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1.  Effect of Abnormal Fasting Plasma Glucose Level on All-Cause Mortality in Older Patients With Acute Myocardial Infarction: Results From the Beijing Elderly Acute Myocardial Infarction Study (BEAMIS) 
Mayo Clinic Proceedings  2011;86(2):94-104.
OBJECTIVE: To assess whether the relationship between abnormal fasting plasma glucose (FPG) levels and patient outcomes holds for both older men and older women with acute myocardial infarction (AMI).
PATIENTS AND METHODS: From April 1, 2004, to October 31, 2006, a total of 2016 consecutive older patients (age ≥65 years) presenting with AMI were screened. Of these patients, 1854 were consecutively enrolled in the study. Patients were categorized into 4 groups: the hypoglycemic group (FPG, ≤90.0 mg/dL [to convert to mmol/L, multiply by 0.0555]; n=443, 23.9%), the euglycemic group (FPG, 90.1-126.0 mg/dL; n=812, 43.8%), the mildly hyperglycemic group (FPG, 126.1-162.0 mg/dL; n=308, 16.6%), and the severely hyperglycemic group (FPG, ≥162.1 mg/dL; n=291, 15.7%). The primary outcomes were rates of in-hospital and 3-year mortality.
RESULTS: Female patients were older and had a higher incidence of diabetes mellitus but lower rates of smoking and use of invasive therapy. Men tended to have a higher frequency of hypoglycemia, whereas women tended to have a higher frequency of hyperglycemia. No significant difference was found in in-hospital (10.9% vs 9.1%; P=.36) or 3-year (24.5% vs 24.5%; P=.99) mortality between male and female patients, and FPG-associated mortality did not vary significantly by sex.
CONCLUSION: An increased FPG level was associated with a relatively higher risk of in-hospital mortality in men but not in women. Nonetheless, increased and decreased FPG levels at admission could predict higher mortality rates regardless of sex. There was a striking U-shaped relationship between FPG levels and in-hospital and 3-year mortality. The effect of abnormal FPG level on outcomes among older patients with AMI did not vary significantly by sex.
An increased fasting plasma glucose level was associated with a relatively higher risk of in-hospital mortality in men but not in women. Nonetheless, increased and decreased fasting plasma glucose levels at admission could predict higher mortality rates regardless of sex.
doi:10.4065/mcp.2010.0473
PMCID: PMC3031433  PMID: 21282483
2.  Molecular and Neurodevelopmental Benefits to Children of Closure of a Coal Burning Power Plant in China 
PLoS ONE  2014;9(3):e91966.
Polycyclic aromatic hydrocarbons (PAH) are major toxic air pollutants released during incomplete combustion of coal. PAH emissions are especially problematic in China because of their reliance on coal-powered energy. The prenatal period is a window of susceptibility to neurotoxicants. To determine the health benefits of reducing air pollution related to coal-burning, we compared molecular biomarkers of exposure and preclinical effects in umbilical cord blood to neurodevelopmental outcomes from two successive birth cohorts enrolled before and after a highly polluting, coal-fired power plant in Tongliang County, China had ceased operation. Women and their newborns in the two successive cohorts were enrolled at the time of delivery. We measured PAH-DNA adducts, a biomarker of PAH-exposure and DNA damage, and brain-derived neurotrophic factor (BDNF), a protein involved in neuronal growth, in umbilical cord blood. At age two, children were tested using the Gesell Developmental Schedules (GDS). The two cohorts were compared with respect to levels of both biomarkers in cord blood as well as developmental quotient (DQ) scores across 5 domains. Lower levels of PAH-DNA adducts, higher concentrations of the mature BDNF protein (mBDNF) and higher DQ scores were seen in the 2005 cohort enrolled after closure of the power plant. In the two cohorts combined, PAH-DNA adducts were inversely associated with mBDNF as well as scores for motor (p = 0.05), adaptive (p = 0.022), and average (p = 0.014) DQ. BDNF levels were positively associated with motor (p = 0.018), social (p = 0.001), and average (p = 0.017) DQ scores. The findings indicate that the closure of a coal-burning plant resulted in the reduction of PAH-DNA adducts in newborns and increased mBDNF levels that in turn, were positively associated with neurocognitive development. They provide further evidence of the direct benefits to children's health as a result of the coal plant shut down, supporting clean energy and environmental policies in China and elsewhere.
doi:10.1371/journal.pone.0091966
PMCID: PMC3960155  PMID: 24647528
3.  Evaluation of the Value of Fasting Plasma Glucose in the First Prenatal Visit to Diagnose Gestational Diabetes Mellitus in China 
Diabetes Care  2013;36(3):586-590.
OBJECTIVE
To evaluate the value of fasting plasma glucose (FPG) value in the first prenatal visit to diagnose gestational diabetes mellitus (GDM).
