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1.  Bleeding outcomes associated with rivaroxaban and dabigatran in patients treated for atrial fibrillation: a systematic review and meta-analysis 
Warfarin is commonly used as a secondary prevention of stroke in patients with atrial fibrillation (AF). However, limitations have been observed even with the use of this medication. Recently, several newer direct oral anticoagulants (DOACs) have been approved for use by the food and drug administrations. Unfortunately, these newer drugs have seldom been compared directly with each other. Therefore, this study aimed to compare the bleeding events associated with rivaroxaban and dabigatran in patients treated for non-valvular AF.
EMBASE, Medline (National Library of Medicine) and the Cochrane Central Registry of Controlled Trials were searched for studies comparing rivaroxaban with dabigatran using the terms ‘rivaroxaban, dabigatran and atrial fibrillation’. Primary endpoints were: any bleeding outcomes, intracranial bleeding and gastro-intestinal (GI) bleeding. Secondary outcomes included stroke/systemic embolism (SE)/transient ischemic attack (TIA), venous thromboembolism and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated. The pooled analyses were carried out with RevMan 5.3 software. All the authors had full access to the data and approved the manuscript as written.
A total number of 4895 patients were included. This analysis showed that rivaroxaban was not associated with a significantly higher bleeding event when compared to dabigatran (OR: 1.28, 95% CI: 0.95–1.72; P = 0.11). GI bleeding was similarly manifested between these two DOACs (OR: 0.98, 95% CI: 0.43–2.25; P = 0.97). Even if intracranial bleeding was higher with the use of rivaroxaban, (OR: 2.18, 95% CI: 0.51–9.25; P = 0.29), the result was not statistically significant. Moreover, stroke/SE/TIA and venous thromboembolism were also not significantly different (OR: 0.81, 95% CI: 0.53–1.23; P = 0.32) and (OR: 2.06, 95% CI: 0.73–5.82; P = 0.17) respectively. However, even if mortality favored dabigatran (OR: 1.42, 95% CI: 0.99–2.06; P = 0.06), this result only approached statistical significance.
Head to head comparison showed that rivaroxaban was not associated with significantly higher bleeding events compared to dabigatran. Intracranial bleeding, GI bleeding, stroke/SE/TIA, venous thromboembolism and mortality were also not significantly different between these two DOACs. However, due to the limited number of patients analyzed, and which were mainly obtained from observational studies, this hypothesis might only be confirmed in future randomized trials. Furthermore, the CHADS2-VASC and HAS-BLED score which might play an important role in predicting bleeding risks should also not be ignored.
PMCID: PMC5216587  PMID: 28056795
Atrial fibrillation; Rivaroxaban; Dabigatran; Bleeding events; Intracranial bleeding; Gastrointestinal bleeding; Oral anticoagulants
2.  Evaluation of Soft Tissue Sarcoma Response to Preoperative Chemoradiotherapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging 
This study aims to assess the utility of quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters in comparison with imaging tumor size for early prediction and evaluation of soft tissue sarcoma response to preoperative chemoradiotherapy. In total, 20 patients with intermediate- to high-grade soft tissue sarcomas received either a phase I trial regimen of sorafenib + chemoradiotherapy (n = 8) or chemoradiotherapy only (n = 12), and underwent DCE-MRI at baseline, after 2 weeks of treatment with sorafenib or after the first chemotherapy cycle, and after therapy completion. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed using the Shutter-Speed model. After only 2 weeks of treatment with sorafenib or after 1 chemotherapy cycle, Ktrans (rate constant for plasma/interstitium contrast agent transfer) and its percent change were good early predictors of optimal versus suboptimal pathological response with univariate logistic regression C statistics values of 0.90 and 0.80, respectively, whereas RECIST LD percent change was only a fair predictor (C = 0.72). Post-therapy Ktrans, ve (extravascular and extracellular volume fraction), and kep (intravasation rate constant), not RECIST LD, were excellent (C > 0.90) markers of therapy response. Several DCE-MRI parameters before, during, and after therapy showed significant (P < .05) correlations with percent necrosis of resected tumor specimens. In conclusion, absolute values and percent changes of quantitative DCE-MRI parameters provide better early prediction and evaluation of the pathological response of soft tissue sarcoma to preoperative chemoradiotherapy than the conventional measurement of imaging tumor size change.
PMCID: PMC5215747  PMID: 28066805
soft tissue sarcoma; therapy response; DCE-MRI; pharmacokinetic modeling; Shutter-Speed model
3.  Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: a systematic review and meta-analysis of recently published studies (2012 – 2016) 
Controversies were previously observed with the concomitant use of clopidogrel and Proton Pump Inhibitors (PPIs), especially omeprazole, following coronary angioplasty. Even though several studies showed no interaction between clopidogrel and PPIs, questions have been raised about the decrease in antiplatelet effects of clopidogrel with PPIs. A previously published meta-analysis showed concomitant use of clopidogrel and PPIs to be associated with higher adverse cardiovascular outcomes. However, data which were used were extracted from studies published before the year 2012. Whether these controversies still exist in this new era is not clear. Therefore, we aim to show if the concomitant use of clopidogrel and PPIs is still associated with higher adverse outcomes following Percutaneous Coronary Intervention (PCI) using data obtained from recently published studies (2012 to 2016).
