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1.  Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion? 
Purpose
To evaluate the relationship between liver tumor motion and diaphragm motion.
Methods and Materials
Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff). The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions.
Results
Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small.
Conclusions
This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.
doi:10.1016/j.ijrobp.2014.07.028
PMCID: PMC4334361  PMID: 25223297
2.  Levels of Cotinine in Dried Blood Specimens from Newborns as a Biomarker of Maternal Smoking Close to the Time of Delivery 
American Journal of Epidemiology  2013;178(11):1648-1654.
The precise quantitation of smoking during pregnancy is difficult in retrospective studies. Routinely collected blood specimens from newborns, stored as dried blood spots, may provide a low-cost method to objectively measure maternal smoking close to the time of delivery. This article compares cotinine levels in dried blood spots to those in umbilical cord blood to assess cotinine in dried blood spots as a biomarker of maternal smoking close to the time of delivery. The California Genetic Disease Screening Program provided dried blood spots from 428 newborns delivered in 2001–2003 with known umbilical cord blood cotinine levels. Cotinine in dried blood spots was measured in 6.35­-mm punches by using liquid chromatography­–tandem mass spectrometry (quantitation limit, 3.1 ng/mL). Repeated measures of cotinine in dried blood spots were highly correlated (R2 = 0.99, P < 0.001) among 100 dried blood spots with cotinine quantitated in 2 separate punches. Linear regression revealed that cotinine levels in dried blood spots were slightly lower than those in umbilical cord blood and predicted umbilical cord blood cotinine levels well (β = 0.95, R2 = 0.80, and P < 0.001 for both cotinine levels in log10 scale). When defining active smoking as a cotinine level of 10 ng/mL or more and using umbilical cord blood cotinine as the criterion standard, we found that measurements of cotinine in dried blood spots had high sensitivity (92.3%) and specificity (99.7%) in the prediction of maternal active smoking. Cotinine levels in dried blood spots are an accurate biomarker of maternal smoking close to the time of delivery.
doi:10.1093/aje/kwt182
PMCID: PMC3842901  PMID: 24068198
cotinine; dried blood spot; maternal smoking; newborn; pregnancy
3.  Suppression of histone deacetylation promotes the differentiation of human pluripotent stem cells towards neural progenitor cells 
BMC Biology  2014;12(1):95.
Background
Emerging studies of human pluripotent stem cells (hPSCs) raise new prospects for neurodegenerative disease modeling and cell replacement therapies. Therefore, understanding the mechanisms underlying the commitment of neural progenitor cells (NPCs) is important for the application of hPSCs in neurodegenerative disease therapies. It has been reported that epigenetic modifications of histones play important roles in neural differentiation, but the exact mechanisms in regulating hPSC differentiation towards NPCs are not fully elucidated.
Results
We demonstrated that suppression of histone deacetylases (HDACs) promoted the differentiation of hPSCs towards NPCs. Application of HDAC inhibitors (HDACi) increased the expression of neuroectodermal markers and enhanced the neuroectodermal specification once neural differentiation was initiated, thereby leading to more NPC generation. Similarly, the transcriptome analysis showed that HDACi increased the expression levels of ectodermal markers and triggered the NPC differentiation related pathways, while decreasing the expression levels of endodermal and mesodermal markers. Furthermore, we documented that HDAC3 but not HDAC1 or HDAC2 was the critical regulator participating in NPC differentiation, and knockdown of HDAC3′s cofactor SMRT exhibited a similar effect as HDAC3 on NPC generation.
Conclusions
Our study reveals that HDACs, especially HDAC3, negatively regulate the differentiation of hPSCs towards NPCs at an earlier stage of neural differentiation. Moreover, HDAC3 might function by forming a repressor complex with its cofactor SMRT during this process. Thus, our findings uncover an important epigenetic mechanism of HDAC3 in the differentiation of hPSCs towards NPCs.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-014-0095-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-014-0095-z
PMCID: PMC4254204  PMID: 25406762
Histone deacetylation; Histone deacetylase inhibitors; Neuroectodermal specification; Neural progenitor cells; Human pluripotent stem cells
4.  Identification of Potential Serum Proteomic Biomarkers for Clear Cell Renal Cell Carcinoma 
PLoS ONE  2014;9(11):e111364.