RESEARCH DESIGN AND METHODS
Medical records of 17,186 pregnant women attending prenatal clinics in 13 hospitals in China, including the Peking University First Hospital (PUFH), were examined. Patients with pre-GDM were excluded; data for FPG at the first prenatal visit and one-step GDM screening with 75-g oral glucose tolerance test (OGTT) performed between 24 and 28 weeks of gestation were collected and analyzed.
RESULTS
The median ± SD FPG value was 4.58 ± 0.437. FPG decreased with increasing gestational age. FPG level at the first prenatal visit was strongly correlated with GDM diagnosed at 24–28 gestational weeks (χ2 = 959.3, P < 0.001). The incidences of GDM were 37.0, 52.7, and 66.2%, respectively, for women with FPG at the first prenatal visit between 5.10 and 5.59, 5.60 and 6.09, and 6.10–6.99 mmol/L. The data of PUFH were not statistically different from other hospitals.
CONCLUSIONS
Pregnant women (6.10 ≤ FPG < 7.00 mmol/L) should be considered and treated as GDM to improve outcomes; for women with FPG between 5.10 and 6.09 mmol/L, nutrition and exercise advice should be provided. An OGTT should be performed at 24–28 weeks to confirm or rule out GDM. Based on our data, we cannot support an FPG value ≥5.10 mmol/L at the first prenatal visit as the criterion for diagnosis of GDM.
doi:10.2337/dc12-1157
PMCID: PMC3579369  PMID: 23193214
4.  Pseudo-ischaemic ECG in a patient with amyotrophic lateral sclerosis surviving for a decade 
BMJ Case Reports  2012;2012:bcr0120125543.
A 58-year-old female with no history of heart disease was admitted to our hospital for abnormal ECG mimicking myocardial ischaemia. The ECG revealed persistent T-wave inversion in almost all leads, especially in precordial leads V2–V6. The patient had no complaints of chest pain, chest distress, short of breath or other atypical myocardial ischaemia symptoms. She had a history of amyotrophic lateral sclerosis (ALS) with a disease course more than 20 years. Examinations help rule out other diseases causing persistent T-wave inversion. Importantly, cardiac catheterisation showed nearly normal coronary arteries that could rule out myocardial ischaemia. Accordingly, the authors presumed that the pseudo-ischaemic ECG was associated with ALS in this patient. The findings of the present case provide new evidence that autonomic nervous system may involve in the pathophysiological progress of ALS.
doi:10.1136/bcr.01.2012.5543
PMCID: PMC3291013  PMID: 22665549
5.  Using Multivariate Regression Model with Least Absolute Shrinkage and Selection Operator (LASSO) to Predict the Incidence of Xerostomia after Intensity-Modulated Radiotherapy for Head and Neck Cancer 
PLoS ONE  2014;9(2):e89700.
Purpose
The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT.
Methods and Materials
Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3+ xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER3m) and 12 months (XER12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R2, chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC.
Results
Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R2 was satisfactory and corresponded well with the expected values.
Conclusions
Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT.
doi:10.1371/journal.pone.0089700
PMCID: PMC3938504  PMID: 24586971
6.  Intestinal Transportations of Main Chemical Compositions of Polygoni Multiflori Radix in Caco-2 Cell Model 
Context. Polygoni Multiflori Radix (PMR) is originated from the root of Polygonum multiflorum Thunb. and used in oriental countries for centuries. However, little researches pay close attention to the absorption of its major constituents. Objective. Transepithelial transport of TSG, RL, PL, and four anthraquinones is carried out. Materials and Methods. Caco-2 cell monolayer, which represented a well-established model for the study of intestinal transport of nutrients and xenobiotics, was used in this paper. Results. The apparent permeability coefficients (Papp) in the Caco-2 cell monolayers were TSG (2.372 × 10−9) < EG (2.391 × 10−9) < EN (2.483 × 10−9) < PL (4.917 × 10−9) < RN (1.707 × 10−8) < RL (1.778 × 10−8) < AE (1.952 × 10−8). Thus, RN, RL, and AE were considered partly absorbed, while other constituents were hardly absorbed. Discussion and Conclusion. Glycosides showed poor permeabilities than aglycones. In the meantime, TSG and EN gave out poor recovery rates in this assay, which indicated that TSG and EN may accumulate or metabolise in the Caco-2 cells. In silico prediction indicated that Gibbs energy (r = 0.751, p < 0.05) and heat of form (r = 0.701, p < 0.05) were strongly positively correlated with Papp.
doi:10.1155/2014/483641
PMCID: PMC3944923
7.  Synergism between upregulation of Rab7 and inhibition of autophagic degradation caused by mycoplasma facilitates intracellular mycoplasma infection 
Molecular Medicine Reports  2014;9(3):793-800.