Electronic databases were searched for recent publications (2012–2016) comparing (clopidogrel plus PPIs) versus clopidogrel alone following PCI. Adverse cardiovascular outcomes were considered as the clinical endpoints. Odds Ratios (OR) with 95% Confidence Intervals (CI) were used as the statistical parameters and the pooled analyses were performed with RevMan 5.3 software.
Eleven studies with a total number of 84,729 patients (29,235 patients from the PPIs group versus 55,494 patients from the non-PPIs group) were included. Results of this analysis showed that short term mortality and Target Vessel Revascularization (TVR) significantly favored the non-PPIs group with OR: 1.55; 95% CI: 1.43–1.68, P < 0.00001 and OR: 1.26; 95% CI: 1.06–1.49, P = 0.009 respectively. Long-term Major Adverse Cardiac Events (MACEs), Myocardial Infarction (MI), Stent Thrombosis (ST) and TVR significantly favored patients who did not use PPIs with OR: 1.37; 95% CI: 1.23–1.53, P < 0.00001, OR: 1.41; 95% CI: 1.26–1.57, P < 0.00001 and OR: 1.38; 95% CI: 1.13–1.70, P = 0.002 and OR: 1.28; 95% CI: 1.01–1.61, P = 0.04 respectively. However, the result for long term mortality was not statistically significant.
The combined use of clopidogrel with PPIs is still associated with significantly higher adverse cardiovascular events such as MACEs, ST and MI following PCI supporting results of the previously published meta-analysis. However, long-term mortality is not statistically significant warranting further analysis with randomized patients.
PMCID: PMC5221663  PMID: 28056809
Proton pump inhibitors; Clopidogrel; Percutaneous coronary intervention; Major adverse cardiac events
4.  Complex Roles of Solution Chemistry on Graphene Oxide Coagulation onto Titanium Dioxide: Batch Experiments, Spectroscopy Analysis and Theoretical Calculation 
Scientific Reports  2017;7:39625.
Although graphene oxide (GO) has been used in multidisciplinary areas due to its excellent physicochemical properties, its environmental behavior and fate are still largely unclear. In this study, batch experiments, spectroscopy analysis and theoretical calculations were addressed to promote a more comprehensive understanding toward the coagulation behavior of GO onto TiO2 under various environmental conditions (pH, co-existing ions, temperature, etc.). The results indicated that neutral pH was beneficial to the removal of GO due to the electrostatic interaction. The presence of cations accelerated GO coagulation significantly owing to the influence of electrical double layer compression. On the contrary, the presence of anions improved the stability of GO primarily because of electrostatic repulsion and steric hindrance. Results of XRD, FTIR and XPS analysis indicated that the coagulation of GO on TiO2 was mainly dominated by electrostatic interactions and hydrogen bonds, which were further evidenced by DFT calculations. The high binding energy further indicated the stability of GO + TiO2 system, suggesting that TiO2 can be used as an effective coagulant for the efficient elimination and coagulation of GO from aqueous solutions. These findings might likely lead to a better understanding of the migration and transformation of carbon nanomaterials in the natural environment.
PMCID: PMC5206720  PMID: 28045053
5.  Efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta‐analysis 
Using a selective α‐adrenoceptor blocker for medical expulsive therapy (MET) is an effective treatment approach widely used for ureteral stones. The aim of the review was to assess the efficacy and safety of silodosin in medical expulstion therapy compared with placebo and tamsulosin.
A systematic search was performed in PubMed, Cochrane Library and Embase to identify randomized controlled trials that compared silodosin with a placebo or tamsulosin for ureteral calculi.
Eight publications involving a total of 1048 patients were used in the analysis, which compared silodosin with placebo and tamsulosin. We found that silodosin was effective in treating ureteral calculi in our meta‐analysis and was superior to tamsulosin in its efficacy. The expulsion rate of all ureteral stones (OR 1.59, 95% CI 1.08, 2.36, P = 0.02), the expulsion rate of distal ureteral stones (OR 2.82, 95% CI 1.70, 4.67, P < 0.0001) and the expulsion time (days) of distal ureteral stones (standard mean difference (SMD) −4.71, 95% CI −6.60, −2.83, P < 0.00001) indicated that silodosin was more effective than the placebo. Moreover, expulsion rate (OR 2.54, 95% CI 1.70, 3.78, P < 0.00001), expulsion time (days) (SMD −2.64, 95% CI −3.64, −1.64, P < 0.00001) and pain episodes (P < 0.00001) indicated that silodosin was more effective than the tamsulosin. Even though silodosin had a significant increase in abnormal ejaculation compared with tamsulosin, no significant differences were observed for complications (OR 1.00, 95% CI 0.58, 1.74, P = 1.00).
