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1.  A comparison of ARMS and direct sequencing for EGFR mutation analysis and Tyrosine Kinase Inhibitors treatment prediction in body fluid samples of Non-Small-Cell Lung Cancer patients 
Background
Epidermal growth factor receptor (EGFR) mutation is strongly associated with the therapeutic effect of tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable. Body fluid was considered to be a feasible substitute for the analysis, but arising problems in clinical practice such as relatively lower mutation rate and poor clinical correlation are not yet fully resolved.
Method
In this study, 50 patients (32 pleural fluids and 18 plasmas) with TKIs therapy experience and with direct sequencing results were selected from 220 patients for further analysis. The EGFR mutation status was re-evaluated by Amplification Refractory Mutation System (ARMS), and the clinical outcomes of TKIs were analyzed retrospectively.
Results
As compared with direct sequencing, 16 positive and 23 negative patients were confirmed by ARMS, and the other 11 former negative patients (6 pleural fluids and 5 plasmas) were redefined as positive, with a fairly well clinical outcome (7 PR, 3 SD, and 1 PD). The objective response rate (ORR) of positive patients was significant, 81.3% (direct sequencing) and 72.7% (ARMS) for pleural fluids, and 80% (ARMS) for plasma. Notably, even reclassified by ARMS, the ORR for negative patients was still relatively high, 60% for pleural fluids and 46.2% for plasma.
Conclusions
When using body fluids for EGFR mutation analysis, positive result is consistently a good indicator for TKIs therapy, and the predictive effect was no less than that of tumor tissue, no matter what method was employed. However, even reclassified by ARMS, the correlation between negative results and clinical outcome of TKIs was still unsatisfied. The results indicated that false negative mutation still existed, which may be settled by using method with sensitivity to single DNA molecule or by optimizing the extraction procedure with RNA or CTC to ensure adequate amount of tumor-derived nucleic acid for the test.
doi:10.1186/1756-9966-30-111
PMCID: PMC3287118  PMID: 22142557
Body Fluids; EGFR Mutation; Direct Sequencing; ARMS; TKIs; NSCLC
2.  Straw Mulching Reduces the Harmful Effects of Extreme Hydrological and Temperature Conditions in Citrus Orchards 
PLoS ONE  2014;9(1):e87094.
Extreme weather conditions with negative impacts can strongly affect agricultural production. In the Danjiangkou reservoir area, citrus yields were greatly influenced by cold weather conditions and drought stress in 2011. Soil straw mulching (SM) practices have a major effect on soil water and thermal regimes. A two-year field experiment was conducted to evaluate whether the SM practices can help achieve favorable citrus fruit yields. Results showed that the annual total runoff was significantly (P<0.05) reduced with SM as compared to the control (CK). Correspondingly, mean soil water storage in the top 100 cm of the soil profile was increased in the SM as compared to the CK treatment. However, this result was significant only in the dry season (Jan to Mar), and not in the wet season (Jul to Sep) for both years. Interestingly, the SM treatment did not significantly increase citrus fruit yield in 2010 but did so in 2011, when the citrus crop was completely destroyed (zero fruit yield) in the CK treatment plot due to extremely low temperatures during the citrus overwintering stage. The mulch probably acted as an insulator, resulting in smaller fluctuations in soil temperature in the SM than in the CK treatment. The results suggested that the small effects on soil water and temperature changes created by surface mulch had limited impact on citrus fruit yield in a normal year (e.g., in 2010). However, SM practices can positively impact citrus fruit yield in extreme weather conditions.
doi:10.1371/journal.pone.0087094
PMCID: PMC3904954  PMID: 24489844
3.  Mysterious abrupt carbon-14 increase in coral contributed by a comet 
Scientific Reports  2014;4:3728.
A large and sudden increase in radiocarbon (14C) around AD 773 are documented in coral skeletons from the South China Sea. The 14C increased by ~ 15‰ during winter, and remain elevated for more than 4 months, then increased and dropped down within two months, forming a spike of 45‰ high in late spring, followed by two smaller spikes. The 14C anomalies coincide with an historic comet collision with the Earth's atmosphere on 17 January AD 773. Comas are known to have percent-levels of nitrogen by weight, and are exposed to cosmic radiation in space. Hence they may be expected to contain highly elevated 14C/12C ratios, as compared to the Earth's atmosphere. The significant input of 14C by comets may have contributed to the fluctuation of 14C in the atmosphere throughout the Earth's history, which should be considered carefully to better constrain the cosmic ray fluctuation.