Objective
To investigate discriminating protein patterns and serum biomarkers between clear cell renal cell carcinoma (ccRCC) patients and healthy controls, as well as between paired pre- and post-operative ccRCC patients.
Methods
We used magnetic bead-based separation followed by matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) to identify patients with ccRCC. A total of 162 serum samples were analyzed in this study, among which there were 58 serum samples from ccRCC patients, 40 from additional paired pre- and post-operative ccRCC patients (n = 20), and 64 from healthy volunteers as healthy controls. ClinProTools software identified several distinct markers between ccRCC patients and healthy controls, as well as between pre- and post-operative patients.
Results
Patients with ccRCC could be identified with a mean sensitivity of 88.38% and a mean specificity of 91.67%. Of 67 m/z peaks that differed among the ccRCC, healthy controls, pre- and post-operative ccRCC patients, 24 were significantly different (P<0.05). Three candidate peaks, which were upregulated in ccRCC group and showed a tendency to return to healthy control values after surgery, were identified as peptide regions of RNA-binding protein 6 (RBP6), tubulin beta chain (TUBB), and zinc finger protein 3 (ZFP3) with the m/z values of 1466.98, 1618.22, and 5905.23, respectively.
Conclusion
MB-MALDI-TOF-MS method could generate serum peptidome profiles of ccRCC, and provide a new approach to identify potential biomarkers for diagnosis as well as prognosis of this malignancy.
doi:10.1371/journal.pone.0111364
PMCID: PMC4219714  PMID: 25368985
5.  Poultry Market Closures and Human Infection with Influenza A(H7N9) Virus, China, 2013–14 
Emerging Infectious Diseases  2014;20(11):1891-1894.
Closure of live poultry markets was implemented in areas affected by the influenza virus A(H7N9) outbreak in China during winter, 2013–14. Our analysis showed that closing live poultry markets in the most affected cities of Guangdong and Zhejiang provinces was highly effective in reducing the risk for H7N9 infection in humans.
doi:10.3201/eid2011.140556
PMCID: PMC4214308  PMID: 25340354
Avian influenza A(H7N9); viruses; live poultry markets; public health; China
6.  Bcl-xL overexpression and its association with the progress of tongue carcinoma 
Apoptosis-related protein B-cell lymphoma-extra large (Bcl-xL) has a crucial role in the control of cell death through its inhibition of apoptosis. This study was designed to investigate the expression of Bcl-xL in relation to the development of tongue carcinoma and whether it has potential as a marker for the clinical diagnosis of tongue carcinoma and as a therapeutic target to evaluate the dynamic of tongue carcinoma progression. A statistical analysis of 100 cases oral tongue carcinoma tissue specimens were performed using pathological grading and clinical TNM staging, and 14 cases corresponding non-tumor tissues as control. The changes in Bcl-xL mRNA expression between different pathological grades and clinical TNM stages of tissue were analyzed by RT-PCR. Additionally, immunohistochemical SP method and Western blot assays were employed to detect changes in Bcl-xL protein expression in different tongue carcinoma tissues. The results showed the expression of Bcl-xL was significantly higher in tongue carcinoma tissues than in normal tongue tissues and was positively associated with the degree of differentiation and the clinical TNM staging, but negatively correlated with the degree of malignancy of the tumor. There was higher expression of Bcl-xL in oral tongue squamous cell carcinoma (OTSCC) tissues compared with oral tongue adenocarcinoma (OTA) tissues, but Bcl-xL expression in tissue with lymph node metastasis was significantly higher than that without lymph node metastasis. Thus, Bcl-xL overexpression may be closely related to the dynamic of the pathogenesis and development of tongue carcinoma. It may be a useful marker for clinical diagnosis and an aid to evaluating the efficacy of therapeutics in tongue carcinoma.
PMCID: PMC4270534  PMID: 25550772
Tongue carcinoma tissues; Bcl-xL; immunohistochemistry; real-time polymerase chain reaction; Western blot
7.  Serum peptidome based biomarkers searching for monitoring minimal residual disease in adult acute lymphocytic leukemia 
Proteome Science  2014;12(1):49.