This meta‐analysis indicated that silodosin was superior to placebo or tamsulosin in the efficacy for distal ureteral calculi with better control of pain. The safety profile of silodosin was similar to tamsulosin though retrograde ejaculation was worse for silodosin use. We conclude that silodosin might have potential as a MET for ureteral stones.
PMCID: PMC4693578  PMID: 26255996
silodosin; ureteral calculi; urolithiasis; medical expulsion therapy; stone and randomized controlled trials
6.  In Vivo and In Vitro Efficacy of Minocycline-Based Combination Therapy for Minocycline-Resistant Acinetobacter baumannii 
Minocycline-based combination therapy has been suggested to be a possible choice for the treatment of infections caused by minocycline-susceptible Acinetobacter baumannii, but its use for the treatment of infections caused by minocycline-resistant A. baumannii is not well established. In this study, we compared the efficacy of minocycline-based combination therapy (with colistin, cefoperazone-sulbactam, or meropenem) to that of colistin in combination with meropenem for the treatment of minocycline-resistant A. baumannii infection. From 2006 to 2010, 191 (17.6%) of 1,083 A. baumannii complex isolates not susceptible to minocycline from the Taiwan Surveillance of Antimicrobial Resistance program were collected. Four representative A. baumannii isolates resistant to minocycline, amikacin, ampicillin-sulbactam, ceftazidime, ciprofloxacin, cefepime, gentamicin, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam were selected on the basis of the diversity of their pulsotypes, collection years, health care setting origins, and geographic areas of origination. All four isolates had tetB and overexpressed adeABC, as revealed by quantitative reverse transcription-PCR. Among all minocycline-based regimens, only the combination with colistin produced a fractional inhibitory concentration index comparable to that achieved with meropenem combined with colistin. Minocycline (4 or 16 μg/ml) in combination with colistin (0.5 μg/ml) also synergistically killed minocycline-resistant isolates in time-kill studies. Minocycline (50 mg/kg of body weight) in combination with colistin (10 mg/kg) significantly improved the survival of mice and reduced the number of bacteria present in the lungs of mice compared to the results of monotherapy. However, minocycline (16 μg/ml)-based therapy was not effective at reducing biofilm-associated bacteria at 24 or 48 h when its effectiveness was compared to that of colistin (0.5 μg/ml) and meropenem (8 μg/ml). The clinical use of minocycline in combination with colistin for the treatment of minocycline-resistant A. baumannii may warrant further investigation.
PMCID: PMC4914616  PMID: 27114274
7.  Rheumatoid Arthritis Patients have Similar Excellent Outcomes after Total Knee Replacement Compared with Osteoarthritis Patients 
The Journal of rheumatology  2015;43(1):46-53.
Although new treatments for rheumatoid arthritis (RA) are extremely effective in preventing disease progression, rates of total knee replacement (TKR) continue to rise. The ongoing need for TKR is problematic, especially as functional outcomes have been reported to be worse than in patients with osteoarthritis (OA). The purpose of this study is to assess pain, function, and quality of life 2 years after TKR in a contemporary RA patients, compared to patients with OA.
Primary TKR cases enrolled between 5/1/2007 and 7/1/2010 in a single institution TKR registry were eligible for this study. Validated RA cases were compared to OA at baseline and at 2-years.
We identified 4,456 eligible TKRs, including 136 RA. Compared to OA, RA TKR had significantly worse pre-operative WOMAC pain (55.9 vs. 46.6; p-value<0.0001) and function (58.7 vs. 47.3; p-value<0.0001) , however there were no differences at 2 years. Within RA, there was no difference for patients who used biologic DMARDs vs. those who did not in pain (p-value= 0.41) or function (p-value= 0.39) at 2 years. In a multivariate regression, controlling for multiple potential confounders, there was no independent association of RA with 2-year pain (p-value=0.18) or function (p-value=0.71).Satisfaction was high for both RA and OA.
RA patients undergoing primary TKR have excellent 2-year outcomes, comparable to OA, in spite of worse pre-operative pain and function. In this contemporary cohort, RA is not an independent risk factor for poor outcomes.
PMCID: PMC5065063  PMID: 26628605
Rheumatoid Arthritis; Arthroplasty; Disease-Modifying Antirheumatic Drugs; Osteoarthritis
8.  Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma 
Theranostics  2017;7(2):357-376.
Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing cis-diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated “sheddable” PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat. By virtue of the pH-dependent stability of borate ester in an aqueous medium, the PEG-shell could “shield” the PBA ligand in systemic circulation to reduce its “off-target effect”, while PEG was detached at tumor extracellular pH (~6.5) to expose intact PBA moiety. Simultaneously, the PBA ligand could bind with overexpressed sialic acid residues on cancer cells, giving rise to enhanced cellular internalization. In addition, the PBA moieties could also couple with each 3'-end ribose of double-stranded siRNA. siRNAs were used as both a payload and a pH-responsive intermolecular cross-linker, and thereby acquired sufficient stability during circulating in blood and a rapidly triggered release in response to acidic endosomal/lysosomal pH-stimuli. As a result, this dual pH-sensitive nanoparticle showed enhanced siRNA uptake, gene silencing efficacy and anti-metastatic effects in vitro. Furthermore, in vivo studies demonstrated that PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration.
PMCID: PMC5197070  PMID: 28042340
Phenylboronic acid; pH-Responsive; Sialic acid targeting; Systemic siRNA delivery; Cancer Metastasis; Orthotopic breast murine model.
9.  Resection of giant mediastinal liposarcoma via ‘⊣ shape’ incision 
Journal of Surgical Case Reports  2017;2017(1):rjw219.
Primary mediastinal liposarcomas are extremely rare conditions often resected through standard median sternotomy or lateral thoracotomy. However, the management of a very huge mediastinal tumor involving hemithorax through these two common surgical approaches is always challenging. Herein, we report a case of applying median sternotomy with a sternum transection plus a right fourth intercostal thoracotomy (‘⊣ shape’ incision) to resect a giant primary anterior mediastinal liposarcoma extending into the whole right thorax. The final pathological diagnosis was a well-differentiated liposarcoma. The patient experienced an uneventful recovery. The ‘⊣ shape’ incision is a good backup for the extension of standard median sternotomy and provides a better exposure for both mediastinum and hemithorax.
PMCID: PMC5204133  PMID: 28044001
10.  eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons 
eLife  null;5:e17517.
Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking down oligophrenin-1—an mRNA whose translation is controlled by p-eIF2α—in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.
PMCID: PMC5154759  PMID: 27960077
synaptic plasticity; psychostimulant abuse; protein synthesis; AMPAR; drug addiciton; Mouse
11.  SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage 
BioMed Research International  2016;2016:8263926.
Sirtuin3 (SIRT3) is an important protein deacetylase which predominantly presents in mitochondria and exhibits broad bioactivities including regulating energy metabolism and counteracting inflammatory effect. Since inflammatory cascade was proved to be critical for pathological damage following subarachnoid hemorrhage (SAH), we investigated the overall expression and cell-specific distribution of SIRT3 in the cerebral cortex of Sprague-Dawley rats with experimental SAH induced by internal carotid perforation. Results suggested that SIRT3 was expressed abundantly in neurons and endothelia but rarely in gliocytes in normal cerebral cortex. After experimental SAH, mRNA and protein expressions of SIRT3 decreased significantly as early as 8 hours and dropped to the minimum value at 24 h after SAH. By contrast, SOD2 expression increased slowly as early as 12 hours after experimental SAH, rose up sharply at the following 12 hours, and then was maintained at a higher level. In conclusion, attenuated SIRT3 expression in cortical neurons was associated closely with enhanced reactive oxygen species generation and cellular apoptosis, implying that SIRT3 might play an important neuroprotective role during early brain injury following SAH.
PMCID: PMC5178331  PMID: 28053989
12.  Urinary Polycyclic Aromatic Hydrocarbon Metabolites as Biomarkers of Exposure to Traffic-Emitted Pollutants 
Environment international  2015;85:104-110.
1-nitro-pyrene has been considered a compound specific to diesel combustion emission, while 1- and 2-nitro-napthalene are mainly produced through photochemical conversion of naphthalene released to the atmosphere. Metabolites of these compounds may serve as biomarkers of exposure to traffic related pollutants. We collected urine samples from 111 healthy and nonsmoking subjects within (i.e., during the Beijing Olympics) and outside (i.e., before and after the Olympics) a traffic control regime to improve Beijing’s air quality. Urines were analyzed for the sum of 1&2-amino-naphthalene (metabolites of 1- and 2-nitro-naphthalene) and 1-amino-pyrene (a metabolite of 1-nitro-pyrene), using an HPLC-fluorescence method. Within the same time periods, PM2.5 mass and constituents were measured, including elemental carbon, sulfate, nitrate, PAHs, carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone, and particle number concentrations. The associations between the urinary metabolites and air pollutants were analyzed using linear mixed-effects models. From the pre- to during-Olympic period, 1&2-amino-naphthalene and 1-hydroxy-pyrene decreased by 23% (p=0.066) and 16% (p=0.049), respectively, while there was no change in 1-amino-pyrene (2% increase, p=0.892). From during- to post-Olympic period, 1&2-amino-naphthalene, 1-amino-pyrene and 1-hydroxy-pyrene concentrations increased by 26% (p=0.441), 37% (p=0.355), and 3% (p=0.868), respectively. Furthermore, 1&2-amino-naphthalene and 1-hydroxy-pyrene were associated with traffic related pollutants in a similar lag pattern. 1-amino-pyrene was associated more strongly with diesel combustion products (e.g. PN and elemental carbon) and not affected by season. Time-lag analyses indicate strongest/largest associations occurred 24–72 hours following exposure. 1&2-amino-naphthalene and 1-hydroxy-pyrene can be used as a biomarker of exposure to general vehicle-emitted pollutants. More data are needed to confirm 1-amino-pyrene as a biomarker of exposure to diesel combustion emissions. Controlling creatinine as an independent variable in the models will provide a moderate adjusting effect on the biomarker analysis.
