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1.  Polarity in migrating neurons is related to a mechanism analogous to cytokinesis 
Current biology : CB  2013;23(13):1215-1220.
Summary
Migrating neurons are bipolar, with a leading process and a trailing process [1]. The proximal region of the leading process displays a concentration of F-actin that contributes to the advance of the soma and the centrosome [2–7]. Here we show that kinesin-6, a microtubule-based motor protein best known for its role in cytokinesis, also concentrates in this region. Depletion of kinesin-6 results in multipolar neurons that are either stationary or continuously change their direction of movement. In such neurons, F-actin no longer concentrates in a single process. During cytokinesis, kinesin-6 forms a complex with a Rho family GTPase activating protein called MgcRacGAP to signal to the actin cytoskeleton so that cortical movements are concentrated in the cleavage furrow [8–13]. During neuronal migration, MgcRacGap also concentrates in the proximal region of the leading process, and inhibition of its activity results in a phenotype similar to kinesin-6 depletion. We conclude that neuronal migration utilizes a cytoskeletal pathway analogous to cytokinesis, with kinesin-6 signaling through MgcRacGap to the actin cytoskeleton to constrain process number and restrict protrusive activity to a single leading process, thus resulting in a bipolar neuron able to move in a directed fashion.
doi:10.1016/j.cub.2013.05.027
PMCID: PMC3710514  PMID: 23791725
2.  Health-Related Quality of Life With Adjuvant Docetaxel- and Trastuzumab-Based Regimens in Patients with Node-Positive and High-Risk Node-Negative, HER2-Positive Early Breast Cancer: Results from the BCIRG 006 Study 
The Oncologist  2013;18(7):812-818.
In the BCIRG 006 trial, eligible patients were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year. Health-related quality-of-life outcomes for adjuvant docetaxel and trastuzumab-based regimens were favorable and support docetaxel plus carboplatin combined with trastuzumab as a more tolerable treatment option.
Background.
This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone.
Methods.
Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy.
Results.
Compliance rates for the EORTC questionnaires were acceptable at 72%–93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up.
Conclusion.
HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.
doi:10.1634/theoncologist.2013-0091
PMCID: PMC3720634  PMID: 23814044
Breast cancer; BCIRG 006; Docetaxel; Trastuzumab; Chemotherapy; Quality of life; Anthracycline-induced cardiotoxicity; Adjuvant therapy
3.  Expression and Functional Characterization of NOD2 in Decidual Stromal Cells Isolated during the First Trimester of Pregnancy 
PLoS ONE  2014;9(6):e99612.
NOD2, one of the cytosolic proteins that contain a nuclear oligomerization domain (NOD), is a pattern recognition receptor (PRR) involved in innate immune responses to intracellular pathogens. Little is known, however, about the effect of NOD2 expression on the maternal–fetal relationship. Our aim was to elucidate the functions of NOD2 in normal decidual stromal cells (DSCs) from the first trimester. Tissues and DSCs were isolated from 26 patients with normal pregnancies that required abortion. The expression of NOD2 in deciduas/decidual stromal cells (DSCs) was examined by real-time PCR, immunohistochemistry, and In-cell western. DSCs containing NOD2 were stimulated by its ligand, muramyl dipeptide (MDP). The secretion of various cytokines and chemokines were measured by ELISA and the apoptotic rate was determined by flow cytometry. Treatment with MDP significantly elevated the expression of both NOD2 mRNA and protein levels in DSCs. In addition, MDP activation of NOD2 significantly increased IL-1β and MCP-1 cytokine expression in a dose dependent manner but had no effect on IL-12 expression. IL-1β and TNF-α also significantly increased the expression of NOD2 in DSCs, suggesting a positive feedback loop mechanism. Moreover, MDP stimulation augmented DSC apoptosis. In summary, the results suggest that NOD2 expression in DSCs plays an important role in protecting the embryo and preventing infection in the maternal-fetal interface.
doi:10.1371/journal.pone.0099612
PMCID: PMC4059701  PMID: 24932916
4.  Survey and analysis of the current state of residency training in medical-school-affiliated hospitals in China 
BMC Medical Education  2014;14:111.
Background
Since the global standards for postgraduate medical education (PGME) were published in January 2003, they have gained worldwide attention. The current state of residency training programs in medical-school-affiliated hospitals throughout China was assessed in this study.
Methods
Based on the internationally recognized global standards for PGME, residents undergoing residency training at that time and the relevant residency training instructors and management personnel from 15 medical-school-affiliated hospitals throughout China were recruited and surveyed regarding the current state of residency training programs. A total of 938 questionnaire surveys were distributed between June 30, 2006 and July 30, 2006; of 892 surveys collected, 841 were valid.