Background
The persistence of minimal residual disease (MRD) during therapy is the strongest adverse prognostic factor in acute lymphocytic leukemia (ALL). This study was to identify serum candidate peptides for monitoring MRD in adult ALL.
Results
A total of 33 peptides in the molecular weight range of 1000-10000 Da were detected using ClinProt system and statistically different between adult patients with ALL and healthy controls. Quick classifier (QC) algorithm was used to obtain a diagnostic model consisting of five peptides that could discriminate patients with ALL from controls with a high sensitivity (100%) and specificity (96.67%). The peptides in the QC model were identified as fibrinogen alpha chain (FGA), glutathione S-transferase P1 (GSTP1), isoform 1 of fibrinogen alpha chain precursor, platelet factor 4 (PF4) by high pressure/performance liquid chromatography mass spectrometry/mass spectrometry. Relative intensities of the five peptides were compared among ALL different groups for the potential importance of MRD evaluation in ALL. The peptides with increased relative intensities in newly diagnosed (ND) ALL patients were found to be decreased in their relative intensities after complete remission (CR) of adult ALL. When ALL patients were refractory & relapsed (RR), relative intensities of the peptides were elevated again. Peptides with decreased relative intensities in ND and RR ALL patients were found to be increased in their relative intensities when ALL patients achieved CR. The findings were validated by ELISA and western blot. Further linear regression analyses were performed to eliminate the influence of platelet and white blood cell counts on serum protein contents and indicated that there were no correlations between the contents of all four proteins (PF4, connective tissue active peptide III, FGA and GSTP1) and white blood cell or platelet counts in ALL different groups and healthy control.
Conclusions
We speculate the five peptides, FGA, isoform 1 of fibrinogen alpha chain precursor, GSTP1, PF4 and connective tissue active peptide III would be potential biomarkers for forecasting relapse, monitoring MRD and evaluating therapeutic response in adult ALL.
Electronic supplementary material
The online version of this article (doi:10.1186/s12953-014-0049-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12953-014-0049-y
PMCID: PMC4195909  PMID: 25317080
Serum peptidome; Biomarker; Adult acute lymphocytic leukemia; Minimal residual disease
8.  Knowledge of Thrombolytic Therapy for Acute Ischemic Stroke among Community Residents in Western Urban China 
PLoS ONE  2014;9(9):e107892.
Background and Purpose
Thrombolytic therapy rate for acute ischemic stroke remains low, and improving public awareness of thrombolytic therapy may be helpful to reduce delay and increase chances of thrombolytic therapy. Our purpose was to survey the level of knowledge about thrombolytic therapy for acute ischemic stroke among community residents in Yuzhong district, Chongqing, China.
Methods
In 2011, a population-based face-to-face interview survey was conducted in Yuzhong district, Chongqing. A total of 1500 potential participants aged ≥18 years old were selected using a multi-stage sampling method.
Results
A total of 1101 participants completed the survey. Only 23.3% (95% CI = 20.8 to 25.8) were aware of thrombolytic therapy for acute ischemic stroke, of whom 59.9% (95% CI = 53.9 to 65.9) knew the time window. Awareness of thrombolytic therapy was higher among young people, those with higher levels of education and household income, those with health insurance, and those who knew all 5 stroke warning signs, while awareness of the time window was higher among those aged 75 years or older. Multivariate logistic regression analysis showed that awareness of thrombolytic therapy was independently associated with age, education level, health insurance and knowledge of stroke warning signs (P<0.05).
Conclusions
In this population-based survey the community residents have poor awareness of thrombolytic therapy for acute ischemic stroke.
doi:10.1371/journal.pone.0107892
PMCID: PMC4164641  PMID: 25222126
9.  Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: A preliminary study 
Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.
doi:10.3892/ijmm.2014.1905
PMCID: PMC4199412  PMID: 25174394
portal hypertension; sodium ferulate; cirrhosis; bile duct ligation; RhoA; Rho-kinase; methoxamine; endothelial nitric oxide synthase; fibrosis
10.  Atoh1 expression levels define the fate of rat cochlear nonsensory epithelial cells in vitro 
Molecular Medicine Reports  2014;10(1):15-20.