PMCID: PMC4765327  PMID: 26382649
PAH metabolites; biomarkers; diesel exhaust particles; exposure assessment; traffic-emitted pollutants
13.  Efficacy and Safety of Propiverine Hydrochloride for Overactive Bladder in Adult: a Systematic Review and Meta-analysis 
The Indian Journal of Surgery  2015;77(Suppl 3):1369-1377.
We carried out a systematic review and meta-analysis to assess the efficacy and safety of propiverine for treating overactive bladder (OAB) in adult. A literature review was performed to identify all published randomized placebo-controlled trials (RCT) of propiverine for the treatment of OAB. The search included the following databases: PUBMED and EMBASE. The reference lists of retrieved studies were also investigated. A systematic review and meta-analysis were conducted. Ten publications involving nine different RCTs were used in the analysis. We found that propiverine was effective in treating OAB in our meta-analysis. The decrease in number of micturitions/24 h (P < 0.00001, the mean decrease was from 1.80 to 2.57) indicated that propiverine was more effective than the placebo. Propiverine also decrease the number of urgency, urgency incontinence, and nocturia and increase urine volume. However, the incidence of difficulty in voiding was higher with propiverine therapy compared with the placebo (P = 0.05, the mean percentage range from 0.34 to 4.93 %). The decrease of total international prostate symptom score (IPSS) (P < 0.0001, the mean decrease was from 12.5 to 16.1) indicated that propiverine add a1-adrenoceptor antagonist was more effective in decreasing the lower urinary tract symptom (LUTS). The combination therapy also decreases the voiding symptom and storage symptom scores and increases maximum flow rate. This meta-analysis shows that propiverine is a safe and effective treatment for OAB. The major adverse event associated with propiverine treatment was difficulty in voiding. Propiverine add a1-adrenoceptor antagonist was more effective in terms of decreasing difficulty in voiding.
PMCID: PMC4775592  PMID: 27011567
Propiverine; Overactive bladder; Alpha-blockers; Meta-analysis; Randomized controlled trials
14.  Rhein and rhubarb similarly protect the blood-brain barrier after experimental traumatic brain injury via gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 signaling pathway 
Scientific Reports  2016;6:37098.
Oxidative stress chiefly contributes to the disruption of the BBB following traumatic brain injury (TBI). The Chinese herbal medicine rhubarb is a promising antioxidant in treating TBI. Here we performed in vivo and in vitro experiments to determine whether rhubarb and its absorbed bioactive compound protected the BBB after TBI by increasing ZO-1 expression through inhibition of gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 pathway. Rats were subjected to the controlled cortical impact (CCI) model, and primary rat cortical astrocytes were exposed to scratch-wound model. The liquid chromatography with tandem mass spectrometry method showed that rhein was the compound absorbed in the brains of CCI rats after rhubarb administration. The wet-dry weights and Evans blue measurements revealed that rhubarb and rhein ameliorated BBB damage and brain edema in CCI rats. Western blots showed that rhubarb and rhein downregulated GFAP in vitro. RT-PCR, immunohistochemistry, Western blot and dichlorodihydrofluorescein diacetate analysis indicated that rhubarb prevented activation of gp91phox subunit of NADPH oxidase induced ROS production, subsequently inhibited ERK/MMP-9 pathway in vivo and in vitro. Interestingly, rhein and rhubarb similarly protected the BBB by inhibiting this signaling cascade. The results provide a novel herbal medicine to protect BBB following TBI via an antioxidative molecular mechanism.
PMCID: PMC5128794  PMID: 27901023
15.  Regulation of α2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2 
Scientific Reports  2016;6:37921.
The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region. Knockdown of each GGA markedly inhibited the dendritic expression of α2B-AR in primary cortical neurons. Consistently, depleting GGA1 and GGA2 attenuated receptor-mediated signal transduction measured as ERK1/2 activation and cAMP inhibition. Although full length α2B-AR associated with GGA2 but not GGA1, its third intracellular loop was found to directly interact with both GGA1 and GGA2. More interestingly, further mapping of interaction domains showed that the GGA1 hinge region and the GGA2 GAE domain bound to multiple subdomains of the loop. These studies have identified an important function and revealed novel mechanisms of the GGA family proteins in the forward trafficking of a cell surface GPCR.