Following fusion of a mycoplasma with a host cell membrane, the inserted components of mycoplasma may then be transported through the endocytic pathway. However, the effects of mycoplasmas on the host cell endomembrane system are largely unknown. In this study, mycoplasma-induced changes in the dynamics of endocytic and autophagic systems were investigated. Endocytosis and autophagy are two major processes involved in the survival of intracellular prokaryotic pathogens. It was found that, immediately following infection, mycoplasmas induce endocytosis in the host cell; however, in the long term the mycoplasmas suppress turnover of the components of the endocytic pathway. Immunofluorescence microscopy revealed that Rab7 and LC3-II are recruited to the intracellular mycoplasma-containing compartments. Western blot analysis and quantitative reverse transcription-polymerase chain reaction (qPCR) showed that mycoplasmas increase expression of Rab7 by upregulating transcription, but increase levels of LC3-II and p62 by post-translational regulation. Furthermore, it was demonstrated that mycoplasma infection causes inhibition of autophagic degradation of LC3-II and p62. In addition, it was found that upregulation of Rab7 and inhibition of autophagic degradation synergistically contributes to intracellular mycoplasma accumulation. In conclusion, these findings suggest that mycoplasmas may manipulate host cell endosomal and autophagic systems in order to facilitate intracellular infection.
doi:10.3892/mmr.2014.1907
PMCID: PMC3926517  PMID: 24452847
mycoplasma; endocytic pathway; autophagy; Rab7; LC3; p62
8.  The Molecular Detection and Clinical Significance of ALK Rearrangement in Selected Advanced Non-Small Cell Lung Cancer: ALK Expression Provides Insights into ALK Targeted Therapy 
PLoS ONE  2014;9(1):e84501.
Background
This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients.
Methods
ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation.
Results
The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival.
Conclusions
Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.
doi:10.1371/journal.pone.0084501
PMCID: PMC3880316  PMID: 24404167
9.  Towards Stratifying Ischemic Components by Cardiac MRI and Multifunctional Stainings in a Rabbit Model of Myocardial Infarction 
Theranostics  2013;4(1):24-35.
Objectives: We sought to identify critical components of myocardial infarction (MI) including area at risk (AAR), MI-core and salvageable zone (SZ) by using cardiac magnetic resonance imaging (cMRI) and multifunctional stainings in rabbits.
Materials and Methods: Fifteen rabbits received 90-min coronary artery (CA) ligation and reopening to induce reperfused MI. First-pass perfusion weighted imaging (PWI90') was performed immediately before CA reperfusion. Necrosis avid dye Evans blue (EB) was intravenously injected for later MI-core detection. One-day later, cMRI with T2-weighted imaging (T2WI), PWI24h and delayed enhancement (DE) T1WI was performed at a 3.0T clinical scanner. The heart was excised and CA was re-ligated with aorta infused by red-iodized-oil (RIO). The heart was sliced into 3-mm sections for digital radiography (DR), histology and planimetry with myocardial salvage index (MSI) and perfusion density rate (PDR) calculated.
Results: There was no significant difference between MI-cores defined by DE-T1WI and EB-staining (31.13±8.55% vs 29.80±7.97%; p=0.74). The AAR was defined similarly by PWI90' (39.93±9.51%), RIO (38.82±14.41%) and DR (38.17±15.98%), underestimated by PWI24h (36.44±5.31%), but overestimated (p<0.01) by T2WI (56.93±8.87%). Corresponding MSI turned out to be 24.17±9.5% (PWI90'), 21.97±9.41% (DR) and 22.68±9.65% (RIO), which were significantly (p<0.01) higher and lower than that with PWI24h (15.15±7.34%) and T2WI (45.52±7.5%) respectively. The PDR differed significantly (p<0.001) between normal myocardium (350.6±33.1%) and the AAR (31.2±15%), suggesting 11-times greater blood perfusion in normal myocardium over the AAR.
Conclusion: The introduced rabbit platform and new staining techniques together with the use of a 3.0T clinical scanner for cMRI enabled visualization of MI components and may contribute to translational cardiac imaging research for improved theranostic management of ischemic heart disease.
doi:10.7150/thno.7188
PMCID: PMC3881225  PMID: 24396513
area at risk; myocardial infarction; rabbits; MRI; Evans blue
10.  Separate calculation of DW-MRI in assessing therapeutic effect in liver tumors in rats 
AIM: To explore whether the antitumor effect of a vascular disrupting agent (VDA) would be enhanced by combining with an antiangiogenic agent, and whether such synergistic effects can be effectively evaluated with separate calculation of diffusion weighted magnetic resonance imaging (DW-MRI).