Atonal homolog 1 (Atoh1) is a basic helix-loop-helix transcription factor that is essential for inner ear hair cell differentiation. Previous studies have reported that Atoh1 gene transfer induces the production of ectopic hair cell-like cells (EHCLCs). In the present study, the effect of different Atoh1 expression levels and the duration of EHCLC formation on the lesser epithelial ridge (LER) of cochleae was examined using a human adenovirus serotype 5 (Ad5) vector encoding atoh1 and the reporter gene EGFP. Different Ad5-EGFP-atoh1/Ad5-EGFP virus titers were added to cultured cochlear explants and EHCLCs were detected in the LER at various time points. The results demonstrated that GFP alone did not induce EHCLCs. By contrast, Atoh1 expression induced EHCLCs as early as 2.5–5 days following EGFP-atoh1 infection in the LER and depending upon the viral titer, the number of EHCLCs increased with time. Higher Ad5-EGFP-atoh1 titers induced enhanced Atoh1 expression, resulting in an increase in EHCLCs. Lower Ad5-EGFP-atoh1 titers required more time for EHCLC formation and very low titers of Ad5-EGFP-atoh1 induced only weak Atoh1 expression and did not trigger EHCLC formation. In conclusion, the present study utilized an appropriate Ad5-EGFP-atoh1 titer range to induce Atoh1 expression and the subsequent production of EHCLCs. The results revealed that the Atoh1 expression level defined the fate of LER cells as either EHCLCs or nonsensory epithelial cells. This evidence may provide an important guideline for future studies into gene therapy strategies for the treatment of deafness.
doi:10.3892/mmr.2014.2202
PMCID: PMC4068718  PMID: 24788407
Atoh1 expression level; ectopic hair cell-like cells; lesser epithelial ridge; virus titer
11.  Comparison of Patients Hospitalized With Influenza A Subtypes H7N9, H5N1, and 2009 Pandemic H1N1 
Hospitalization with H7N9 virus infection is associated with older age and chronic heart disease, and patients have a longer duration of hospitalization than patients with H5N1 or pH1N1. This suggests that host factors are an important contributor to H7N9 severity.
Background. Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections.
Methods. We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population.
Results. The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24–17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154).
Conclusions. The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.
doi:10.1093/cid/ciu053
PMCID: PMC3967826  PMID: 24488975
influenza A(H7N9); influenza A(H5N1); clinical epidemiology
12.  Self-Esteem Modulates the Time Course of Self-Positivity Bias in Explicit Self-Evaluation 
PLoS ONE  2013;8(12):e81169.
Researchers have suggested that certain individuals may show a self-positivity bias, rating themselves as possessing more positive personality traits than others. Previous evidence has shown that people evaluate self-related information in such a way as to maintain or enhance self-esteem. However, whether self-esteem would modulate the time course of self-positivity bias in explicit self-evaluation has never been explored. In the present study, 21 participants completed the Rosenberg self-esteem scale and then completed a task where they were instructed to indicate to what extent positive/negative traits described themselves. Behavioral data showed that participants endorsed positive traits as higher in self-relevance compared to the negative traits. Further, participants’ self-esteem levels were positively correlated with their self-positivity bias. Electrophysiological data revealed smaller N1 amplitude and larger late positive component (LPC) amplitude to stimuli consistent with the self-positivity bias (positive-high self-relevant stimuli) when compared to stimuli that were inconsistent with the self-positivity bias (positive-low self-relevant stimuli). Moreover, only in individuals with low self-esteem, the latency of P2 was more pronounced in processing stimuli that were consistent with the self-positivity bias (negative-low self-relevant stimuli) than to stimuli that were inconsistent with the self-positivity bias (positive-low self-relevant stimuli). Overall, the present study provides additional support for the view that low self-esteem as a personality variable would affect the early attentional processing.
doi:10.1371/journal.pone.0081169
PMCID: PMC3855207  PMID: 24339908
13.  New species and records of the stonefly genus Neoperla (Plecoptera, Perlidae) from Jinhuacha Nature Reserve, Guangxi of China 
ZooKeys  2013;37-48.