PMCID: PMC5128807  PMID: 27901063
16.  Hand, Foot, and Mouth Disease in Hunan Province, China, 2009-2014: Epidemiology and Death Risk Factors 
PLoS ONE  2016;11(11):e0167269.
Hand, foot, and mouth disease (HFMD) is an arising public health problem in Asia, including China. Epidemiological data is necessary to enable judicious public health responses and interventions. We analyzed the epidemiological and laboratory data of 759,301 HFMD cases reported to the Hunan Provincial Center for Disease Control and Prevention from 1 January 2009 to 31 December 2014. Univariate and multivariable conditional logistic regression analyses were used to identify risk factors of fatality in HFMD. The incidence of HFMD was highest among children aged 1–3 years, compared with other age groups. Of the total HFMD cases, 7,222 (0.95%) were considered severe and 338 (0.04%) were fatal. Enterovirus-A71 was the major cause of severe and fatal cases (65.75% and 88.78%, respectively). For severe cases, the median time from symptom onset to diagnosis was 0.5 days (interquartile range [IQR] 0–1.5 days); the median time from diagnosis to severe illness was 2 days (IQR 1–3 days). For fatal cases, the median time from symptom onset to diagnosis was 0.5 days (IQR 0–1.5 days); the median time from diagnosis to death was 1.5 days (IQR 0.5–2.5 days). In multivariable analysis, the abuse of antibiotic, glucocorticoid and pyrazolone in village clinics at basic medical institutions were identified as independent risk factors for HFMD fatal cases. In conclusion, our results suggest that the future direction to control and respond to HFMD is intensive surveillance of enterovirus-A71 and improving the ability to diagnose disease and treat patients, especially in basic medical institutions.
PMCID: PMC5127556  PMID: 27898715
17.  EST Pipeline System: Detailed and Automated EST Data Processing and Mining 
Expressed sequence tags (ESTs) are widely used in gene survey research these years. The EST Pipeline System, software developed by Hangzhou Genomics Institute (HGI), can automatically analyze different scalar EST sequences by suitable methods. All the analysis reports, including those of vector masking, sequence assembly, gene annotation, Gene Ontology classification, and some other analyses, can be browsed and searched as well as downloaded in the Excel format from the web interface, saving research efforts from routine data processing for biological rules embedded in the data.
PMCID: PMC5172240  PMID: 15629036
EST; pipeline; data mining; relational database; Java/J2EE
18.  Two ghrelin receptor agonists for adults with malnutrition: a systematic review and meta-analysis 
Nutrition Journal  2016;15:97.
Ghrelin receptor agonists have been established to be important in ameliorating the nutritional conditions in patients with malnutrition. However, some studies have reported inconsistent results. We aimed to coalesce the available evidence on the efficacy of ghrelin receptor agonists for the treatment of malnutrition.
We searched PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE for relevant articles published through March 2016. Studies comparing the efficacy of ghrelin receptor agonists versus placebo in malnourished patients were eligible for inclusion.
A total of 12 studies involving 1377 patients were included. Compared with placebo, ghrelin receptor agonists could increase the energy intake (standard mean difference [SMD] 2.67, 95% confidence interval [CI] 1.48 to 3.85, P < 0.001), lean body mass (weighted mean difference [WMD] 0.25 kg, 95% CI 0.07 to 0.42, P = 0.006), fat mass (WMD 0.92 kg, 95% CI 0.05 to 1.8, P = 0.038), and grip strength (WMD 0.31 kg, 95% CI 0.207 to 0.414, P < 0.001) of patients with malnutrition.
Our analysis indicated that ghrelin receptor agonists could improve the poor nutritional state of malnourished patients by increasing their energy intake, ameliorating their irregular body composition and improving their grip strength. However, these results might be less conclusive due to the limited sample sizes and one potential publication that has not been released.
PMCID: PMC5112740  PMID: 27852245
Ghrelin; Ghrelin receptor agonist; Anamorelin; Malnutrition; Anorexia; Cachexia
19.  Lasing with Pumping Levels of Si Nanocrystals on Silicon Wafer 
It is reported that the silicon nanocrystals (NCs) are fabricated by using self-assembly growth method with the annealing and the electron beam irradiation processes in the pulsed laser depositing, on which the visible lasing with higher gain (over 130 cm−1) and the enhanced emission in optical telecommunication window are measured in photoluminescence (PL). It is interesting that the enhanced visible electroluminescence (EL) on silicon nanocrystals (Si-NCs) is obviously observed by the naked eyes, and the light-emitting diode (LED) of the Si-NCs with external quantum efficiency of 20% is made on silicon chip in our laboratory. A four-level system is built for emission model in nanosilicon, in which the PL and EL measurement and transmission electron microscope (TEM) analysis demonstrate that the pumping levels with shorter lifetime from the rising energy of the Si quantum dots due to the quantum confinement effect occur, and the electronic localized states with longer lifetime owing to impurities bonding on Si-NCs surface are formed in the crystallized process to produce the inversion of population for lasing, where the optical gain is generated.