Results
For six items, the total proportions of “basically meets standards” and “completely meets standards” were <70% for the basic standards. These items were identified in the fields of “training settings and educational resources”, “evaluation of training process”, and “trainees”. In all fields other than “continuous updates”, the average scores of the western regions were significantly lower than those of the eastern regions for both the basic and target standards. Specifically, the average scores for the basic standards on as many as 25 of the 38 items in the nine fields were significantly lower in the western regions. There were significant differences in the basic standards scores on 13 of the 38 items among trainees, instructors, and managers.
Conclusions
The residency training programs have achieved satisfactory outcomes in the hospitals affiliated with various medical schools in China. However, overall, the programs remain inadequate in certain areas. For the governments, organizations, and institutions responsible for PGME, such global standards for PGME are a very useful self-assessment tool and can help identify problems, promote reform, and ultimately standardize PGME.
doi:10.1186/1472-6920-14-111
PMCID: PMC4059472  PMID: 24885865
Residency training; Global standards for postgraduate medical education; Medical-school-affiliated hospitals; China
5.  MicroRNA-mRNA functional pairs for cisplatin resistance in ovarian cancer cells 
Chinese Journal of Cancer  2014;33(6):285-294.
Ovarian cancer is the leading cause of death in women worldwide. Cisplatin is the core of first-line chemotherapy for patients with advanced ovarian cancer. Many patients eventually become resistant to cisplatin, diminishing its therapeutic effect. MicroRNAs (miRNAs) have critical functions in diverse biological processes. Using miRNA profiling and polymerase chain reaction validation, we identified a panel of differentially expressed miRNAs and their potential targets in cisplatin-resistant SKOV3/DDP ovarian cancer cells relative to cisplatin-sensitive SKOV3 parental cells. More specifically, our results revealed significant changes in the expression of 13 of 663 miRNAs analyzed, including 11 that were up-regulated and 2 that were down-regulated in SKOV3/DDP cells with or without cisplatin treatment compared with SKOV3 cells with or without cisplatin treatment. miRNA array and mRNA array data were further analyzed using Ingenuity Pathway Analysis software. Bioinformatics analysis suggests that the genes ANKRD17, SMC1A, SUMO1, GTF2H1, and TP73, which are involved in DNA damage signaling pathways, are potential targets of miRNAs in promoting cisplatin resistance. This study highlights candidate miRNA-mRNA interactions that may contribute to cisplatin resistance in ovarian cancer.
doi:10.5732/cjc.013.10136
PMCID: PMC4059866  PMID: 24589211
Ovarian cancer; cisplatin resistance; miRNA; TP73
6.  Autoantibody Response to Murine Double Minute 2 Protein in Immunodiagnosis of Hepatocellular Carcinoma 
Journal of Immunology Research  2014;2014:906532.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Although new therapeutic strategies have been continuously developed and applied to clinical treatment for HCC, the prognosis is still very poor. Thus, early detection of HCC may enhance effective and curative management. In this study, autoantibody responses to MDM2 protein in HCC patient's serum were evaluated by enzyme-linked immunosorbent assay (ELISA) and part sera were evaluated by Western blotting and indirect immunofluorescence assay. Immunohistochemistry (IHC) over tissue array slides was also performed to analyze protein expression of MDM2 in HCC and control tissues. The prevalence of autoantibodies against MDM2 was significantly higher than that in liver cirrhosis (LC), chronic hepatitis (CH), and normal human sera (NHS). The average titer of autoantibodies against MDM2 in HCC serum was higher compared to that in LC, CH, and NHS. A high titer of autoantibodies against MDM2 in ELISA could be observed in the serum in 6 to 9 months before the clinical diagnosis of HCC in the serum of several HCC patients with serial bleeding samples. Our preliminary data indicate that MDM2 and anti-MDM2 system may be a potential biomarker for early stage HCC screening and immunodiagnosis.
doi:10.1155/2014/906532
PMCID: PMC4053260  PMID: 24955377
7.  Suppression of Akt-mTOR Pathway-A Novel Component of Oncogene Induced DNA Damage Response Barrier in Breast Tumorigenesis 
PLoS ONE  2014;9(5):e97076.
DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized ‘normal-like’ breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.
doi:10.1371/journal.pone.0097076
PMCID: PMC4014598  PMID: 24811059
8.  Comparative analysis of pharmacovigilance methods in the detection of adverse drug reactions using electronic medical records  
Objective
Medication  safety requires that each drug be monitored throughout its market life as early detection of adverse drug reactions (ADRs) can lead to alerts that prevent patient harm. Recently, electronic medical records (EMRs) have emerged as a valuable resource for pharmacovigilance. This study examines the use of retrospective medication orders and inpatient laboratory results documented in the EMR to identify ADRs.