Two new Neoperla species (Neoperla mesospina, Neoperla latispina) are described from the adult male stage from the Jinhuacha Nature Reserve, Guangxi of China. The new species are compared with similar taxa. Taxonomic remarks are also provided for N. transversprojecta Du & Sivec and N. yao Stark. The latter species is newly recorded for Guangxi.
doi:10.3897/zookeys.351.6259
PMCID: PMC3837494  PMID: 24294087
Plecoptera; Perlidae; Neoperla mesospina; Neoperla latispina; new species; China
14.  Demethylation of Cancer/Testis Antigens and CpG ODN Stimulation Enhance Dendritic Cell and Cytotoxic T Lymphocyte Function in a Mouse Mammary Model 
BioMed Research International  2013;2013:196894.
Background. Cancer/testis antigens (CTAs) are ideal targets for cancer immunotherapy in virtue of their restricted expression profile in normal tissues. However, CTA-targeted immunotherapy has been rather disappointing clinical setting for CTAs are downregulated by cytosine-phosphate-guanosine (CpG) methylation in their promoter regions, so that tumor cells have low immunogenicity. Methods. We reinduced mouse CTA P1A through demethylation process and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/c (H-2d) mice with dendritic cells pulsed with a P1A-specific peptide and CpG oligodeoxynucleotide (ODN) immune adjuvant. Results. We found that demethylation and CpG ODN immune adjuvant stimulation facilitated DC maturation and enhanced the allogenic capacity of P1A-specific CTLs against target cells both in vitro and in vivo. Conclusions. Our results suggested that CTA induction and immune adjuvant stimulation is a feasible strategy in cancer immunotherapy.
doi:10.1155/2013/196894
PMCID: PMC3835908  PMID: 24294600
15.  Administration of dexamethasone protects mice against ischemia/reperfusion induced renal injury by suppressing PI3K/AKT signaling 
Dexamethasone (DEX), a ligand for glucocorticoid receptor (GR), has long been used in the clinical practice due to its anti-inflammatory and immunosuppressive properties. Given that ischemia/reperfusion (IR)-induced renal injury is featured by the excessive immune response; the current study is therefore designed to address the impact of dexamethasone on IR-induced renal injury, a common disorder in the clinical settings. Precondition of mice with 4 mg/kg of dexamethasone significantly attenuated IR-induced injury as manifested by the improved renal function along with ameliorated pathological changes and suppressed inflammatory infiltration. Mechanistic studies revealed that dexamethasone promotes GR activation, and by which it attenuates the signals for PI3K/AKT activation. Attenuated PI3K/AKT signaling thus suppresses inflammatory response which then protects kidneys from IR-induced injury. All together, our data support that dexamethasone could be a good alternative therapy for prevention and treatment of IR-induced renal injury in the clinical practice.
PMCID: PMC3816805  PMID: 24228098
Inflammatory response; dexamethasone; ischemia/reperfusion injury; glucocorticoid receptor; PI3K/AKT signaling
16.  Fenofibrate Attenuated Glucose-Induced Mesangial Cells Proliferation and Extracellular Matrix Synthesis via PI3K/AKT and ERK1/2 
PLoS ONE  2013;8(10):e76836.
Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot. The results showed that treatment of mesangial cells (MCs) with fenofibrate repressed high-glucose induced up-regulation of extracellular matrix Collagen-IV, and inhibited entry of cell cycle into the S phase. This G1 arrest and ECM inhibition was caused by the reduction of phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. On the contrary, PPARα siRNA accelerated high glucose-induced cell cycle progression by ERK1/2 and AKT activation. Taken together, fenofibrate ameliorated glucose-induced mesangial cell proliferation and matrix production via its inhibition of PI3K/AKT and ERK1/2 signaling pathways. Such mechanisms may contribute to the favorable effects of treatment using fenofibrate in diabetic nephropathy.
doi:10.1371/journal.pone.0076836
PMCID: PMC3793917  PMID: 24130796
17.  Prevalence of stress hyperglycemia among hepatopancreatobiliary postoperative patients 
Objective: The aim of this study was to determine the prevalence of stress hyperglycemia and its association with mortality among hepatopancreatobiliary postoperative patients admitted. Methods: Retrospectively analysis was made on 706 cases of the hepatopancreatobiliary postoperative patients from three Grade A hospitals in Hunan province from November 2011 to June 2012, including the incidence and risk factors of patients with stress hyperglycemia. Results: The incidence of stress hyperglycemia of pancreatic postoperative patients was 34.28%. The incidence of pancreatic surgery, simple cholecystectomy and biliary tract and liver surgery in patients with stress hyperglycemia was 63.08%, 20.83% and 32.21%, respectively. Stress hyperglycemia was associated with the first postoperative glucose values, duration of surgery, whether the anemia and the presence or absence of hypoproteinemia (P<0.05), but was no related with sex, weight and previous history (P>0.05). Conclusion: Stress hyperglycemia is common among emergency admissions and these patients have significantly higher mortality rate compared to other patients (P=0.001). Postoperative first blood glucose levels, duration of surgery, whether the anemia and the presence or absence of hypoproteinemia were stress hyperglycemia risk factors for patients.