METHODS: Thirty-seven rats with implanted liver tumors were randomized into the following three groups: (1) ZD6126, a kind of VDA; (2) ZDTHA, ZD6126 in combination with an antiangiogenic, thalidomide; and (3) control. Morphological DW-MRI were performed and quantified before, 4 h and 2 d after treatment. The apparent diffusion coefficient (ADC) values were calculated separately for low b values (ADClow), high b values (ADChigh) and all b values (ADCall). The tissue perfusion contribution, ADCperf, was calculated as ADClow-ADChigh. Imaging findings were finally verified by histopathology.
RESULTS: The combination therapy with ZDTHA significantly delayed tumor growth due to synergistic effects by inducing cumulative tumor necrosis. In addition to delaying tumor growth, ZDTHA caused tumor necrosis in an additive manner, which was verified by HE staining. Although both ADChigh and ADCall in the ZD6126 and ZDTHA groups were significantly higher compared to those in the control group on day 2, the entire tumor ADChigh of ZDTHA was even higher than that of ZD6126, but the significant difference was not observed for ADCall between ZDTHA and ZD6126. This indicated that the perfusion insensitive ADChigh values calculated from high b value images performed significantly better than ADCall for the monitoring of tumor necrosis on day 2. The perfusion sensitive ADCperf derived from ADClow by excluding high b value effects could better reflect the reduction of blood flow due to the vessel shutdown induced by ZD6126, compared to the ADClow at 4 h. The ADCperf could provide valuable perfusion information from DW-MRI data.
CONCLUSION: The separate calculation of ADC is more useful than conventional averaged ADC in evaluating the efficacy of combination therapy with ZD6126 and thalidomide for solid tumors.
doi:10.3748/wjg.v19.i47.9092
PMCID: PMC3870564  PMID: 24379636
Diffusion weighted imaging; Magnetic resonance imaging; Therapeutic assessment; Liver tumor; Rats; Vascular disrupting agent; Antiangiogenic agent; Animal model; Rodents
11.  Prmt7 is dispensable in tissue culture models for adipogenic differentiation 
F1000Research  2013;2:279.
Protein arginine methylation is a common posttranslational modification that has been implicated in numerous biological processes including gene expression. The mammalian genome encodes nine protein arginine methyltransferases (Prmts) that catalyze monomethylation, asymmetric dimethylation, and symmetric dimethylation on arginine residues. Protein arginine methyltransferase 7 (Prmt7) is categorized as a type II and type III enzyme that produces symmetric dimethylated arginine and monomethylated arginine, respectively. However, the biological role of Prmt7 is not well characterized. We previously showed that Prmt5, a type II Prmt that associates with Brg1-based SWI/SNF chromatin remodeling complex, is required for adipocyte differentiation. Since Prmt7 also associates with Brg1-based SWI/SNF complex and modifies core histones, we hypothesized that Prmt7 might play a role in transcriptional regulation of adipogenesis. In the present study, we determined that the expression of Prmt7 did not change throughout adipogenic differentiation of C3H10T1/2 mesenchymal cells. Knockdown or over-expression of Prmt7 had no effect on lipid accumulation or adipogenic gene expression in differentiating C3H10T1/2 cells or in C/EBPα-reprogrammed NIH3T3 fibroblasts. Based on these results, we conclude that Prmt7, unlike Prmt5, is dispensable for adipogenic differentiation in tissue culture models.
doi:10.12688/f1000research.2-279.v1
PMCID: PMC3962006
12.  Role of contrast-enhanced ultrasound in evaluating the efficiency of ultrasound guided percutaneous microwave ablation in patients with renal cell carcinoma 
Radiology and Oncology  2013;47(4):398-404.
Background
The aim of the study was to evaluate the efficiency and feasibility of contrast-enhanced ultrasound (CEUS) with Sonovue in assessing of renal cell carcinomas (RCCs) following ultrasound (US)-guided percutaneous microwave ablation (MWA).
Patinets and methods
Seventy-nine patients (60 males and 19 females) with 83 lesions (mean size 3.2±1.6 cm) were treated by US-guided percutaneous MWA. The CEUS results of the third day after the ablation were compared with the synchronous contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) results and biopsy pathological results. The follow-up was performed by CEUS and CT/MRI after 1, 3, 6 months and every 6 months subsequently. The combination of clinical follow-up results and CT/MRI imaging findings was the reference standard of CEUS results for evaluating the therapeutic effect. The identification of residual or recurrence tumour was assessed by two blinded radiologists.