doi:10.1038/srep03728
PMCID: PMC3893640  PMID: 24430984
4.  The Use of Integrative Therapies in Patients with Amyotrophic Lateral Sclerosis in Shanghai, China 
Objective. To investigate the current use of integrative therapies (IT) in the treatment of patients with amyotrophic lateral sclerosis (ALS). Methods. A cross-sectional, multicenter clinical epidemiological survey was conducted in 12 hospitals in Shanghai. We investigated the type and frequency of IT use and determined whether the use of IT correlated with demographic, social, or disease-specific characteristics in our patient population. Results. A total of 231 (89.5%) of 258 patients with ALS were eligible for the study and 229 (99% of all) of 231 reported the use of at least one IT for the treatment of ALS. Vitamins and Chinese herb decoctions, Chinese herb compounds, massage therapy, and acupuncture were the 5 most commonly used therapies. There was a strong association between education level, income, and use of IT. A household income of more than 75,000 RMB ($49,995) correlated with multiple IT use, and married patients used IT more often than single individuals. The main reasons for using IT were to treat weakness and fatigue, muscle atrophy, the development of ALS, depression, insomnia, limb pain or numbness, and side effects associated with Riluzole. Conclusion. The use of IT is common in patients with ALS in Shanghai. Vitamins and TCM are the most used additional therapies and the widespread and largely unexamined use of IT for ALS requires more attention.
doi:10.1155/2013/613596
PMCID: PMC3865630  PMID: 24363770
6.  Role of Macrophage Migration Inhibitory Factor in the Proliferation of Smooth Muscle Cell in Pulmonary Hypertension 
Mediators of Inflammation  2012;2012:840737.
Pulmonary hypertension (PH) contributes to the mortality of patients with lung and heart diseases. However, the underlying mechanism has not been completely elucidated. Accumulating evidence suggests that inflammatory response may be involved in the pathogenesis of PH. Macrophage migration inhibitory factor (MIF) is a critical upstream inflammatory mediator which promotes a broad range of pathophysiological processes. The aim of the study was to investigate the role of MIF in the pulmonary vascular remodeling of hypoxia-induced PH. We found that MIF mRNA and protein expression was increased in the lung tissues from hypoxic pulmonary hypertensive rats. Intensive immunoreactivity for MIF was observed in smooth muscle cells of large pulmonary arteries (PAs), endothelial cells of small PAs, and inflammatory cells of hypoxic lungs. MIF participated in the hypoxia-induced PASMCs proliferation, and it could directly stimulate proliferation of these cells. MIF-induced enhanced growth of PASMCs was attenuated by MEK and JNK inhibitor. Besides, MIF antagonist ISO-1 suppressed the ERK1/2 and JNK phosphorylation induced by MIF. In conclusion, the current finding suggested that MIF may act on the proliferation of PASMCs through the activation of the ERK1/2 and JNK pathways, which contributes to hypoxic pulmonary hypertension.
doi:10.1155/2012/840737
PMCID: PMC3270469  PMID: 22363104
7.  Clathrin-Mediated Endocytosis in Living Host Cells Visualized through Quantum Dot Labeling of Infectious Hematopoietic Necrosis Virus▿† 
Journal of Virology  2011;85(13):6252-6262.
Infectious hematopoietic necrosis virus (IHNV) is an important fish pathogen that infects both wild and cultured salmonids. As a species of the genus Novirhabdovirus, IHNV is a valuable model system for exploring the host entry mechanisms of rhabdoviruses. In this study, quantum dots (QDs) were used as fluorescent labels for sensitive, long-term tracking of IHNV entry. Using live-cell fluorescence microscopy, we found that IHNV is internalized through clathrin-coated pits after the virus binds to host cell membranes. Pretreatment of host cells with chlorpromazine, a drug that blocks clathrin-mediated endocytosis, and clathrin light chain (LCa) depletion using RNA interference both resulted in a marked reduction in viral entry. We also visualized transport of the virus via the cytoskeleton (i.e., actin filaments and microtubules) in real time. Actin polymerization is involved in the transport of endocytic vesicles into the cytosol, whereas microtubules are required for the trafficking of clathrin-coated vesicles to early endosomes, late endosomes, and lysosomes. Disrupting the host cell cytoskeleton with cytochalasin D or nocodazole significantly impaired IHNV infectivity. Furthermore, infection was significantly affected by pretreating the host cells with bafilomycin A1, a compound that inhibits the acidification of endosomes and lysosomes. Strong colocalizations of IHNV with endosomes indicated that the virus is internalized into these membrane-bound compartments. This is the first report in which QD labeling is used to visualize the dynamic interactions between viruses and endocytic structures; the results presented demonstrate that IHNV enters host cells via clathrin-mediated endocytic, cytoskeleton-dependent, and low-pH-dependent pathways.