PMCID: PMC3798216  PMID: 24179574
Hepatopancreatobiliary postoperative patients; postoperative; stress hyperglycemia; prevalence
18.  A Survey of the Perceived Risk for Stroke among Community Residents in Western Urban China 
PLoS ONE  2013;8(9):e73578.
Background and Purpose
Persons who perceive their risk for stroke can promote the intervention of stroke risk factors and reduce the risk of stroke occurrence. Our purpose was to assess the knowledge of stroke risk factors and the level of perceived risk for stroke.
Methods
In 2011, a population-based face-to-face interview survey was conducted in Yuzhong district, Chongqing. A total of 1500 potential participants aged ≥18 years old were selected using a multi-stage sampling method. The knowledge of stroke risk factors and perceived risk for stroke was surveyed.
Results
A total of 941 participants completed the questionnaire survey. The respondents’ awareness rate of stroke risk factors ranged between 53.3% and 87.2%. The community residents’ perceived risk for stroke was only 17.7%. Multiple logistic regression analysis showed that 45–64 years age group, a history of hypertension, hyperlipidemia, heart disease, and stroke were independent predictors of perceived risk for stroke. Perceived risk for stroke increased as the number of risk factors increased (P<0.001). However, even for respondents with three or more risk factors, only 41% perceived themselves to be at risk for stroke.
Conclusions
In this population-based survey, few community residents perceived risk for stroke, even among those with multiple stroke risk factors, most did not perceive themselves to be at risk for stroke. Persons with 45–64 years old, a history of hypertension, hyperlipidemia, heart disease or stroke were more likely to perceive risk for stroke. The awareness of the risk for stroke has yet to be enhanced among community residents.
doi:10.1371/journal.pone.0073578
PMCID: PMC3770616  PMID: 24039989
19.  Timed high-fat diet in the evening affects the hepatic circadian clock and PPARα-mediated lipogenic gene expressions in mice 
Genes & Nutrition  2013;8(5):457-463.
A long-term high-fat diet may result in a fatty liver. However, whether or not high-fat diets affect the hepatic circadian clock is controversial. The objective of this study is to investigate the effects of timed high-fat diet on the hepatic circadian clock and clock-controlled peroxisome proliferator-activated receptor (PPAR) α-mediated lipogenic gene expressions. Mice were orally administered high-fat milk in the evening for 4 weeks. The results showed that some hepatic clock genes, such as Clock, brain-muscle-Arnt-like 1 (Bmal1), Period 2 (Per2), and Cryptochrome 2 (Cry2) exhibited obvious changes in rhythms and/or amplitudes. Alterations in the expression of clock genes, in turn, further altered the circadian rhythm of PPARα expression. Among the PPARα target genes, cholesterol 7α-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl-coenzyme A reductase, low-density lipoprotein receptor, lipoprotein lipase, and diacylglycerol acyltransferase (DGAT) showed marked changes in rhythms and/or amplitudes. In particular, significant changes in the expressions of DGAT and CYP7A1 were observed. The effects of a high-fat diet on the expression of lipogenic genes in the liver were accompanied by increased hepatic cholesterol and triglyceride levels. These results suggest that timed high-fat diets at night could change the hepatic circadian expressions of clock genes Clock, Bmal1, Per2, and Cry2 and subsequently alter the circadian expression of PPARα-mediated lipogenic genes, resulting in hepatic lipid accumulation.
doi:10.1007/s12263-013-0333-y
PMCID: PMC3755129  PMID: 23417480
High-fat diet; Clock genes; Peroxisome proliferator-activated receptor α; Lipid metabolism; Mice
20.  A cyclic fluctuation model for 24-h ambulatory blood pressure monitoring in Chinese patients with mild to moderate hypertension 
Acta Pharmacologica Sinica  2013;34(8):1043-1051.