Methods
Using 12 years of EMR data from Vanderbilt University Medical Center (VUMC), we designed a study to correlate abnormal laboratory results with specific drug administrations by comparing the outcomes of a drug-exposed group and a matched unexposed group. We assessed the relative merits of six pharmacovigilance measures used in spontaneous reporting systems (SRSs): proportional reporting ratio (PRR), reporting OR (ROR), Yule's Q (YULE), the χ2 test (CHI), Bayesian confidence propagation neural networks (BCPNN), and a gamma Poisson shrinker (GPS).
Results
We systematically evaluated the methods on two independently constructed reference standard datasets of drug–event pairs. The dataset of Yoon et al contained 470 drug–event pairs (10 drugs and 47 laboratory abnormalities). Using VUMC's EMR, we created another dataset of 378 drug–event pairs (nine drugs and 42 laboratory abnormalities). Evaluation on our reference standard showed that CHI, ROR, PRR, and YULE all had the same F score (62%). When the reference standard of Yoon et al was used, ROR had the best F score of 68%, with 77% precision and 61% recall.
Conclusions
Results suggest that EMR-derived laboratory measurements and medication orders can help to validate previously reported ADRs, and detect new ADRs.
doi:10.1136/amiajnl-2012-001119
PMCID: PMC3628053  PMID: 23161894
Pharmacovigilance; Post-marketing drug surveillance; Adverse drug reactions; Automated laboratory signals; Electronic medical records
9.  Rational development of a serum-free medium and fed-batch process for a GS-CHO cell line expressing recombinant antibody 
Cytotechnology  2012;65(3):363-378.
A serum-free medium (CHO-SFM) together with a fed-batch process was developed for the cultivation of a recombinant GS-CHO cell line producing TNFR-Fc. According to the metabolic characteristics of GS-CHO cell, a basal medium was prepared by supplementing DMEM:F12:RPMI1640 (2:1:1) with amino acids, insulin, transferrin, Pluronic F68 and some other ingredients. Statistical optimization approaches based on Plackett–Burman and central composite designs were then adopted to identify additional positive determinants and determine their optimal concentrations, which resulted in the final CHO-SFM medium formulations. The maximum antibody titer reached was 90.95 mg/l in the developed CHO-SFM, which was a 18 % and 10 fold higher than that observed in the commercial EX-CELL™ 302 medium (76.95 mg/l) and basal medium (8.28 mg/l), respectively. Subsequently, a reliable, reproducible and robust fed-batch strategy was designed according to the offline measurement of glucose, giving a final antibody yield of 378 mg/l, which was a threefold improvement over that in conventional batch culture (122 mg/l) using CHO-SFM. In conclusion, the use of design of experiment (DoE) method facilitated the development of CHO-SFM medium and fed-batch process for the production of recombinant antibody using GS-CHO cells.
doi:10.1007/s10616-012-9488-4
PMCID: PMC3597181  PMID: 22907508
GS-CHO cell; Recombinant antibody; SFM; Design of experiment (DoE); Fed-batch process
10.  Differential freezing resistance and photoprotection in C3 and C4 eudicots and grasses 
Journal of Experimental Botany  2013;64(8):2183-2191.
Globally, C4 plants dominate hot, open environments, but this general pattern is underpinned by important differences in the biogeography of C4 lineages. In particular, the species richness of C4 Poaceae (grasses) increases strongly with increasing temperature, whereas that of the major C4 eudicot group Chenopodiaceae correlates positively with aridity. Freezing tolerance is a crucial determinant of biogeographical relationships with temperature and is mediated by photodamage and cellular disruption by desiccation, but little is known about differences between C4 families. This study hypothesized that there is a greater risk of freezing damage via these mechanisms in C4 Poaceae than Chenopodiaceae, that freezing protection differs between the taxonomic groups, and that freezing tolerance of species is linked to arid habitat preference. Chlorophyll fluorescence, water relations, and freezing injury were compared in four C3 and six C4 species of Poaceae and Chenopodiaceae from the same Mongolian flora. Contrary to expectations, freezing-induced leaf mortality and photodamage were lower in Poaceae than Chenopodiaceae species, and unrelated to photosynthetic pathway. The freezing resistance of Poaceae species resulted from constitutive protection and cold acclimation and an ability to protect the photosynthetic apparatus from photodamage. Freezing protection was associated with low osmotic potential and low tissue elasticity, and freezing damage was accompanied by electrolyte leakage, consistent with cell-membrane disruption by ice. Both Chenopodiaceae and Poaceae had the potential to develop cold acclimation and withstand freezing during the growing season, which conflicted with the hypothesis. Instead, freezing tolerance was more closely associated with life history and ecological preference in these Mongolian species.
doi:10.1093/jxb/ert075
PMCID: PMC3654411  PMID: 23599273
C3 photosynthesis; C4 photosynthesis; Chenopodiaceae; cold acclimation; freezing tolerance; photodamage; Poaceae; water relations.