PMCID: PMC5110452  PMID: 27848235
Silicon nanocrystal; Pulsed laser deposition; Visible lasing; Four-level system
20.  Assessing the feasibility and quality of shared decision making in China: evaluating a clinical encounter intervention for Chinese patients 
Patient preference and adherence  2016;10:2341-2350.
The aim of this study was to evaluate the feasibility of using the Statin Choice decision aid to have discussions about starting a statin medication for cardiovascular risk reduction in Chinese patients with stable coronary artery diseases.
A prospective, pilot study of the Statin Choice decision aid in two teaching hospitals in Northern China was conducted. A total of seven clinicians were enrolled and underwent a 12-hour, group-based, in-person training on shared decision making (SDM) and the Statin Choice decision aid. Then, these clinicians used the Statin Choice decision aid in patients during a clinical encounter. A total of 86 patients aged 40−80 years, who had stable angina, were enrolled. All clinical encounters were video recorded. A team of three researchers viewed and scored all the encounter recordings to evaluate the SDM process and fidelity to the intervention using the OPTION scale and Fidelity scale, respectively. All the patients were followed up for 12 months to record adherence to statin and any major adverse cardiac events (MACEs).
The average scores on the OPTION normalized score and Fidelity scale were 21 (range, 3–32; out of a possible, 48) and 10 (range, 6–10; out of a possible, 10), respectively. This suggested that Chinese clinicians who were using Statin Choice in their patients were able to exhibit behaviors consistent with SDM at a level that is similar to that reported in Western countries. After SDM, the statin adherence was 94.5% (69/73), and the proportion of MACEs was 2.9% (2/69).
Using an encounter decision aid developed in the US, it was feasible to implement SDM in a referral cardiology practice in Mainland China. Further work to ensure that the encounter aid is pertinent to the Chinese population and that SDM is tested in at-risk patients could contribute to the implementation of SDM across Mainland China.
PMCID: PMC5115624  PMID: 27881912
Statin Choice; decision aid; stable angina; statin adherence; shared decision making; China
21.  Neuroprotection of Gueichih-Fuling-Wan on cerebral ischemia/ reperfusion injury in streptozotocin-induced hyperglycemic rats via the inhibition of the cellular apoptosis pathway and neuroinflammation 
BioMedicine  2016;6(4):21.
Background: Risks of stroke link with complications of hyperglycemia. Gueichih-Fuling-Wan (GFW), according to Chinese Medical Code literature, has the promotion of blood circulation and attenuates the swollen plot. Recent pharmacological studies have pointed out its efficacy in patients with cerebral ischemia or diabetes. Therefore, this study determined whether GFW has the protection against cerebral ischemia/ reperfusion (I/R) injury in streptozotocin (STZ)-induced hyperglycemic rats and LPS-induced inflammation in BV-2 microglial cells.
Methods: Extracts of GFW were filtered and frozen to dry for use. Hyperglycemia was induced by intraperitoneal injection of 70 mg/kg STZ. Fourteen days after STZ injection, GFW (1, 2 and 4 g/kg) was orally administered once daily for seven days. Rats were subjected to cerebral ischemia/reperfusion and sacrificed for infarction analysis and neuronal apoptosis detection twenty-one days after STZ injection. MTT assay was used for cell viability; nitrite quantification and western blot analysis of iNOS and COX-2 were used to explore the effects of GFW on LPS-induced inflammation in BV-2 microglial cells.
Results: GFW significantly ameliorated cerebral infarction while dosage was more than 1 g/kg (by 38.03% at 2 g/kg and 52.44% at 4 g/kg), and attenuated neurological deficits by 23.48% (at 2 g/kg) and 47.25% (at 4 g/kg). Furthermore, GFW (2, 4 g/kg) notably decreased TUNEL- and cleaved caspase-3-positive cells in the immunohistochemical stain (P < 0.01 and P < 0.001, respectively). GFW remarkably increased in Bcl-2 and decreased in caspase-3 and Bax/Bcl-2 ratio protein expressions by Western blot. GFW (0.25, 0.5, 1 mg/ ml) significantly reduced LPS-induced NO production in BV-2 microglial cells. And GFW attenuated iNOS and COX-2 expression in LPS-treated BV-2 cells. Conclusions: In summary, GFW has good bioactivities to protect cerebral I/R injury in hyperglycemic rats, which might be due to inhibition of cellular apoptosis and neuroinflammation.