Aim:
The conventional method for analyzing 24-h ambulatory blood pressure monitoring (24-h ABPM) is insufficient to deal with the large amount of data collected. The aim of this study was to develop a novel cyclic fluctuation model for 24-h ABPM in Chinese patients with mild to moderate hypertension.
Methods:
The data were obtained from 4 independent antihypertensive drug clinical trials in Chinese patients with mild to moderate hypertension. The measurements of 24-h ABPM at the end of the placebo run-in period in study 1 were used to develop the cyclic fluctuation model. After evaluated, the structural model was used to analyze the measurements in the other 3 studies. Models were fitted using NONMEM software.
Results:
The cyclic fluctuation model, which consisted of 2 cosine functions with fixed-effect parameters for rhythm-adjusted 24-h mean blood pressure, amplitude and phase shift, successfully described the blood pressure measurements of study 1. Model robustness was validated by the bootstrap method. The measurements in the other 3 studies were well described by the same structural model. Moreover, the parameters from all the 4 studies were very similar. Visual predictive checks demonstrated that the cyclic fluctuation model could predict the blood pressure fluctuations in the 4 studies.
Conclusion:
The cyclic fluctuation model for 24-h ABPM deepens our understanding of blood pressure variability, which will be beneficial for drug development and individual therapy in hypertensive patients.
doi:10.1038/aps.2013.45
PMCID: PMC4003025  PMID: 23770980
blood pressure; 24-h ambulatory blood pressure monitoring; cyclic fluctuation model; NONMEM; hypertension; Chinese
21.  Potential biomarkers for adult acute myeloid leukemia minimal residual disease assessment searched by serum peptidome profiling 
Proteome Science  2013;11:39.
Background
Post treatment minimal residual disease (MRD) determination contributes to impending relapse prediction, chemotherapy response and clinical outcomes assessment, guiding clinicians to develop reasonable and effective individual chemotherapy options after induction/consolidation. This study was to identify serum candidate peptides for monitoring adult acute myeloid leukemia (AML) MRD.
Results
47 statistically different expressed peptide peaks were obtained in the molecular weight range of 700-10000 Da. Quick classifier (QC) model had optimal distinction efficiency, in the training set with a sensitivity of 90% and a specificity of 93.33%. Peptides were identified as ubiquitin-like modifier activating enzyme 1(UBA1), isoform 1 of fibrinogen alpha chain precursor and platelet factor 4(PF4). The peptide up-regulated in newly diagnosed AML patients were decreased to the normal level after CR. When refractory & relapsed, relative intensity was elevated again. Results were contrary to down-regulated peptide peaks. Western blot demonstrated that levels of the UBA1 protein did not differ between the leukemia and normal cells. Levels of isoform 1 of fibrinogen alpha chain precursor protein and PF4 protein were both decreased in leukemia cells comparing with normal cells. The serum levels of the PF4 in the newly diagnosed AML patients and healthy controls were significantly different. Further correlation analysis did not indicate the correlated relation between platelet counts and PF4 content, the correlation coefficient was 0.097. Kaplan–Meier analyses of overall survival showed that relative intensity of peptides was correlated with patient’s clinical outcome.
Conclusions
We speculate the peptides can be used as potential markers for monitoring minimal residual disease and clinical outcome assessment.
doi:10.1186/1477-5956-11-39
PMCID: PMC3751134  PMID: 23915341
Weak cation exchange magnetic beads; MALDI-TOF-MS; Serum peptidome profiling; Adult acute myeloid leukemia; Minimal residual disease
22.  Age-Specific Incidence of Breast Cancer Subtypes: Understanding the Black–White Crossover 
Background Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black–white crossover). We used newly available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity.
Methods We classified 91908 invasive breast cancers diagnosed in California between January 1, 2006, and December 31, 2009, by subtype based on tumor expression of estrogen receptor (ER) and progesterone receptor (PR)—together referred to as hormone receptor (HR)—and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes were classified as ER or PR positive and HER2 negative (HR+/HER2−), ER or PR positive and HER2 positive (HR+/HER2+), ER and PR negative and HER2 positive (HR−/HER2+), and ER, PR, and HER2 negative (triple-negative). We calculated and compared age-specific incidence rates, incidence rate ratios, and 95% confidence intervals by subtype and race (black, white, Hispanic, and Asian). All P values are two-sided.
