transmission; China
16.  Effect of “Deqi” during the Study of Needling “Wang's Jiaji” Acupoints Treating Spasticity after Stroke 
Background. Acupuncture has been shown to reduce spasticity and prevent the onset of spasticity after stroke. The purpose of this study is to assess the effect of “Deqi” during needling “Wang's Jiaji” acupoints treating spasticity in the early stage of stroke. Methods. This study is a multicenter, prospective, randomized, controlled trial. 238 patients with stroke (<21 days) participated and were randomly allocated to the verum-acupuncture (n = 121) group or sham-acupuncture group (n = 117). The verum-acupuncture group received verum acupuncture required to produce the sense of “Deqi” while the sham-acupuncture group received sham acupuncture without “Deqi.” Patients in both groups followed the same 30 min acupuncture regimen 5 times per week for a period of 4 weeks. Scales of MAS, FMA, ADL, MBI, NIHSS, SS-QOL, and MRS were measured at baseline and at 2, 4, and 12 weeks after intervention. Results. Significant differences were observed between two groups. The MRS rating composition has the statistical difference after 4 weeks (P = 0.017). The score of MAS, FMA, Barthel, and SSQOL in verum-acupuncture group has increased significantly compared with the sham-acupuncture group after 12 weeks. There was 14% reduction of higher muscle tension in the verum-acupuncture group. Conclusion. Acupuncture “Wang's Jiaji” points with sensation of “Deqi” in the early stage may reduce the occurrence and decrease the severity of spasticity after stroke.
PMCID: PMC4247953  PMID: 25477996
17.  Potential therapeutic mechanism of genistein in breast cancer involves inhibition of cell cycle regulation 
Molecular Medicine Reports  2014;11(3):1820-1826.
Genistein can prevent tumorigenesis and reduce the incidence of diseases that are dependent upon estrogen. Previous research, however, has shown that genistein can also increase the risk of breast cancer. Thus, the aim of the present study was to investigate the mechanism underlying the effect of genistein in breast cancer and to determine whether genistein produces a therapeutic effect or promotes the development of breast cancer. Gene microarray data obtained from three samples treated with alcohol (control group), three samples treated with 3 μmol/l genistein and three samples treated with 10 μmol/l genistein for 48 h, were downloaded from the Gene Expression Omnibus database. Analysis of the differentially expressed genes (DEGs) and functional enrichment in the two genistein groups was performed. The interaction networks of the DEGs were constructed and the overlapping network was extracted. Finally, the functions and pathways of the DEGs in the overlapping network were enriched. In total, 224 DEGs coexisted in the two genistein groups, and the most significant function of these was the cell cycle. The number and the fold change of expression values of the DEGs in the 10 μmol/l genistein group were significantly higher compared with that of the 3 μmol/l genistein group. The most significant function and pathway of the DEGs in the overlapping network was the cell cycle involving several genes, including GLIPR1, CDC20, BUB1, MCM2 and CCNB1. Thus, genistein stimulation resulted in gene expression changes in breast cancer cell lines and discrepancies increased with higher doses of genistein. The DEGs were most significantly associated with cell cycle regulation.
PMCID: PMC4270317  PMID: 25385471
genistein; breast cancer; differentially expressed genes; cell cycle
18.  A Non-Invasive Laboratory Panel as a Diagnostic and Prognostic Biomarker for Thrombotic Microangiopathy: Development and Application in a Chinese Cohort Study 
PLoS ONE  2014;9(11):e111992.
Thrombotic microangiopathy (TMA) in the kidney is a histopathologic lesion that occurs in a number of clinical settings and is often associated with poor renal prognosis. The standard test for the diagnosis of TMA is the renal biopsy; noninvasive parameters such as potential biomarkers have not been developed.