Results
On the third day after MWA, CEUS showed 68 of 83 lesions (68/83, 81.9%) successfully ablated and 15 of 83 (18.1%) with residual tumours. Among residual tumours, 13 (86.7%) were confirmed by contrast-enhanced CT/MRI findings and biopsy results. The sensitivity, specificity, accuracy, positive and negative predictive value of CEUS evaluating the short-term MWA effectiveness were 100%, 97.1%, 97.6%, 86.7% and 100%, respectively. During the six years follow-up (median 26 months), the CEUS showed recurrence in 7 patients, and six of them achieved consistent results on CEUS and CT/MRI imaging. The sensitivity, specificity, accuracy, positive and negative predictive value for CEUS evaluating long-term MWA effectiveness were 85.7%, 98.7%, 97.6%, 85.7% and 98.7%, respectively.
Conclusions
The post-procedural CEUS demonstrated as an effective and feasible method in evaluating a therapeutic effect of RCCs following MWA.
doi:10.2478/raon-2013-0038
PMCID: PMC3814286  PMID: 24294186
contras enhanced ultrasound; microwave ablation; renal cell carcinoma
13.  In Vitro Cytotoxicity and In Vivo Acute and Chronic Toxicity of Xanthii Fructus and Its Processed Product 
BioMed Research International  2013;2013:403491.
Xanthii Fructus (XF), the fruit of Xanthium sibiricum Patr., was used in the treatment of rhinitis and related nasal disease. Adverse effects of Xanthii Fructus are frequently reported these years. In the paper, in vitro renal cytotoxicity and in vivo acute and chronic toxicity researches of Xanthii Fructus (XF) and its processed product (processed Xanthii Fructus (PXF)) were carried out. Water extraction of XF displayed no cell membrane damage effects even in the highest concentration (100 μg/mL); however, it might affect the function of renal cell mitochondria. Acute toxicities were observed only in high and middle dosage groups. Fortunately, the single dose administration of XF or PXF was safe even at the highest daily dosage. Twelve-week chronic toxicity assays were performed in SD rats with low, middle, and high dosage. Notable changes in body weight and blood cell and BUN and Scr changes sporadically occurred in middle and high groups after the 9th week. Serum HA and HPCIII values were sustained increasing from the 4th week to the 8th week in Group V male rats, which indicated that the renal fibrosis risks still existed although no fibrosis was found in the pathological examination of the liver and kidney.
doi:10.1155/2013/403491
PMCID: PMC3858965  PMID: 24371823
14.  Initial Testing of the Investigational NEDD8 Activating Enzyme Inhibitor MLN4924 by the Pediatric Preclinical Testing Program 
Pediatric blood & cancer  2011;59(2):10.1002/pbc.23357.
Background
MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins.
Procedures
MLN4924 was tested against the PPTP in vitro panel using 96 hour exposure time at concentrations ranging from 1.0 nM to 10 μM. It was tested in vivo at a dose of 100 mg/kg [66 mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily × 5 days. Treatment duration was 3 weeks.
Results
The median relative IC50 for MLN4924 against the PPTP cell lines was 143 nM, (range 15 nM to 678 nM) with that for the Ewing panel being significantly lower (31 nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values > 2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilms tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels.
Conclusions
MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts.
doi:10.1002/pbc.23357
PMCID: PMC3823062  PMID: 22012946
Preclinical Testing; Developmental Therapeutics; MLN4924
15.  Identification of a Novel Strain of Human Papillomavirus from Children with Diarrhea in China 
Genome Announcements  2013;1(5):e00761-13.
A highly divergent human papillomavirus (HPV) strain, HPV-L55, was identified in fecal samples from children hospitalized with diarrhea in China. The L1 gene of HPV-L55 shares <75% identity with previously reported HPVs, indicating that this virus represents a novel type of HPV. Phylogenetic analysis classified this virus as a member of the gammapapillomaviruses.
doi:10.1128/genomeA.00761-13
PMCID: PMC3790082  PMID: 24092778
16.  Gene-specific alterations of hepatic nuclear receptor regulated gene expression by ligand activation or hepatocyte-selective knockout inhibition of RXRα signaling during inflammation 
Background
Inflammation leads to transcriptional downregulation of many hepatic genes, particulary those activated by RXRα-heterodimers. Inflammation-mediated reduction of nuclear RXRα levels is a main factor in reduced nuclear receptor (NR)–regulated hepatic gene expression, eventually leading to cholestasis and liver damage.
Aim
To investigate roles for RXRα in hepatic gene expression during inflammation, using two complementary mouse models: ligand–activation of RXRα, and in mice expressing hepatocyte-specific expression of RXRα missing its DNA-binding-domain (DBD; hs-RxrαΔex4−/−)
Methods
To activate RXRα, mice were gavage-fed with LG268 or vehicle for 5 days. To inhibit RXRα function, hs-RxrαΔex4−/− were used. All mice were IP-injected with LPS or saline for 16 hrs prior to analysis of hepatic RNA, protein and NR-DNA binding.