11.  Plasma Sphingolipids as Potential Indicators of Hepatic Necroinflammation in Patients with Chronic Hepatitis C and Normal Alanine Aminotransferase Level 
PLoS ONE  2014;9(4):e95095.
Accurate estimation of hepatic necroinflammation caused by chronic hepatitis C (CHC) is crucial for prediction of prognosis and design of therapeutic strategy, which is particularly true for CHC patients with normal alanine aminotransferase (ALT) level. Recent studies have shown that sphingolipids have a close relationship with hepatitis C virus infection. The present study aimed to identify plasma sphingolipids related to hepatic necroinflammation. We included 120 treatment-naïve CHC patients and 64/120 had normal ALT levels (<40 U/L). CHC patients who underwent liver biopsies were subjected to Scheuer scoring analysis for scope of hepatic inflammation. Plasma sphingolipids were detected by high-performance liquid chromatography tandem mass spectrometry. Our results showed 44 plasma sphingolipids were detected altogether. Of all detected sphingolipids, hexosylceramide (HexCer) (d18∶1/22∶0) and HexCer (d18∶1/24∶0) showed a significant difference among G0/G1, G2, and G3/G4 (P<0.05). For identifying hepatic necroinflammation (G≥2), after adjusting other factors, the odds ratio (OR) of HexCer (d18∶1/22∶0) reached 1.01 (95% confidence interval [CI]: 1.00–1.02). Furthermore, the area under the curve (AUC) of HexCer (d18∶1/22∶0) was 0.7 (P = 0.01) and approached that of ALT (AUC = 0.78). However, in CHC patients with normal ALT, HexCer (d18∶1/22∶0) was an independent factor (OR: 1.02, 95% CI: 1.01–1.03) to identify the hepatic necroinflammation (G≥2). HexCer (d18∶1/22∶0) not only showed the largest AUC (0.78, P = 0.001), but also exhibited the highest specificity of all indicators. These results indicate that plasma HexCer (d18∶1/22∶0) is a potential indicator to distinguish hepatic necroinflammation in CHC patients. For CHC with normal ALT, the ability of HexCer (d18∶1/22∶0) to distinguish hepatic necroinflammation might be superior to conventional serum indicators.
doi:10.1371/journal.pone.0095095
PMCID: PMC3988168  PMID: 24736528
12.  Fusion Transcript Discovery in Formalin-Fixed Paraffin-Embedded Human Breast Cancer Tissues Reveals a Link to Tumor Progression 
PLoS ONE  2014;9(4):e94202.
The identification of gene fusions promises to play an important role in personalized cancer treatment decisions. Many rare gene fusion events have been identified in fresh frozen solid tumors from common cancers employing next-generation sequencing technology. However the ability to detect transcripts from gene fusions in RNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissues, which exist in very large sample repositories for which disease outcome is known, is still limited due to the low complexity of FFPE libraries and the lack of appropriate bioinformatics methods. We sought to develop a bioinformatics method, named gFuse, to detect fusion transcripts in FFPE tumor tissues. An integrated, cohort based strategy has been used in gFuse to examine single-end 50 base pair (bp) reads generated from FFPE RNA-Sequencing (RNA-Seq) datasets employing two breast cancer cohorts of 136 and 76 patients. In total, 118 fusion events were detected transcriptome-wide at base-pair resolution across the 212 samples. We selected 77 candidate fusions based on their biological relevance to cancer and supported 61% of these using TaqMan assays. Direct sequencing of 19 of the fusion sequences identified by TaqMan confirmed them. Three unique fused gene pairs were recurrent across the 212 patients with 6, 3, 2 individuals harboring these fusions respectively. We show here that a high frequency of fusion transcripts detected at the whole transcriptome level correlates with poor outcome (P<0.0005) in human breast cancer patients. This study demonstrates the ability to detect fusion transcripts as biomarkers from archival FFPE tissues, and the potential prognostic value of the fusion transcripts detected.
doi:10.1371/journal.pone.0094202
PMCID: PMC3984112  PMID: 24727804
13.  The role of VuMATE1 expression in aluminium-inducible citrate secretion in rice bean (Vigna umbellata) roots 
Journal of Experimental Botany  2013;64(7):1795-1804.