We analyzed routine parameters in a cohort of 220 patients with suspected TMA and developed a diagnostic laboratory panel by logistic regression. The levels of candidate markers were validated using an independent cohort (n = 46), a cohort of systemic lupus erythematosus (SLE) (n = 157) and an expanded cohort (n = 113), as well as 9 patients with repeat biopsies.
Of the 220 patients in the derivation cohort, 51 patients with biopsy-proven TMA presented with a worse renal prognosis than those with no TMA (P = 0.002). Platelet and L-lactate dehydrogenase (LDH) levels showed an acceptable diagnostic value of TMA (AUC = 0.739 and 0.756, respectively). A panel of 4 variables - creatinine, platelets, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats 13) activity and LDH - can effectively discriminate patients with TMA (AUC = 0.800). In the validation cohort, the platelet and LDH levels and the 4-variable panel signature robustly distinguished patients with TMA. The discrimination effects of these three markers were confirmed in patients with SLE. Moreover, LDH levels and the 4-variable panel signature also showed discrimination values in an expanded set. Among patients undergoing repeat biopsy, increased LDH levels and panel signatures were associated with TMA status when paired evaluations were performed. Importantly, only the 4-variable panel was an independent prognostic marker for renal outcome (hazard ratio = 3.549; P<0.001).
The noninvasive laboratory diagnostic panel is better for the early detection and prognosis of TMA compared with a single parameter, and may provide a promising biomarker for clinical application.
PMCID: PMC4221199  PMID: 25372665
19.  Metastasis to the proximal ureter from prostatic adenocarcinoma: A rare metastatic pattern 
Canadian Urological Association Journal  2014;8(11-12):E859-E861.
Prostate cancer is one of the most common male malignancies, but it rarely metastasizes to the proximal ureter. We report a case of a 76-year-old man who presented with flank pain and lower urinary tract symptoms. Abdominal computed tomography scan revealed multiple filling defects at the middle of the left ureter, enlarged retroperitoneal lymph nodes, and probable psoas invasion. The patient underwent nephroureterectomy with excision of a cuff of bladder, and was found to have an adhesion between the middle part of left ureter and psoas intraoperatively. The pathological examination displayed positive immunohistochemical staining with prostate-specific antigen and prostate acid phostate, supporting the diagnosis of metastatic ureteral tumour from prostate cancer. In this case, periureteral soft tissue and ureteral muscular layer were infiltrated by metastatic tumour, whereas the mucosa was spared. The periureteral lymphatic pathway played an important role in the metastatic procedure of prostate cancer to the proximal ureter.
PMCID: PMC4250253  PMID: 25485016
20.  Efficacy and safety of ginger-salt-indirect moxibustion for urge urinary incontinence after stroke: protocol for a pilot multicentre randomised controlled trial 
BMJ Open  2014;4(10):e006326.
Ginger-salt-indirect moxibustion is widely applied to treat urge urinary incontinence after stroke, which is a common complication in stroke survivors. Moxa cone moxibustion and moxa box moxibustion are the main techniques of ginger-salt-indirect moxibustion. Our previous study had shown that ginger-salt-indirect moxibustion using moxa cones was feasible and effective for urination disorders post-stroke. This pilot study aims to assess the feasibility of conducting research to evaluate the efficacy and safety of ginger-salt-indirect moxibustion for patients with post-stroke urge urinary incontinence.
Methods and analysis
This is a multicentre, prospective, single-blinded, pilot randomised controlled trial. 120 eligible patients will be randomly allocated to three groups. Treatment group A (n=40) will receive moxa cone moxibustion and routine care; treatment group B (n=40) will receive moxa box moxibustion and routine care; control group (n=40) will only receive routine care for stroke recovery. The entire moxibustion treatment will consist of a total of 28 sessions during the course of 4 weeks. The primary outcome measure will be the increase in mean volume per void assessed at week 4 from the first moxibustion session (baseline). Secondary outcome measures will include mean frequency of urination per day and quality of life assessments measured by completion of the Incontinence Quality of Life Questionnaire and Barthel Index. All outcome measures will be assessed at baseline and at 4 and 16 weeks from baseline. Adverse events in the three groups will be recorded to assess the safety of moxibustion.