doi:10.1128/JVI.00109-11
PMCID: PMC3126507  PMID: 21525360
8.  Regulation of G1 Arrest and Apoptosis in Hypoxia by PERK and GCN2-Mediated eIF2α Phosphorylation12 
Neoplasia (New York, N.Y.)  2010;12(1):61-68.
Hypoxia is a common microenvironment in solid tumors and is correlated with tumor progression by regulating cancer cell survival. Recent studies suggest that activation of double-stranded RNA-dependent protein kinase-like endoplasmic reticulum-related kinase (PERK) and phosphorylation of α subunit of eIF2 (eIF2α) confer cell adaptation to hypoxic stress. However, eIF2α is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2α kinase(s) (eIF2AK)-increased cell survival is not clear. In this report, we provide evidence that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2α phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2α phosphorylation lead to G1 arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2α by knocking out either PERK or GCN2 suppresses hypoxia-induced G1 arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2α inhibits G1 arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2α phosphorylation serve as a “switch” in regulation of G1 arrest or apoptosis under hypoxic conditions.
PMCID: PMC2805884  PMID: 20072654
9.  Recipient-Related Clinical Risk Factors for Primary Graft Dysfunction after Lung Transplantation: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e92773.
Background
Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors. Herein, we carried out a systematic review and meta-analysis of published literature to identify recipient-related clinical risk factors associated with PGD development.
Method
A systematic search of electronic databases (PubMed, Embase, Web of Science, Cochrane CENTRAL, and Scopus) for studies published from 1970 to 2013 was performed. Cohort, case-control, or cross-sectional studies that examined recipient-related risk factors of PGD were included. The odds ratios (ORs) or mean differences (MDs) were calculated using random-effects models
Result
Thirteen studies involving 10042 recipients met final inclusion criteria. From the pooled analyses, female gender (OR 1.38, 95% CI 1.09 to 1.75), African American (OR 1.82, 95%CI 1.36 to 2.45), idiopathic pulmonary fibrosis (IPF) (OR 1.78, 95% CI 1.49 to 2.13), sarcoidosis (OR 4.25, 95% CI 1.09 to 16.52), primary pulmonary hypertension (PPH) (OR 3.73, 95%CI 2.16 to 6.46), elevated BMI (BMI≥25 kg/m2) (OR 1.83, 95% CI 1.26 to 2.64), and use of cardiopulmonary bypass (CPB) (OR 2.29, 95%CI 1.43 to 3.65) were significantly associated with increased risk of PGD. Age, cystic fibrosis, secondary pulmonary hypertension (SPH), intra-operative inhaled nitric oxide (NO), or lung transplant type (single or bilateral) were not significantly associated with PGD development (all P>0.05). Moreover, a nearly 4 fold increased risk of short-term mortality was observed in patients with PGD (OR 3.95, 95% CI 2.80 to 5.57).
Conclusions
Our analysis identified several recipient related risk factors for development of PGD. The identification of higher-risk recipients and further research into the underlying mechanisms may lead to selective therapies aimed at reducing this reperfusion injury.
doi:10.1371/journal.pone.0092773
PMCID: PMC3962459  PMID: 24658073
10.  Producing aglycons of ginsenosides in bakers' yeast 
Scientific Reports  2014;4:3698.
Ginsenosides are the primary bioactive components of ginseng, which is a popular medicinal plant that exhibits diverse pharmacological activities. Protopanaxadiol, protopanaxatriol and oleanolic acid are three basic aglycons of ginsenosides. Producing aglycons of ginsenosides in Saccharomyces cerevisiae was realized in this work and provides an alternative route compared to traditional extraction methods. Synthetic pathways of these three aglycons were constructed in S. cerevisiae by introducing β-amyrin synthase, oleanolic acid synthase, dammarenediol-II synthase, protopanaxadiol synthase, protopanaxatriol synthase and NADPH-cytochrome P450 reductase from different plants. In addition, a truncated 3-hydroxy-3-methylglutaryl-CoA reductase, squalene synthase and 2,3-oxidosqualene synthase genes were overexpressed to increase the precursor supply for improving aglycon production. Strain GY-1 was obtained, which produced 17.2 mg/L protopanaxadiol, 15.9 mg/L protopanaxatriol and 21.4 mg/L oleanolic acid. The yeast strains engineered in this work can serve as the basis for creating an alternative way for producing ginsenosides in place of extractions from plant sources.