Aluminium (Al)-activated citrate secretion plays an important role in Al resistance in a number of plant species, such as rice bean (Vigna umbellata). This study further characterized the regulation of VuMATE1, an aluminium-activated citrate transporter. Al stress induced VuMATE1 expression, followed by the secretion of citrate. Citrate secretion was specific to Al stress, whereas VuMATE1 expression was not, which could be explained by a combined regulation of VuMATE1 expression and Al-specific activation of VuMATE1 protein. Pre-treatment with a protein translation inhibitor suppressed VuMATE1 expression, indicating that de novo biosynthesis of proteins is required for gene expression. Furthermore, post-treatment with a protein translation inhibitor inhibited citrate secretion, indicating that post-transcriptional regulation of VuMATE1 is critical for citrate secretion. Protein kinase and phosphatase inhibitor studies showed that reversible phosphorylation was important not only for transcriptional regulation of VuMATE1 expression but also for post-translational regulation of VuMATE1 protein activity. These results suggest that citrate secretion is dependent on both transcriptional and post-transcriptional regulation of VuMATE1. Additionally, VuMATE1 promoter–β-glucuronidase fusion lines revealed that VuMATE1 expression was restricted to the root apex and was entirely Al induced, indicating the presence of cis-acting elements regulating root tip-specific and Al-inducible gene expression, which will be an important resource for genetic improvement of plant Al resistance.
doi:10.1093/jxb/ert039
PMCID: PMC3638816  PMID: 23408830
aluminium toxicity; cis-acting element; promoter; reversible phosphorylation; signalling transduction; transcription factor.
14.  Neuroprotective Effect of a Formula, Moschus Combined with Borneolum Synthcticum, from Traditional Chinese Medicine on Ischemia Stroke in Rats 
Moschus compatible with borneolum synthcticum is a well-known herb pair in Traditional Chinese Medicine and the present study aims to assess the neuroprotective effect of a formula composed of this herb pair on ischemia stroke in rats. The middle cerebral artery occlusion model of focal cerebral ischemia in rat was performed by using intraluminal suture method. The behavioral scores, infarct volume, and neuron ultrastructure of model and formula-treated rats were investigated after the 2 h of ischemia and 24 h of reperfusion. Meanwhile the expression levels of caspase-3, caspase-9, Bcl-2, and Bax were measured by western blot analysis. The formula treatment showed obvious neuroprotective effect according to significant decrease of the neurological scores (P < 0.01) and the infarct volumes (P < 0.05) when compared to the MCAO group. We also observed that this formula had antiapoptosis activity on neuron cell under electron microscope. Furthermore, our result supported the idea that pro- and postadministration of this formula had an antiapoptosis effect by decreasing remarkably the expression of caspase-3 and caspase-9 (P < 0.05) as well as increasing significantly the ratio of Bcl-2 to Bax (P < 0.01). All evidences demonstrated the neuroprotective effect of this formula on ischemia stroke due to decrease of brain infract volume and modulation of the expression of apoptosis-related proteins.
doi:10.1155/2014/157938
PMCID: PMC3982284  PMID: 24782904
15.  Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure 
AIM: To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure (ACLF) patients with chronic hepatitis B virus (HBV) infection as the single etiology.
METHODS: Full length and caspase cleaved cytokeratin 18 (detected as M65 and M30 antigens) represent circulating indicators of necrosis and apoptosis. M65 and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls (n = 33), patients with chronic hepatitis B (CHB, n = 55) and patients with ACLF (n = 81). According to the 3-mo survival period, ACLF patients were defined as having spontaneous recovery (n = 33) and non-spontaneous recovery which included deceased patients and those who required liver transplantation (n = 48).
RESULTS: Both biomarker levels significantly increased gradually as liver disease progressed (for M65: P < 0.001 for all; for M30: control vs CHB, P = 0.072; others: P < 0.001 for all). In contrast, the M30/M65 ratio was significantly higher in controls compared with CHB patients (P = 0.010) or ACLF patients (P < 0.001). In addition, the area under receiver operating characteristic curve (AUC) analysis demonstrated that both biomarkers had diagnostic value (AUC ≥ 0.80) in identifying ACLF from CHB patients. Interestingly, it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients (P = 0.032). The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores at the 3-mo survival period, the AUC of the M30/M65 ratio was 0.66 with a sensitivity of 52.9% and the highest specificity of 92.6% (MELD:AUC = 0.71; sensitivity, 79.4%; specificity, 63.0%; Child-Pugh: AUC = 0.77; sensitivity, 61.8%; specificity, 88.9%).
CONCLUSION: M65 and M30 are strongly associated with liver disease severity. The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in patients with HBV-related ACLF.
doi:10.3748/wjg.v20.i9.2403
PMCID: PMC3942845  PMID: 24605039
Acute-on-chronic liver failure; Chronic hepatitis B virus infection; Liver disease stage; Liver disease severity; Serum M65 level; Serum M30 level; Prognostic value
16.  Characterization of ELISA Detection of Broad-spectrum Anti- Epstein-Barr Virus Antibodies Associated with Nasopharyngeal Carcinoma 
Journal of medical virology  2012;85(3):524-529.