Results
LG268-treatment attenuated the LPS-mediated reductions of several RXRα-regulated genes, coinciding with maintained RXRα occupancy in both Bsep and Ostβ promoters. Lacking full hepatocyte-RXRα function (hs-RxrαΔex4−/− mice) led to enhancement of LPS-mediated changes in gene expression, but surprisingly, maintenance of RNA levels of some RXRα-regulated genes. Investigations revealed that Hs-Rxrα−/− hepatocytes expressed an internally-truncated, ~44 kDa, RXRα-form. DNA-binding capacity of NR-heterodimers was equivalent in wt and hs-RxrαΔex4−/− livers, but reduced by LPS in both. ChIP-QPCR revealed reduced RXRα occupancy to the Bsep RXRα:FXR site was reduced, but not absent, in hs-RxrαΔex4−/− livers.
Conclusions
There are differential regulatory roles for hepatic RXRα, both in basal and inflammatory states, suggesting new and complex multi-domain roles for RXRα in regulating hepatic gene expression. Moreover, there is an unexpected non-obligate role for the DBD of RXRα.
doi:10.1111/j.1478-3231.2011.02664.x
PMCID: PMC3788689  PMID: 22098603
liver; inflammation; nuclear receptor; RXRa; mouse; LG268; rexinoid; gene expression; DNA-binding
17.  Practice guidelines for ultrasound-guided percutaneous microwave ablation for hepatic malignancy 
Primary liver cancer and liver metastases are among the most frequent malignancies worldwide, with an increasing number of new cases and deaths every year. Traditional surgery is only suitable for a limited proportion of patients and imaging-guided percutaneous thermal ablation has achieved optimistic results for management of hepatic malignancy. This synopsis outlines the first clinical practice guidelines for ultrasound-guided percutaneous microwave ablation therapy for hepatic malignancy, which was created by a joint task force of the Society of Chinese Interventional Ultrasound. The guidelines aim at standardizing the microwave ablation procedure and therapeutic efficacy assessment, as well as proposing the criteria for the treatment candidates.
doi:10.3748/wjg.v19.i33.5430
PMCID: PMC3761095  PMID: 24023485
Practice guidelines; Microwave radiation; Catheter ablation; Liver cancer; Ultrasound
18.  Electrical Impedance Spectroscopy as Electrical Biopsy for Monitoring Radiation Sequelae of Intestine in Rats 
BioMed Research International  2013;2013:974614.
Electrical impedance is one of the most frequently used parameters for characterizing material properties. The resistive and capacitive characteristics of tissue may be revealed by electrical impedance spectroscopy (EIS) as electrical biopsy. This technique could be used to monitor the sequelae after irradiation. In this study, rat intestinal tissues after irradiation were assessed by EIS system based on commercially available integrated circuits. The EIS results were fitted to a resistor-capacitor circuit model to determine the electrical properties of the tissue. The variations in the electrical characteristics of the tissue were compared to radiation injury score (RIS) by morphological and histological findings. The electrical properties, based on receiver operation curve (ROC) analysis, strongly reflected the histological changes with excellent diagnosis performance. The results of this study suggest that electrical biopsy reflects histological changes after irradiation. This approach may significantly augment the evaluation of tissue after irradiation. It could provide rapid results for decision making in monitoring radiation sequelae prospectively.
doi:10.1155/2013/974614
PMCID: PMC3777171  PMID: 24093111
19.  Proteomic identification of neurotrophins in the eutopic endometrium of women with endometriosis 
Fertility and sterility  2012;98(3):713-719.
Objective
To evaluate neurotrophin (NT) expression in the endometrium of women with and without endometriosis
Design
Prospective, cross-sectional, translational study
Setting
Academic hospital
Patient(s)
Thirty-three reproductive age women undergoing laparoscopy for infertility, pelvic pain, intramural fibroids, or tubal ligation
Intervention(s)
Endometrial biopsies, protein microarrays, RT-PCR, ELISAs and Western blotting
Main Outcome Measures
Neurotrophin proteins and mRNAs in eutopic endometrial biopsies
Results
Among seven neurotrophic proteins detected on the antibody microarrays, RT-PCR analysis confirmed nerve growth factor (NGF), NT-4/5, and brain-derived neurotrophic factor (BDNF) mRNAs in endometrial tissue. Quantitative ELISAs revealed that NT-4/5 (806 ± 701 vs. 256 ± 190 pg/100 mg protein, P=0.04) and BDNF (121 ± 97 vs. 14 ± 11 ng/100 mg protein, P<0.01) concentrations were significantly higher in women with endometriosis. NGF (100 ± 74 vs. 93 ± 83 pg/100 mg protein) levels did not differ between cases and controls (P=0.83).