PMCID: PMC5112181  PMID: 27854047
Gueichih-Fuling-Wan; Cerebral Ischemia/ Reperfusion Injury; Hyperglycemia; Cellular Apoptosis; Neuroinflammation
22.  Dramatically Enhanced Visible Light Response of Monolayer ZrS2 via Non-covalent Modification by Double-Ring Tubular B20 Cluster 
The ability to strongly absorb light is central to solar energy conversion. We demonstrate here that the hybrid of monolayer ZrS2 and double-ring tubular B20 cluster exhibits dramatically enhanced light absorption in the entire visible spectrum. The unique near-gap electronic structure and large built-in potential at the interface will lead to the robust separation of photoexcited charge carriers in the hybrid. Interestingly, some Zr and S atoms, which are catalytically inert in isolated monolayer ZrS2, turn into catalytic active sites. The dramatically enhanced absorption in the entire visible light makes the ZrS2/B20 hybrid having great applications in photocatalysis or photodetection.
PMCID: PMC5104703  PMID: 27832524
Electronic structure; Enhanced visible-light response; ZrS2/B20 hybrid; First-principles
23.  Quantitative determination of betamethasone sodium phosphate and betamethasone dipropionate in human plasma by UPLC-MS/MS and a bioequivalence study 
The compound medicine of betamethasone sodium phosphate (BSP) and betamethasone dipropionate (BDP) is widely used for diverse glucocorticoid-sensitive acute and chronic diseases such as asthma, rheumatoid arthritis and systemic lupus erythematosus. It will be useful and beneficial to validate sensitive method for the determination of BSP, BDP and their metabolites for their pharmacokinetic study. Hereby, an ultra-high pressure liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been validated for the determination of BSP, BDP and their metabolites betamethasone (BOH), betamethasone 17-monodipropionate (B17P) and betamethasone 21-monodipropionate (B21P) in human plasma. Liquid-liquid extraction with ether and n-hexane (v/v, 4:1) was used for sample preparation of BDP, BOH, B17P and B21P with beclomethasone dipropionate as internal standard (IS), while solid phase extraction was adopted for sample preparation of BSP using prednisolone as IS. The chromatographic separation was performed on a Hypurity C18 column (150 mm×2.1 mm, 5 μm) for BOH, BDP, B21P and B17P, and a Luna C18 (2) column (150 mm×2.0 mm, 5 μm) for BSP. Electrospray ionization interfaced with positive multiple reaction monitoring (MRM) scan mode was used for mass spectrometric detection. The standard calibration curves were linear within the range of 2.525 × 10−9−403.9 × 10−9 mol·dm−3 for BSP, 0.125 × 10−9−55.81 × 10−9 mol·dm−3 for BDP, 0.278 × 10−9−74.95 × 10−9 mol·dm−3 for BOH, 0.098 × 10−9−4.688 × 10−9 mol·dm−3 for B17P and 0.226 × 10−9−5.411 × 10−9 mol·dm−3 for B21P, respectively. The validated method was successfully applied to a bioequivalence study in 23 healthy subjects after they were injected with this compound medicine BSP and BDP.
Graphic abstract
PMCID: PMC5042352  PMID: 27695531
betamethasone; betamethasone sodium phosphate; betamethasone dipropionate; UPLC-MS; human plasma
24.  HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation 
Cell stem cell  2015;17(5):597-610.
Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)+ AML CD34+ cells while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates a HDAC8-mediated p53-inactivating mechanism promoting LSC activity, and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)+ LSCs.
Graphical Abstract
PMCID: PMC4636961  PMID: 26387755
25.  Positive expression of KIF20A indicates poor prognosis of glioma patients 
OncoTargets and therapy  2016;9:6741-6749.
Glioma patients have a poor overall survival; however, patients can show distinct clinical outcomes due to the high heterogeneity of the tumor, which may be indicated by certain clinicobiological parameters. Kinesin family member 20A (KIF20A), which participates in cytokinesis and intracellular transportation, has been recently reported to be upregulated in pancreatic cancer, breast cancer, and bladder cancer. In the current study, we investigated the expression of KIF20A in gliomas and its significance in predicting the prognosis after surgery. We found that KIF20A positive expression in glioma tissues correlated significantly with Ki67 protein expression and advanced World Health Organization grade. Univariate and multivariate analysis revealed that KIF20A can act as an independent prognostic factor for predicting the overall survival of glioma patients. Moreover, we demonstrated that KIF20A can positively regulate the expression of Ki67 in glioma cell lines. Correspondingly, overexpression of KIF20A can promote cell proliferation and invasion, whereas knockdown of KIF20A can inhibit cell viability and invasion capacity. In vitro study also showed that under the treatment of plumbagin, an anticancer drug, KIF20A expression decreased in a dose-dependent manner. In addition, the overexpression of KIF20A can also increase the drug resistance toward plumbagin, which provided the possibility that KIF20A may contribute to the chemotherapy resistance of gliomas.
PMCID: PMC5098585  PMID: 27843327
glioma; invasion; KIF20A; prognosis; proliferation

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