Epstein-Barr virus (EBV) infection is associated with undifferentiated nasopharyngeal carcinomas (NPC). A distinct seroreactivity pattern to EBV is predictive of subsequent risk of sporadic and familial nasopharyngeal carcinomas. There are currently no accepted screening tools for guiding the clinical management of individuals at high-risk for nasopharyngeal carcinomas, particularly unaffected relatives from nasopharyngeal carcinoma multiplex families. Therefore, the reproducibility of a panel of largely synthetic peptide-based anti-EBV antibody ELISAs was evaluated and their ability to distinguish nasopharyngeal carcinoma cases from controls was explored. IgG and IgA antibodies against 6 different EBV antigens (10 assays, total) were tested on sera from 97 individuals representing the full spectrum of anti-EBV seroprevalence (i.e., healthy individuals with no known EBV seroreactivity, healthy individuals with known EBV seroreactivity, and nasopharyngeal carcinoma cases). Each specimen was tested in triplicate to assess within-batch and across-batch variation, and the triplicate testing was repeated on two separate days. Reproducibility was assessed by the coefficients of variation (CV) and intraclass correlation coefficients (ICC). All markers were detectable in 17% or more of samples. For all but one marker, the overall, within-batch, and across-batch CVs were below 15%, and the ICCs were above 70% for all but three markers. Sensitivity of these markers to detect prevalent nasopharyngeal carcinomas ranged from 22–100%, and among unaffected controls, most distinguished those with and without known seropositivity. In conclusion, a large number of EBV markers can be measured reliably in serum samples using peptide-based anti-EBV ELISAs.
doi:10.1002/jmv.23498
PMCID: PMC3553325  PMID: 23280934
Epstein-Barr virus; EBNA1; VCA; IgA; nasopharyngeal carcinoma; screening
17.  Saponin-rich fraction from Clematis chinensis Osbeck roots protects rabbit chondrocytes against nitric oxide-induced apoptosis via preventing mitochondria impairment and caspase-3 activation 
Cytotechnology  2012;65(2):287-295.
Our previous study reported that the saponin-rich fraction from Clematis chinensis Osbeck roots (SFC) could effectively alleviate experimental osteoarthritis induced by monosodium iodoacetate in rats through protecting articular cartilage and inhibiting local inflammation. The present study was performed to investigate the preventive effects of SFC on articular chondrocyte, and explore the underlying mechanisms. Primary rabbit chondrocytes were cultured and exposed to sodium nitroprusside (SNP), a NO donor. After treatment with different concentrations of SFC (30, 100, 300, 1,000 μg/ml) for 24 h, nucleic morphology, apoptotic rate, mitochondrial function and caspase-3 activity of chondrocytes were examined. The results showed that SNP induced remarkable apoptosis of rabbit chondrocytes evidenced by Hoechst 33258 staining and flow cytometry analysis, and SFC prevented the apoptosis in a concentration-dependent manner. Further studies indicated that SFC could prevent the depolarization of mitochondrial membrane potential (∆ψm) in SNP-treated chondrocytes and suppress the activation of caspase-3. It can be concluded that the protection of SFC on articular chondrocytes is associated with the anti-apoptosis effects via inhibiting the mitochondrion impairment and caspase-3 activation.
doi:10.1007/s10616-012-9485-7
PMCID: PMC3560881  PMID: 22821055
Clematis chinensis; Osteoarthritis; Chondrocyte; Apoptosis; Nitric oxide
18.  Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions 
Background
To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features.
Methods
Between July 2005 and July 2012, 4,453 ultrasound-detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features.
Results
Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter ≤10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01).
Conclusions
Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm.
doi:10.1186/1477-7819-12-7
PMCID: PMC3895748  PMID: 24400744
Breast; Beast cancer; Core needle biopsy; Surgical excision; Ultrasound
19.  The phylogenetic significance of the carpophore in Apiaceae 
Annals of Botany  2012;110(8):1531-1543.
Background and aims
Fruit structural characters have traditionally been important in the taxonomy of the family Apiaceae. Previous investigations using a limited number of taxa have shown that the carpophore may be especially useful in helping to circumscribe subfamily Azorelloideae. The present study examines, for the first time, carpophore structure in 92 species from 43 genera, representing all subfamilies of Apiaceae, and including all genera assigned to subfamily Azorelloideae. Phylogenetic interpretations are made for the first time, using all available information, and a standard terminology is proposed to describe the various character states found in carpophores.
Methods
Carpophore structure was studied in detail using light microscopy.