Conclusions
Neurotrophins are synthesized in situ within the endometrium. NT-4/5 and BDNF proteins were more concentrated in biopsies from endometriosis cases than controls, whereas NGF levels were similar. We hypothesize that the local production of NTs induces sensory innervation of endometrium of women with endometriosis. These NTs represent novel targets for the diagnosis and treatment of endometriosis.
doi:10.1016/j.fertnstert.2012.05.027
PMCID: PMC3432681  PMID: 22717347
nerves; endometriosis; proteomics; endometrium; pro-neurotrophins
20.  Molecular and cellular effects of NEDD8 activating enzyme (NAE) inhibition in myeloma 
Molecular cancer therapeutics  2012;11(4):942-951.
The NEDD8 activating enzyme (NAE) is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases (CRLs), which regulate degradation of a distinct subset of proteins. The more targeted impact of NAE on protein degradation prompted us to study MLN4924, an investigational NAE inhibitor, in preclinical multiple myeloma (MM) models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability (EC50=25–150nM) in a panel of human MM cell lines. MLN4924 was similarly active against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive parental cells. MLN4924 had sub-μM activity (EC50 values <500nM) against primary CD138+ MM patient cells and exhibited at least additive effect when combined with dexamethasone, doxorubicin and bortezomib against MM.1S cells. The bortezomib-induced compensatory up-regulation of transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment, suggesting distinct functional roles of NAE vs 20S proteasome. MLN4924 was well tolerated at doses up to 60mg/kg 2x daily and significantly reduced tumor burden in both a subcutaneous and an orthotopic mouse model of MM. These studies provide the framework for the clinical investigation of MLN4924 in MM.
doi:10.1158/1535-7163.MCT-11-0563
PMCID: PMC3755358  PMID: 22246439
myeloma; cancer; NEDD8; NAE; microenvironment
21.  Chaihu-Shugan-San Administration Ameliorates Perimenopausal Anxiety and Depression in Rats 
PLoS ONE  2013;8(8):e72428.
Chaihu-Shugan-San (CSS) is a traditional Chinese herbal formula that is widely used for treating perimenopausal symptoms in China; however, its mechanisms remain unknown. The present study was designed to investigate potential CSS mechanisms in rats with unpredicted chronic mild stress (UCMS) and normally aging rats (52 weeks of age). We performed the sucrose consumption test along with the forced swimming test to confirm depression-like behavior and the open field test (OFT) to confirm anxiety-like behavior in the animals. In addition, we used an enzyme-linked immunosorbent assay to measure serum and hippocampal estradiol (E2) levels and a quantitative real-time polymerase chain reaction to assess hippocampal mRNA levels of estrogen receptors (ERs) α and β as well as G protein-coupled receptor 30 (GPR30). We found that CSS administration resulted in a significant increase in the ratio of hippocampal ERα and ERβ mRNA (ERα/ERβ ratio) in UCMS rats (p<0.001). However, no significant changes were observed in E2 levels, ERα mRNA expression, and GPR30 mRNA expression. In contrast, changes in ERα/ERβ mRNA ratio were sensitively associated with changes in mood states in the animal models. These findings suggest that enhancement of ERα/ERβ ratio may play a role in the pharmacological mechanisms of CSS. Furthermore, this ratio can be employed as a potential index for evaluating mood states in animal models and can be considered as a therapeutic target for perimenopausal anxiety and depression in the future.
doi:10.1371/journal.pone.0072428
PMCID: PMC3754981  PMID: 24015243
22.  Identification of a Novel Picornavirus in Healthy Piglets and Seroepidemiological Evidence of Its Presence in Humans 
PLoS ONE  2013;8(8):e70137.
In this study, we describe a novel porcine parechovirus-like virus (tentatively named PLV-CHN) from healthy piglets in China using 454 high-throughput sequencing. The complete genome of the virus comprises 6832 bp, encoding a predicted polyprotein of 2132 amino acids that is most similar to Ljungan virus (32% identity). A similar virus that belongs to a novel Picornaviridae genus, named swine pasivirus 1 (SPaV-1), was reported during the preparation of this paper. Sequence analysis revealed that PLV-CHN and SPaV1 shared 82% nucleotide identity and 89% amino acid identity. Further genomic and phylogenetic analyses suggested that both SPaV1 and PLV-CHN shared similar genomic characteristics and belong to the same novel Picornaviridae genus. A total of 36 (20.0%) fecal samples from 180 healthy piglets were positive for PLV-CHN by RT-PCR, while no fecal samples from 100 healthy children and 100 children with diarrhea, and no cerebrospinal fluid samples from 196 children with suspected viral encephalitis, was positive for the virus. However, Western blot and enzyme-linked immunosorbent assays using recombinant PLV-CHN VP1 polypeptide as an antigen showed a high seroprevalence of 63.5% in the healthy population. When grouped by age, the antibody-positivity rates showed that the majority of children under 12 years of age have been infected by the virus. It was suggested that PLV-CHN, SPaV1, or an as-yet-uncharacterized virus can infect humans early in life. Thus, investigation of the role of this novel virus is vital.
doi:10.1371/journal.pone.0070137
PMCID: PMC3735577  PMID: 23936384
23.  Prospective registration, bias risk and outcome-reporting bias in randomised clinical trials of traditional Chinese medicine: an empirical methodological study 
BMJ Open  2013;3(7):e002968.