doi:10.1038/srep03698
PMCID: PMC3892717  PMID: 24424342
11.  Detection of Fusobacterium Nucleatum and fadA Adhesin Gene in Patients with Orthodontic Gingivitis and Non-Orthodontic Periodontal Inflammation 
PLoS ONE  2014;9(1):e85280.
Fusobacterium nucleatum is one of the most abundant gram-negative bacilli colonizing the subgingival plaque and closely associated with periodontal disease. However it is unclear whether F. nucleatum is involved in gingival inflammation under orthodontic appliance. A novel adhesin, FadA, which is unique to oral Fusobacteria, is required for F. nucleatum binding and invasion to epithelial cells and thus may play an important role in colonization of Fusobacterium in the host. In this study, we evaluated the prevalence of F. nucleatum and its virulence factor FadA adhesion gene (fadA) in 169 subgingival biofilm samples from 55 cases of gingivitis patients with orthodontic appliances, 49 cases of gingivitis patients without orthodontic treatment, 35 cases of periodontitis patients and 30 cases of periodontally healthy people via PCR. The correlations between the F. nucleatum/fadA and gingivitis index(GI)was also analyzed. The detection rate of F. nucleatum/fadA in periodontitis group and non-orthodontic gingivitis group was higher than the other two groups (p<0.01) while it was higher in orthodontic gingivitis group than in health people (p<0.05). An obviously positive correlation was observed between the prevalence of F. nucleatum/fadA and GI. F. nucleatum carrying fadA may be more closely related to the development of gingivitis and periodontal disease compared with orthodontic gingivitis.
doi:10.1371/journal.pone.0085280
PMCID: PMC3887018  PMID: 24416378
12.  Novel GATA6 Mutations Associated with Congenital Ventricular Septal Defect or Tetralogy of Fallot 
DNA and Cell Biology  2012;31(11):1610-1617.
Congenital heart disease (CHD) is the most common form of developmental malformation and is the leading noninfectious cause of infant mortality. Emerging evidence indicates that genetic defects are involved in the pathogenesis of CHD. Nevertheless, CHD is genetically heterogeneous, and the molecular basis for CHD in a majority of patients remains unknown. In this study, the whole coding region of GATA6, a gene encoding a zinc-finger transcription factor crucial for normal cardiogenesis, was sequenced in 380 unrelated patients with CHD. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional effect of the mutations was characterized using a luciferase reporter assay system. As a result, two novel heterozygous GATA6 mutations, p.D404Y and p.E460X, were identified in two families with ventricular septal defect and tetralogy of Fallot, respectively. The mutations co-segregated with CHD in the families with complete penetrance, and were absent in 400 control chromosomes. Functional analysis demonstrated that the mutated GATA6 proteins were associated with significantly decreased transactivational activity in comparison with their wild-type counterpart. These findings provide novel insight into the molecular mechanism implicated in CHD, suggesting potential implications for the early prophylaxis and personalized treatment of CHD.
The transcription factor GATA6 is a zinc finger DNA-binding protein that has been shown to be essential for cardiac development. In this article, two novel heterologous polymorphisms were associated with two cardiac malformations in families.
doi:10.1089/dna.2012.1814
PMCID: PMC3482375  PMID: 23020118
13.  Functional Dissection of Regulatory Models Using Gene Expression Data of Deletion Mutants 
PLoS Genetics  2013;9(9):e1003757.
Genome-wide gene expression profiles accumulate at an alarming rate, how to integrate these expression profiles generated by different laboratories to reverse engineer the cellular regulatory network has been a major challenge. To automatically infer gene regulatory pathways from genome-wide mRNA expression profiles before and after genetic perturbations, we introduced a new Bayesian network algorithm: Deletion Mutant Bayesian Network (DM_BN). We applied DM_BN to the expression profiles of 544 yeast single or double deletion mutants of transcription factors, chromatin remodeling machinery components, protein kinases and phosphatases in S. cerevisiae. The network inferred by this method identified causal regulatory and non-causal concurrent interactions among these regulators (genetically perturbed genes) that are strongly supported by the experimental evidence, and generated many new testable hypotheses. Compared to networks reconstructed by routine similarity measures or by alternative Bayesian network algorithms, the network inferred by DM_BN excels in both precision and recall. To facilitate its application in other systems, we packaged the algorithm into a user-friendly analysis tool that can be downloaded at http://www.picb.ac.cn/hanlab/DM_BN.html.