Results We did not observe an age-related black–white crossover in incidence for any molecular subtype of breast cancer. Compared with white women, black women had statistically significantly higher rates of triple-negative breast cancer at all ages but statistically significantly lower rates of HR+/HER2− breast cancers after age 35 years (all P < .05). The age-specific incidence of HR+/HER2+ and HR−/HER2+ subtypes did not vary markedly between white and black women.
Conclusions The black–white crossover in breast cancer incidence occurs only when all breast cancer subtypes are combined and relates largely to higher rates of triple-negative breast cancers and lower rates of HR+/HER2− breast cancers in black vs white women.
doi:10.1093/jnci/djs264
PMCID: PMC3640371  PMID: 22773826
23.  Are benefits conferred with greater socioeconomic position undermined by racial discrimination among African American men? 
Journal of men's health  2012;9(2):127-136.
Background
conventional wisdom suggests that increased socioeconomic resources should be related to better health. Considering the body of evidence demonstrating the significant association between racial discrimination and depression, we examined whether exposure to racial discrimination could attenuate the positive effects of increased levels of socioeconomic position (SEP) among African Americans. Specifically, this paper investigated the joint interactive effects of SEP and racial discrimination on the odds of depression among African Americans.
Methods
racial discrimination was measured using two measures, major and everyday discrimination. Study objectives were achieved using data from the National Survey of American Life, which included a nationally representative sample of African Americans (n =3570). Logistic regression models were used to estimate the effects of SEP and racial discrimination on the odds of depression.
Results
reports of racial discrimination were associated with increased risk of depression among American African men who possessed greater levels of education and income. Among African American men, significant, positive interactions were observed between education and experiences of major discrimination, which were associated with greater odds of depression (P = 0.02). Additionally, there were positive interactions between income and both measures of racial discrimination (income x everyday discrimination, P = 0.013; income x major discrimination, P = 0.02), which were associated with increased odds of depression (P = 0.02).
Conclusions
it is possible that experiences of racial discrimination could, in part, diminish the effects of increased SEP among African American men.
doi:10.1016/j.jomh.2012.03.006
PMCID: PMC3371660  PMID: 22707995
African Americans; Racial discrimination; Socioeconomic position; Depression
24.  California Very Preterm Birth Study: design and characteristics of the population- and biospecimen bank-based nested case-control study 
Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the U.S. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from state-wide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants of different types of VPTB with the ultimate aim of reducing infant mortality, morbidity and racial disparities in these health outcomes in the US and elsewhere.
doi:10.1111/j.1365-3016.2011.01252.x
PMCID: PMC3536480  PMID: 22471684
Study design; California Very Preterm Birth Study
25.  Changes in ADF/destrin expression in the development of hair cells following Atoh1-induced ectopic regeneration 
The aim of this study was to investigate the effects of actin depolymerizing factor (ADF)/destrin and position changes of kinetosomes in the development of hair cells following Atoh1-induced ectopic regeneration in the basilar membrane of mice. We observed through immunofluorescence at various time-points the expression of ADF/destrin and the specific kinetosome marker, γ-tubulin, in hair cells following ectopic regeneration induced by adenovirus transfection, overexpression of Atoh1 and in vitro culture. Changes of ADF/destrin distribution and kinetosome position during in vitro culture of new hair cells [Myo7a(+)] following Atoh1-induced ectopic regeneration are consistent with the changes in ADF/destrin expression and the polar migration of kinetosomes in hair cells of the cochlear sensory epithelium in normal development. ADF/destrin is involved in the development of the auditory epithelium and the development and structural rearrangement of ectopically regenerated hair cells in mammals. The kinetosomes of hair cells following Atoh1-induced ectopic regeneration show positional changes in vitro at different time-points.
doi:10.3892/etm.2013.1089
PMCID: PMC3735608  PMID: 23935742
actin depolymerizing factor/destrin; hair cell; kinocilium; planar cell polarity

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