Ethics and dissemination
Research ethics was approved by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine Affiliated to the Capital Medical University (ref: 2013BL-094). Written informed consent will be obtained from all participants. Study results will be published in peer reviewed journals.
Trial registration number
ISRCTN 44706974.
PMCID: PMC4208054  PMID: 25335962
21.  RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response 
PLoS Genetics  2014;10(10):e1004693.
Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases.
Author Summary
TDP-43 is linked to pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How TDP-43 contributes to the development of these degenerative diseases remains unsolved, and the full range of TDP-43 functions has yet to be established. In the present study, we explored a conversed function of TDP-43 in regulating protein homeostasis from C. elegans to mammals. Under conditions of stress, TDP-43 translocates from the nucleus to the cytoplasm, competes with FOXO transcription factors for binding to 14-3-3 proteins, and releases FOXO for nuclear translocation and activation. These data are consistent with the ability of TDP-43 to regulate protein aggregation. Together the results provide important insight into the role of TDP-43 in stress responses and disease mechanisms. Since chronic stress is associated with neurodegenerative diseases, the TDP-43 switch could be kept in overdrive mode in these disorders, with its capacity to buffer further stress and maintain protein homeostasis being compromised. This mechanism also suggests that other RNA-processing proteins that exhibit similar stress-induced behavior may be coupled to other cellular pathways to provide coordinated reprogramming in stress responses.
PMCID: PMC4199500  PMID: 25329970
22.  The efficacy of a thrombin-based hemostatic agent in primary total knee arthroplasty: a meta-analysis 
Total knee arthroplasty (TKA) is a popular procedure in severe osteoarthritis. But perioperative bleeding remains a problem. Floseal® is a mixture of thrombin and bovine gelatin which can benefit a lot on reducing intraoperative and postoperative bleeding. However, there is no enough evidence judging its safety and efficiency. So a meta-analysis is conducted by us to evaluate the efficacy and safety of a thrombin-based hemostatic agent compared with conventional methods in TKA.
Two independent reviewers selected literatures published before August 2014 from MEDLINE, Embase, and The Cochrane Central Register of Controlled Trials. Other internet databases were also performed to identify trials according to the Cochrane Collaboration guidelines. High-quality randomized controlled trials (RCTs), prospective control trials (PCTs), and case controlled trials (CCTs) were selected. The meta-analysis was undertaken using RevMan 5.1 for Windows.
Three RCTs, one PCT, and one CCT met the inclusion criteria. There were significant differences in hemoglobin decline and calculated total blood loss between the Floseal® group and control group. There were no significant differences in postoperative drainage volume, rate of transfusion requirement, incidence of wound infection, deep vein thrombosis (DVT), and pulmonary embolism (PE) between treatment and control groups.
The present meta-analysis indicates that a thrombin-based hemostatic agent can reduce hemoglobin decline and calculated total blood loss after TKA and is not related to adverse reactions or complications such as wound infection, DVT, and PE.
PMCID: PMC4212119  PMID: 25316253
Floseal®; Thrombin; Arthroplasty; Meta-analysis
23.  Prediabetes Is Associated with HNF-4α P2 Promoter Polymorphism rs1884613: A Case-Control Study in Han Chinese Population and an Updated Meta-Analysis 
Disease Markers  2014;2014:231736.