Author Summary
The complex functions of a living cell are carried out through hierarchically organized regulatory pathways composed of complex interactions between regulators themselves and between regulators and their targets. Here we developed a Bayesian network inference algorithm, Deletion Mutant Bayesian Network (DM_BN) to reverse engineer the yeast regulatory network based on the hypothesis that components of the same protein complexes or the same regulatory pathways share common target genes. We used this approach to analyze expression profiles of 544 single or double deletion mutants of transcription factors, chromatin remodeling machinery components, protein kinases and phosphatases in S. cerevisiae. The Bayesian network inferred by this method identified causal regulatory relationships and non-causal concurrent interactions among these regulators in different cellular processes, strongly supported by the experimental evidence and generated many testable hypotheses. Compared to networks reconstructed by routine similarity measures or by alternative Bayesian network algorithms, the network inferred by DM_BN excels in both precision and recall. To facilitate its application in other systems, we packaged the algorithm into a user-friendly analysis tool that can be downloaded at http://www.picb.ac.cn/hanlab/DM_BN.html.
doi:10.1371/journal.pgen.1003757
PMCID: PMC3764135  PMID: 24039601
14.  Increased CD70 expression is associated with clinical resistance to cisplatin-based chemotherapy and poor survival in advanced ovarian carcinomas 
OncoTargets and therapy  2013;6:615-619.
Background
CD70 has been regarded as a novel potential therapeutic target for multiple cancers. In this study, we characterized the expression of the CD70 protein in ovarian carcinomas and assessed its clinical-pathological prognostic value.
Materials and methods
The expression of CD70 in advanced ovarian cancer specimens was assessed by immunohistochemistry. Our results indicated that 16 out of 92 (17.4%) advanced ovarian serous carcinoma tumors showed a high level of CD70 expression. Furthermore, CD70 overexpression was significantly associated with cisplatin-based chemotherapy responses. The high CD70 expression subgroup demonstrated a higher incidence of chemotherapy resistance than the low CD70 subgroup (68.8% versus 25.0%, P = 0.001). Furthermore, univariate analysis conducted on subsets of ovarian carcinoma indicated that high CD70 expression was also associated with decreased survival rates; retained significance was observed on multivariate analysis.
Conclusion
Given the elevated expression of CD70 and its relationship with drug resistance and poor prognosis, our findings suggest that a minor proportion of ovarian carcinomas with CD70 overexpression might be a candidate for the emerging anti-CD70 antibody drug conjugates or therapeutic anti-CD70 antibodies.
doi:10.2147/OTT.S44445
PMCID: PMC3681401  PMID: 23776334
ovarian carcinoma; CD70; immunohistochemistry; survival; chemotherapy resistance
15.  Pyrvinium targets autophagy addiction to promote cancer cell death 
Cell Death & Disease  2013;4(5):e614-.
Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that the inhibition of autophagy is mammalian target of rapamycin independent but depends on the transcriptional inhibition of autophagy genes. Moreover, the combination of pyrvinium with autophagy stimuli improves its toxicity against cancer cells, and pretreatment of cells with 3-MA or siBeclin1 partially protects cells from pyrvinium-induced cell death under glucose starvation, suggesting that targeted autophagy addiction is involved in pyrvinium-mediated cytotoxicity. Finally, in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-𝒟-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone. This study supports a novel cancer therapeutic strategy based on targeting autophagy addiction and implicates using pyrvinium as an autophagy inhibitor in combination with chemotherapeutic agents to improve their therapeutic efficacy.
doi:10.1038/cddis.2013.142
PMCID: PMC3674351  PMID: 23640456
pyrvinium pamoate; autophagy addiction; apoptosis; 2-deoxy-𝒟-glucose
16.  Sodium Laurate, a Novel Protease- and Mass Spectrometry-Compatible Detergent for Mass Spectrometry-Based Membrane Proteomics 
PLoS ONE  2013;8(3):e59779.