Background
Clinical trials on Traditional Chinese Medicine (TCM) should be registered in a publicly accessible international trial register and report on all outcomes. We systematically assessed and evaluated TCM trials in registries with their subsequent publications.
Objective
To describe the characteristics of TCM trials, estimate bias risk and outcome-reporting bias in clinical trials.
Data sources and study selection
Fifteen trial registries were searched from their inception to July 2012 to identify randomised trials on TCM including Chinese herbs, acupuncture and/or moxibustion, cupping, tuina, qigong, etc.
Data extraction
We extracted data including TCM specialty and treated disease/conditions from the registries and searched for subsequent publications in PubMed and Chinese databases. We compared information in the registries of completed trials with any publications focusing on study design, sample size, randomisation, bias risk including reporting bias from the register protocol.
Results
1096 registered randomised trials were identified evaluating TCM, of which 505 were completed studies (46.1%). The most frequent conditions were pain (13.3%), musculoskeletal (11.7%), nervous (8.7%), digestive (7.1%), circulatory (6.5%), respiratory (6.3%), mental and behavioural disorders (6.2%) and cancer (6.0%). The trial register data identified parallel, phase II/III randomised trials with sample size estimations and blinding, but limited information about randomisation (sequence generation and allocation concealment). Comparing trial registration data of 115 completed trials (22.8%) with their subsequent 136 publications, inconsistencies were identified in one or more of the following: sample size (11%), outcome assessor blinding (37.5%), primary outcomes (29%) and safety (28%) reporting.
Conclusions
Increasing numbers of clinical trials investigating a variety of TCM interventions have been registered in international trial registries. The study design of registered TCM trials has improved in estimating sample size, use of blinding and placebos. However, selective outcome reporting is widespread and similar to conventional medicine and therefore study conclusions should be interpreted with caution.
doi:10.1136/bmjopen-2013-002968
PMCID: PMC3717464  PMID: 23864210
24.  Correction: Transcriptome Analysis Reveals Markers of Aberrantly Activated Innate Immunity in Vitiligo Lesional and Non-Lesional Skin 
PLoS ONE  2013;8(7):10.1371/annotation/fbf9e317-e3ab-4f9a-b317-3de6abff890f.
doi:10.1371/annotation/fbf9e317-e3ab-4f9a-b317-3de6abff890f
PMCID: PMC3735665
25.  Lipomatous metaplasia identified in rabbits with reperfused myocardial infarction by 3.0 T magnetic resonance imaging and histopathology 
BMC Medical Imaging  2013;13:18.
Background
Cardiac lipomatous metaplasia (LM) occurs in patients with chronic ischemic heart disease and heart failure with unclear mechanisms. We studied coronary occlusion/reperfusion-induced myocardial infarction (MI) in rabbits during a 9-months follow-up using 3.0 T magnetic resonance scanner, and confirmed the presence of MI in acute phase and LM in chronic phase using histopathology.
Methods
MI was surgically induced in 10 rabbits by 90-min coronary artery occlusion and reperfusion. Forty-eight hours later, multiparametric cardiac magnetic resonance imaging (cMRI) was performed at a 3.0 T clinical scanner for MI diagnosis and cardiac function analysis. Afterwards, seven rabbits were scarified for histochemical staining with triphenyltetrazolium chloride (TTC), and hematoxylin-eosin (HE), and 3 were scanned with cMRI at 2 days, 2 weeks, 2 months and 9 months for longitudinal observations of morphological and functional changes, and the fate of the animals. Post-mortem TTC, HE and Masson's trichrome (MTC) were studied for chronic stage of MI.
Results
The size of acute MI correlated well between cMRI and TTC staining (r2=0.83). Global cardiac morphology-function analysis showed significant correlation between increasing acute MI size and decreasing ejection fraction (p<0.001). During 9 months, cMRI documented evolving morphological and functional changes from acute MI to chronic scar transformation and fat deposition with a definite diagnosis of LM established by histopathology.
Conclusions
Acute MI and chronic LM were induced in rabbits and monitored with 3.0 T MRI. Studies on this platform may help investigate the mechanisms and therapeutic interventions for LM.
doi:10.1186/1471-2342-13-18
PMCID: PMC3707856  PMID: 23815556
Acute myocardial infarction; Animal model; Chronic ischemia; Cardiovascular magnetic resonance imaging; Lipomatous metaplasia

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