Background. Controversy remains for the association between hepatocyte nuclear factor 4α (HNF-4α) P2 promoter polymorphism rs1884613 and type 2 diabetes (T2D). There was no association test of this polymorphism with prediabetes and T2D in the Chinese population. Moreover, an updated meta-analysis in various ethnic groups is needed to establish the contribution of rs1884613 to T2D risk. Methods. Using the Sequenom MassARRAY platform approach, we genotyped rs1884613 of HNF-4α in the P2 promoter region among 490 T2D patients, 471 individuals with prediabetes, and 575 healthy controls. All the individuals were recruited from 16 community health service centers in Nanshan district in Shenzhen province. Using STATA 11.0 software, meta-analysis was performed to summarize the overall contribution of rs1884613 to T2D risk. Results. Polymorphism rs1884613 was associated with genetic susceptibility to prediabetes in the whole samples (OR = 1.40, 95% CI = 1.16–1.68, P = 0.0001) and the female subgrouped samples (OR = 1.48, 95% CI = 1.14–1.92, P = 0.003) after adjusting for age and body mass index (BMI). In contrast, there was no association of rs1884613 with T2D in the whole samples and male in our case-control study and meta-analysis. Conclusions. Our results suggest that rs1884613 contributes to susceptibility to prediabetes, whereas this polymorphism may not play an important role in the development of T2D.
PMCID: PMC4226192  PMID: 25400315
24.  IL6-174G/C polymorphism and fracture risk 
Several studies have examined the associations of polymorphism in interleukin-6 (IL6) with fracture risk. However, the results were conflicting. Thus, a meta-analysis was conducted to determine the relationship between IL6-174C/G polymorphism and risk of fracture. Databases including PubMed, EMBASE, Wanfang were searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. Six studies were included in this meta-analysis. IL6-174C/G polymorphism was associated with a significantly increased risk of fracture (OR=1.32; 95% CI, 1.10-1.58; I2=11%; Figure 1). In the subgroup analysis according to gender, women (RR=1.26; 95% CI, 1.09-1.46; I2=0%) was significantly associated with risk of fracture. In the age subgroup analysis, old population (RR=1.27; 95% CI, 1.11-1.48; I2=0%) showed increased fracture risk. However, young population did show increased risk of fracture (RR=1.95; 95% CI, 0.70-5.47; I2=51%). Postmenopausal women also showed an increased fracture risks (RR=1.24; 95% CI, 1.08-1.44; I2=0%). This meta-analysis suggested that IL6-174C/G polymorphism contributed the development of fracture.
PMCID: PMC4238497  PMID: 25419434
Fracture; interleukin-6; meta-analysis; polymorphism
25.  Anterior versus posterior approach for treatment of thoracolumbar burst fractures: a meta-analysis 
European Spine Journal  2013;22(10):2176-2183.
To critically review and summarize the literature comparing the results of surgery via an anterior approach and that via a posterior approach for the treatment of thoracolumbar burst fractures to identify the better approach.
In this meta-analysis, we conducted electronic searches of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and other databases using the search terms “thoracolumbar fractures”, “anterior”, “posterior”, “controlled clinical trials”. Relevant journals or conference proceedings were also searched manually. Data extraction and quality assessment were in accordance with Cochrane Collaboration guidelines. The analysis was performed on individual patient data from all the trials that met the selection criteria. Sensitivity analysis was performed when there was significant heterogeneity. Results were expressed as risk difference for dichotomous outcomes and mean difference for continuous outcomes with 95 % confidence interval.
Four randomized clinical trials and three controlled clinical trials comparing the results of the anterior versus posterior approach in the treatment of thoracolumbar burst fractures were retrieved; these studies included 179 and 152 patients in the anterior and posterior approach groups, respectively. There were no differences in terms of neurological recovery, return to work, complications and Cobb angle between the two groups. The anterior approach was associated with longer operative time, greater blood loss and higher cost than the posterior approach.
The posterior approach may be more effective than the anterior approach. However, more high-quality, randomized controlled trials are required to compare these approaches and guide clinical decision-making.
Level of Evidence Level II, therapeutic study. See the Guidelines for Authors for a complete description of level of evidence.
PMCID: PMC3804690  PMID: 24013718
Anterior approach; Posterior approach; Thoracolumbar burst fractures; Meta-analysis

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