The hydrophobic nature of most membrane proteins severely complicates their extraction, proteolysis and identification. Although detergents can be used to enhance the solubility of the membrane proteins, it is often difficult for a detergent not only to have a strong ability to extract membrane proteins, but also to be compatible with the subsequent proteolysis and mass spectrometric analysis. In this study, we made evaluation on a novel application of sodium laurate (SL) to the shotgun analysis of membrane proteomes. SL was found not only to lyse the membranes and solubilize membrane proteins as efficiently as SDS, but also to be well compatible with trypsin and chymotrypsin. Furthermore, SL could be efficiently removed by phase transfer method from samples after acidification, thus ensuring not to interfere with the subsequent CapLC-MS/MS analysis of the proteolytic peptides of proteins. When SL was applied to assist the digestion and identification of a standard protein mixture containing bacteriorhodoposin and the proteins in rat liver plasma membrane-enriched fractions, it was found that, compared with other two representative enzyme- and MS-compatible detergents RapiGest SF (RGS) and sodium deoxycholate (SDC), SL exhibited obvious superiority in the identification of membrane proteins particularly those with high hydrophobicity and/or multiple transmembrane domains.
doi:10.1371/journal.pone.0059779
PMCID: PMC3610932  PMID: 23555778
17.  The Translin-TRAX complex/C3PO is a ribonuclease in tRNA processing 
Summary
The conserved Translin-TRAX complexes, also known as C3PO, have been implicated in many biological processes, but how they function remains unclear. Recently, C3PO was shown to be an endoribonuclease that promotes RNA interference in animal cells. Here we show that C3PO does not play a significant role in RNAi in the filamentous fungus Neurospora crassa. Instead, the Neurospora C3PO functions as a ribonuclease that removes the 5′ pre-tRNA fragments after the processing of pre-tRNAs by RNase P. In addition, the translin and trax mutants have elevated levels of tRNA and protein translation and are more resistant to a cell-death inducing agent. Finally, we showed that C3PO is also involved in tRNA processing in mouse embryonic fibroblast cells. Together, this study identified the endogenous RNA substrates of C3PO and provides a potential explanation for its roles in seemingly diverse biological processes.
doi:10.1038/nsmb.2337
PMCID: PMC3414638  PMID: 22773104
18.  Successful treatment of refractory cutaneous infection caused by Mycobacterium marinum with a combined regimen containing amikacin 
Background:
The incidence of Mycobacterium marinum infection has been increasing. First-line antituberculous drugs and other common antibiotics are effective for most cutaneous M. marinum infections; however, treatment failure still occurs in some rare cases. We report a case of a 70-year-old man with refractory cutaneous infection caused by M. marinum. Reasons for delayed diagnosis and related factors of the refractory infection are also discussed.
Methods:
Samples of lesional skin were inoculated on Löwenstein–Jensen medium for acid-fast bacilli. Species of mycobacterium were identified by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis. We then carried out genotyping by using mycobacterial interspersed repetitive units and sequencing of heat shock protein 65 (hsp65) and 16S rDNA genes.
Results:
Tissue cultures for acid-fast bacilli were positive. PCR-RFLP analysis and sequencing of hsp65 and 16S rDNA genes confirmed the isolated organisms to be M. marinum. Systemic therapy with rifampicin, clarithromycin, and amikacin empirically over 6 months led to complete resolution of skin lesions leaving only some residual scars.
Conclusion:
Key diagnostic elements for M. marinum infections include a high index of suspicion raised by chronic lesions, poor response to conventional treatments, and a history of fish-related exposure. Strong clinical suggestion of M. marinum infection warrants initial empirical treatment. The duration of therapy is usually several months or even longer, especially for elderly patients. Amikacin can be considered in multidrug therapy for treatment of some refractory M. marinum infections.
doi:10.2147/CIA.S36371
PMCID: PMC3514062  PMID: 23226012
amikacin; clarithromycin; skin infection; Mycobacterium marinum; nontuberculous mycobacteria
19.  Automatic Annotation of Radiological Observations in Liver CT Images 
We aim to predict radiological observations using computationally-derived imaging features extracted from computed tomography (CT) images. We created a dataset of 79 CT images containing liver lesions identified and annotated by a radiologist using a controlled vocabulary of 76 semantic terms. Computationally-derived features were extracted describing intensity, texture, shape, and edge sharpness. Traditional logistic regression was compared to L1-regularized logistic regression (LASSO) in order to predict the radiological observations using computational features. The approach was evaluated by leave one out cross-validation. Informative radiological observations such as lesion enhancement, hypervascular attenuation, and homogeneous retention were predicted well by computational features. By exploiting relationships between computational and semantic features, this approach could lead to more accurate and efficient radiology reporting.