Key Results
Carpophores, when present, may be categorized into two main groups (B and C) based mainly on the arrangement of the vascular bundles in transverse section, and further divided into six sub-types according to the length of the carpophore (short in B1 and C1) and whether they are entire (B1–B3 and C1) or bifurcate (B4 and C2). Free carpophores are absent in subfamily Mackinlayoideae, and in tribes Lichtensteinieae and Phlyctidocarpeae, which have two opposite vascular bundles (Group A). Entire carpophores with one or two vascular bundles, or bifurcate carpophores with lateral vascular bundles (arranged side by side within the commissural plane), are the main types characterizing Azorelloideae. The short, hygroscopic carpophores found in Choritaenia are unique in Apiaceae and provide additional evidence for the exclusion of this genus from Azorelloideae. Carpophore type C2 is typical for most Apioideae sensu lato (exceptions are, for example, Arctopus and Alepidea, which have type B2).
Conclusions
A single carpophore and ventral vascular bundles not forming free carpophores are proposed to be the ancestral conditions in Apiaceae, while bifurcate carpophores with opposite vascular bundles are the derived state, present in most Apioideae. Secondary reductions seem to have occurred in several unrelated lineages in all major groups, e.g. many Azorelloideae, several protoapioids (including nearly all members of the tribe Saniculeae) and 29 euapioid genera (e.g. some Oenantheae).
doi:10.1093/aob/mcs204
PMCID: PMC3503491  PMID: 22966116
Apiaceae; Apiales; Azorelloideae; carpophore; descriptive terminology; euapioids; phylogeny; protoapioids; Umbelliferae; vascular bundle
20.  An Antibody-based Blood Test Utilizing a Panel of Biomarkers as a New Method for Improved Breast Cancer Diagnosis 
Biomarkers in Cancer  2013;5:71-80.
In order to develop a new tool for diagnosis of breast cancer based on autoantibodies against a panel of biomarkers, a clinical trial including blood samples from 507 subjects was conducted. All subjects showed a breast abnormality on exam or breast imaging and final biopsy pathology of either breast cancer patients or healthy controls. Using an enzyme-linked immunosorbent assay, the samples were tested for autoantibodies against a predetermined number of biomarkers in various models that were used to determine a diagnosis, which was compared to the clinical status. Our new assay achieved a sensitivity of 95.2% [CI = 92.8–96.8%] at a fixed specificity of 49.5%. Receiver-operator characteristic curve analysis showed an area under the curve of 80.1% [CI = 72.6–87.6%]. These results suggest that a blood test which is based on models comprising several autoantibodies to specific biomarkers may be a new and novel tool for improving the diagnostic evaluation of breast cancer.
doi:10.4137/BIC.S13236
PMCID: PMC3855201  PMID: 24324350
breast cancer; autoantibodies; diagnostic testing; biomarkers
21.  β3 Integrin Promotes TGF-β1/H2O2/HOCl-Mediated Induction of Metastatic Phenotype of Hepatocellular Carcinoma Cells by Enhancing TGF-β1 Signaling 
PLoS ONE  2013;8(11):e79857.
In addition to being an important mediator of migration and invasion of tumor cells, β3 integrin can also enhance TGF-β1 signaling. However, it is not known whether β3 might influence the induction of metastatic phenotype of tumor cells, especially non-metastatic tumor cells which express low level of β3. Here we report that H2O2 and HOCl, the reactive oxygen species produced by neutrophils, could cooperate with TGF-β1 to induce metastatic phenotype of non-metastatic hepatocellular carcinoma (HCC) cells. TGF-β1/H2O2/HOCl, but not TGF-β1 or H2O2/HOCl, induced β3 expression by triggering the enhanced activation of p38 MAPK. Intriguingly, β3 in turn promoted TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of HCC cells by enhancing TGF-β1 signaling. β3 promoted TGF-β1/H2O2/HOCl-induced expression of itself via positive feed-back effect on p38 MAPK activation, and also promoted TGF-β1/H2O2/HOCl-induced expression of α3 and SNAI2 by enhancing the activation of ERK pathway, thus resulting in higher invasive capacity of HCC cells. By enhancing MAPK activation, β3 enabled TGF-β1 to augment the promoting effect of H2O2/HOCl on anoikis-resistance of HCC cells. TGF-β1/H2O2/HOCl-induced metastatic phenotype was sufficient for HCC cells to extravasate from circulation and form metastatic foci in an experimental metastasis model in nude mice. Inhibiting the function of β3 could suppress or abrogate the promoting effects of TGF-β1/H2O2/HOCl on invasive capacity, anoikis-resistance, and extravasation of HCC cells. These results suggest that β3 could function as a modulator to promote TGF-β1/H2O2/HOCl-mediated induction of metastatic phenotype of non-metastatic tumor cells, and that targeting β3 might be a potential approach in preventing the induction of metastatic phenotype of non-metastatic tumor cells.
doi:10.1371/journal.pone.0079857
PMCID: PMC3832483  PMID: 24260309
22.  Identifying Inconsistencies in SNOMED CT Problem Lists using Structural Indicators 
The National Library of Medicine has published the CORE and the VA/KP problem lists to facilitate the usage of SNOMED CT for encoding diagnoses and clinical data of patients in electronic health records. Therefore, it is essential for the content of the problem lists to be as accurate and consistent as possible. This study assesses the effectiveness of using a concept’s word length and number of parents, two structural indicators for measuring concept complexity, to identify inconsistencies with high probability. The method is able to isolate concepts with over 40% expected of being erroneous. A structural indicator for concepts which is able to identify 52% of the examined concepts as having errors in synonyms is also presented. The results demonstrate that the concepts in problem lists are not free of inconsistencies and further quality assurance is needed to improve the quality of these concepts.