PMCID: PMC3540508  PMID: 23304295
20.  Research Advances at the Institute for Nutritional Sciences at Shanghai, China12 
Advances in Nutrition  2011;2(5):428-439.
Nutrition-related health issues have emerged as a major threat to public health since the rebirth of the economy in China starting in the 1980s. To meet this challenge, the Chinese Academy of Sciences established the Institute for Nutritional Sciences (INS) at Shanghai, China ∼8 y ago. The mission of the INS is to apply modern technologies and concepts in nutritional research to understand the molecular mechanism and provide means of intervention in the combat against nutrition-related diseases, including type 2 diabetes, metabolic syndrome, obesity, cardiovascular diseases, and many types of cancers. Through diligent and orchestrated efforts by INS scientists, graduate students, and research staff in the past few years, the INS has become the leading institution in China in the areas of basic nutritional research and metabolic regulation. Scientists at the INS have made important progress in many areas, including the characterization of genetic and nutritional properties of the Chinese population, metabolic control associated with nutrient sensing, molecular mechanisms underlying glucose and lipid metabolism, regulation of metabolism by adipokines and inflammatory pathways, disease intervention using functional foods or extracts of Chinese herbs, and many biological studies related to carcinogenesis. The INS will continue its efforts in understanding the optimal nutritional needs for Chinese people and the molecular causes associated with metabolic diseases, thus paving the way for effective and individualized intervention in the future. This review highlights the major research endeavors undertaken by INS scientists in recent years.
doi:10.3945/an.111.000703
PMCID: PMC3183593  PMID: 22332084
21.  Multiple Classifier System for Remote Sensing Image Classification: A Review 
Sensors (Basel, Switzerland)  2012;12(4):4764-4792.
Over the last two decades, multiple classifier system (MCS) or classifier ensemble has shown great potential to improve the accuracy and reliability of remote sensing image classification. Although there are lots of literatures covering the MCS approaches, there is a lack of a comprehensive literature review which presents an overall architecture of the basic principles and trends behind the design of remote sensing classifier ensemble. Therefore, in order to give a reference point for MCS approaches, this paper attempts to explicitly review the remote sensing implementations of MCS and proposes some modified approaches. The effectiveness of existing and improved algorithms are analyzed and evaluated by multi-source remotely sensed images, including high spatial resolution image (QuickBird), hyperspectral image (OMISII) and multi-spectral image (Landsat ETM+). Experimental results demonstrate that MCS can effectively improve the accuracy and stability of remote sensing image classification, and diversity measures play an active role for the combination of multiple classifiers. Furthermore, this survey provides a roadmap to guide future research, algorithm enhancement and facilitate knowledge accumulation of MCS in remote sensing community.
doi:10.3390/s120404764
PMCID: PMC3355439  PMID: 22666057
multiple classifier system; classifier ensemble; remote sensing; classification
22.  MicroRNA-134 as a potential plasma biomarker for the diagnosis of acute pulmonary embolism 
Background
Acute pulmonary embolism (APE) remains a diagnostic challenge due to a variable clinical presentation and the lack of a reliable screening tool. MicroRNAs (miRNAs) regulate gene expression in a wide range of pathophysiologic processes. Circulating miRNAs are emerging biomarkers in heart failure, type 2 diabetes and other disease states; however, using plasma miRNAs as biomarkers for the diagnosis of APE is still unknown.
Methods
Thirty-two APE patients, 32 healthy controls, and 22 non-APE patients (reported dyspnea, chest pain, or cough) were enrolled in this study. The TaqMan miRNA microarray was used to identify dysregulated miRNAs in the plasma of APE patients. The TaqMan-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate the dysregulated miRNAs. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the miRNA identified as the candidate biomarker.
Results
Plasma miRNA-134 (miR-134) level was significantly higher in the APE patients than in the healthy controls or non-APE patients. The ROC curve showed that plasma miR-134 was a specific diagnostic predictor of APE with an area under the curve of 0.833 (95% confidence interval, 0.737 to 0.929; P < 0.001).
Conclusions
Our findings indicated that plasma miR-134 could be an important biomarker for the diagnosis of APE. Because of this finding, large-scale investigations are urgently needed to pave the way from basic research to clinical utilization.
doi:10.1186/1479-5876-9-159
PMCID: PMC3189884  PMID: 21943159
23.  Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic Gluconeogenesis 
Nature medicine  2010;16(10):1152-1156.
During fasting, mammals maintain glucose homeostasis by stimulating hepatic gluconeogenesis1. Elevations in circulating glucagon (GLU) and epinephrine trigger the cAMP mediated phosphorylation of Creb and dephosphorylation of the Creb coactivator Crtc22. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment3–6. Here we show that Creb activity during fasting is modulated by Cryptochromes (Cry1 and Cry2), core components of the clock that are rhythmically expressed in the liver. Cry was elevated during the night/day transition, when it reduced fasting gluconeogenic gene expression by blocking GLU-mediated increases in intracellular cAMP concentrations and in the PKA-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry inhibited accumulation of cAMP in response to G protein coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry appeared to modulate GPCR activity directly through interaction with Gsα . As hepatic over-expression of Cry lowered blood glucose concentrations and improved insulin sensitivity in insulin resistant db/db mice, our results suggest that compounds which enhance Cry activity may provide therapeutic benefit to individuals with type II diabetes.
doi:10.1038/nm.2214
PMCID: PMC2952072  PMID: 20852621
24.  Targeting wild-type and T315I Bcr-Abl by combining allosteric with ATP-site inhibitors 
Nature  2010;463(7280):501-506.
SUMMARY
In an effort to find new pharmacological modalities to overcome resistance to ATP-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry we demonstrate that GNF-2 binds to the myristate binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analog of GNF-2 having improved pharmacokinetic properties, when utilized in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I Bcr-Abl and displayed in vivo efficacy against the recalcitrant T315I Bcr-Abl mutant in a murine bone-marrow transplantation model. These results demonstrate that therapeutically relevant inhibition of Bcr-Abl activity can be achieved using inhibitors that bind to the myristate binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
doi:10.1038/nature08675
PMCID: PMC2901986  PMID: 20072125
25.  Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats 
Respiratory Research  2010;11(1):182.
Background
Pulmonary vascular structure remodeling (PVSR) is a hallmark of pulmonary hypertension. P27kip1, one of critical cyclin-dependent kinase inhibitors, has been shown to mediate anti-proliferation effects on various vascular cells. Beta-estradiol (β-E2) has numerous biological protective effects including attenuation of hypoxic pulmonary hypertension (HPH). In the present study, we employed β-E2 to investigate the roles of p27kip1 and its closely-related kinase (Skp-2) in the progression of PVSR and HPH.
Methods
Sprague-Dawley rats treated with or without β-E2 were challenged by intermittent chronic hypoxia exposure for 4 weeks to establish hypoxic pulmonary hypertension models, which resemble moderate severity of hypoxia-induced PH in humans. Subsequently, hemodynamic and pulmonary pathomorphology data were gathered. Additionally, pulmonary artery smooth muscle cells (PASMCs) were cultured to determine the anti-proliferation effect of β-E2 under hypoxia exposure. Western blotting or reverse transcriptional polymerase chain reaction (RT-PCR) were adopted to test p27kip1, Skp-2 and Akt-P changes in rat lung tissue and cultured PASMCs.
Results
Chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of right ventricle/left ventricle plus septum (RV/LV+S) ratio, medial width of pulmonary arterioles, accompanied with decreased expression of p27kip1 in rats. Whereas, β-E2 treatment repressed the elevation of RVSP, RV/LV+S, attenuated the PVSR of pulmonary arterioles induced by chronic hypoxia, and stabilized the expression of p27kip1. Study also showed that β-E2 application suppressed the proliferation of PASMCs and elevated the expression of p27kip1 under hypoxia exposure. In addition, experiments both in vivo and in vitro consistently indicated an escalation of Skp-2 and phosphorylated Akt under hypoxia condition. Besides, all these changes were alleviated in the presence of β-E2.
Conclusions
Our results suggest that β-E2 can effectively attenuate PVSR and HPH. The underlying mechanism may partially be through the increased p27kip1 by inhibiting Skp-2 through Akt signal pathway. Therefore, targeting up-regulation of p27kip1 or down-regulation of Skp-2 might provide new strategies for treatment of HPH.
doi:10.1186/1465-9921-11-182
PMCID: PMC3022723  PMID: 21182801

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