PMCID: PMC3900119  PMID: 24551319
23.  Genetic Variation in the PNPLA3 Gene and Hepatocellular Carcinoma in USA: Risk and Prognosis Prediction 
Molecular carcinogenesis  2013;52(0):10.1002/mc.22057.
Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case–control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68–6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13–71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05–5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26–3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.
doi:10.1002/mc.22057
PMCID: PMC3808509  PMID: 23776098
molecular epidemiology; genetic susceptibility; case–control; single nucleotide polymorphism
24.  Toxicity and Immunogenicity of Enterotoxigenic Escherichia coli Heat-Labile and Heat-Stable Toxoid Fusion 3xSTaA14Q-LTS63K/R192G/L211A in a Murine Model 
PLoS ONE  2013;8(10):e77386.
Diarrhea is the second leading cause of death to young children. Enterotoxigenic Escherichia coli (ETEC) are the most common bacteria causing diarrhea. Adhesins and enterotoxins are the virulence determinants in ETEC diarrhea. Adhesins mediate bacterial attachment and colonization, and enterotoxins including heat-labile (LT) and heat-stable type Ib toxin (STa) disrupt fluid homeostasis in host cells that leads to fluid hyper-secretion and diarrhea. Thus, adhesins and enterotoxins have been primarily targeted in ETEC vaccine development. A recent study reported toxoid fusions with STa toxoid (STaP13F) fused at the N- or C-terminus, or inside the A subunit of LTR192G elicited neutralizing antitoxin antibodies, and suggested application of toxoid fusions in ETEC vaccine development (Liu et al., Infect. Immun. 79:4002-4009, 2011). In this study, we generated a different STa toxoid (STaA14Q) and a triple-mutant LT toxoid (LTS63K/R192G/L211A, tmLT), constructed a toxoid fusion (3xSTaA14Q-tmLT) that carried 3 copies of STaA14Q for further facilitation of anti-STa immunogenicity, and assessed antigen safety and immunogenicity in a murine model to explore its potential for ETEC vaccine development. Mice immunized with this fusion antigen showed no adverse effects, and developed antitoxin antibodies particularly through the IP route. Anti-LT antibodies were detected and were shown neutralizing against CT in vitro. Anti-STa antibodies were also detected in the immunized mice, and serum from the IP immunized mice neutralized STa toxin in vitro. Data from this study indicated that toxoid fusion 3xSTaA14Q-tmLT is safe and can induce neutralizing antitoxin antibodies, and provided helpful information for vaccine development against ETEC diarrhea.
doi:10.1371/journal.pone.0077386
PMCID: PMC3795625  PMID: 24146989
25.  Peroxiredoxin 1 is a tumor-associated antigen in esophageal squamous cell carcinoma 
Oncology Reports  2013;30(5):2297-2303.
Peroxiredoxin 1 (Prdx1) is an antioxidant and plays an important role in H2O2-mediated cell signaling. We previously found that the expression level of Prdx1 was elevated in esophagus squamous cell carcinoma (ESCC) tissue using a proteomics approach. Since overexpressed protein can induce an autoimmune response, to further examine whether serum from ESCC patients exhibits immunoreactivity against Prdx1, autoantibody responses to Prdx1 were evaluated by ELISA, western blotting and indirect immunofluorescence assay in sera from patients with ESCC and normal individuals. Immunohistochemical study with tissue array slides and western blot analysis with cancer cell lines were also performed to analyze the protein expression profiles of Prdx1 in ESCC tissues and cancer cell lines. The results demonstrated that the positive rate of autoantibody against Prdx1 in ESCC sera was 13.2% (9/68), whereas this rate was 0% (0/89) in normal individuals. Data also showed that expression of Prdx1 was significantly increased in ESCC tissues when compared to expression in paired adjacent normal tissues (P<0.05). The data indicate that Prdx1 may contribute to malignant transformation of the esophagus, and may be used as a biomarker in the immunodiagnosis of ESCC.
doi:10.3892/or.2013.2714
PMCID: PMC3820583  PMID: 24009050
autoantibody; peroxiredoxin 1; esophageal squamous cell carcinoma; biomarker; immunodiagnosis

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