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2.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine if less telomere content was associated with treatment-related second malignant neoplasms (SMNs) in childhood cancer survivors.
Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at time of sample collection, years of follow up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content (TC) as a continuous variable to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
There was an inverse relationship between TC and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single copy gene ratio (95% CI, 0.09–1.02, p=0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR 0.04, 95% CI, 0.00–0.55, p=0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
3.  When drug discovery meets web search: Learning to Rank for ligand-based virtual screening 
The rapid increase in the emergence of novel chemical substances presents a substantial demands for more sophisticated computational methodologies for drug discovery. In this study, the idea of Learning to Rank in web search was presented in drug virtual screening, which has the following unique capabilities of 1). Applicable of identifying compounds on novel targets when there is not enough training data available for these targets, and 2). Integration of heterogeneous data when compound affinities are measured in different platforms.
A standard pipeline was designed to carry out Learning to Rank in virtual screening. Six Learning to Rank algorithms were investigated based on two public datasets collected from Binding Database and the newly-published Community Structure-Activity Resource benchmark dataset. The results have demonstrated that Learning to rank is an efficient computational strategy for drug virtual screening, particularly due to its novel use in cross-target virtual screening and heterogeneous data integration.
To the best of our knowledge, we have introduced here the first application of Learning to Rank in virtual screening. The experiment workflow and algorithm assessment designed in this study will provide a standard protocol for other similar studies. All the datasets as well as the implementations of Learning to Rank algorithms are available at
Graphical AbstractThe analogy between web search and ligand-based drug discovery
PMCID: PMC4333300
Learning to Rank; Virtual screening; Drug discovery; Data integration
4.  Outbreak-Associated Novel Avipoxvirus in Domestic Mallard Ducks, China 
Emerging Infectious Diseases  2015;21(2):372-373.
PMCID: PMC4313631  PMID: 25625217
Avipoxvirus; duck; outbreak; China; viruses; mallard
5.  Efficacy, Pharmacokinetics, and Biodistribution of Thermosensitive Chitosan/β-Glycerophosphate Hydrogel Loaded with Docetaxel 
AAPS PharmSciTech  2014;15(2):417-424.
Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/β-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.
PMCID: PMC3969486  PMID: 24442774
antitumor efficacy; biodistribution; chitosan/β-glycerophosphate; docetaxel; pharmacokinetics
6.  Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies 
Journal of Virology  2014;88(14):7796-7805.
The recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naïve-antibody library (containing ∼1011 antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 μg/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses.
IMPORTANCE A novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV.
PMCID: PMC4097770  PMID: 24789777
7.  Molecular Variation and Horizontal Gene Transfer of the Homocysteine Methyltransferase Gene mmuM and its Distribution in Clinical Pathogens 
The homocysteine methyltransferase encoded by mmuM is widely distributed among microbial organisms. It is the key enzyme that catalyzes the last step in methionine biosynthesis and plays an important role in the metabolism process. It also enables the microbial organisms to tolerate high concentrations of selenium in the environment. In this research, 533 mmuM gene sequences covering 70 genera of the bacteria were selected from GenBank database. The distribution frequency of mmuM is different in the investigated genera of bacteria. The mapping results of 160 mmuM reference sequences showed that the mmuM genes were found in 7 species of pathogen genomes sequenced in this work. The polymerase chain reaction products of one mmuM genotype (NC_013951 as the reference) were sequenced and the sequencing results confirmed the mapping results. Furthermore, 144 representative sequences were chosen for phylogenetic analysis and some mmuM genes from totally different genera (such as the genes between Escherichia and Klebsiella and between Enterobacter and Kosakonia) shared closer phylogenetic relationship than those from the same genus. Comparative genomic analysis of the mmuM encoding regions on plasmids and bacterial chromosomes showed that pKF3-140 and pIP1206 plasmids shared a 21 kb homology region and a 4.9 kb fragment in this region was in fact originated from the Escherichia coli chromosome. These results further suggested that mmuM gene did go through the gene horizontal transfer among different species or genera of bacteria. High-throughput sequencing combined with comparative genomics analysis would explore distribution and dissemination of the mmuM gene among bacteria and its evolution at a molecular level.
PMCID: PMC4278250  PMID: 25552925
comparative genomics; homocysteine methyltransferase gene; horizontal gene transfer; molecular variation
8.  RNA-seq data analysis at the gene and CDS levels provides a comprehensive view of transcriptome responses induced by 4-hydroxynonenal 
Molecular bioSystems  2013;9(12):10.1039/c3mb70114j.
Reactive electrophiles produced during oxidative stress, such as 4-hydroxynonenal (HNE), are increasingly recognized as contributing factors in a variety of degenerative and inflammatory diseases. Here we used the RNA-seq technology to characterize transcriptome responses in RKO cells induced by HNE at subcytotoxic and cytotoxic doses. RNA-seq analysis rediscovered most of the differentially expressed genes reported by microarray studies and also identified novel gene responses. Interestingly, differential expression detection at the coding DNA sequence (CDS) level helped to further improve the consistency between the two technologies, suggesting the utility and importance of the CDS level analysis. RNA-seq data analysis combining gene and CDS levels yielded an informative and comprehensive picture of gradually evolving response networks with increasing HNE doses, from cell protection against oxidative injury at low dose, initiation of cell apoptosis and DNA damage at middle dose and significant deregulation of cellular functions at high dose. These evolving dose-dependent pathway changes, which cannot be observed by the gene level analysis alone, clearly reveal the HNE cytotoxic effect and are supported by IC50 experiments. Additionally, differential expression at the CDS level provides new insights of isoform regulation mechanisms. Taken together, our data demonstrate the power of RNA-Seq to identify subtle transcriptome changes and to characterize effects induced by HNE through the generation of high-resolution data coupled with differential analysis at both gene and CDS levels.
PMCID: PMC3864034  PMID: 24056865
9.  ‘Cool and quiet’ therapy for malignant hyperthermia following severe traumatic brain injury: A preliminary clinical approach 
Malignant hyperthermia increases mortality and disability in patients with brain trauma. A clinical treatment for malignant hyperthermia following severe traumatic brain injury, termed ‘cool and quiet’ therapy by the authors of the current study, was investigated. Between June 2003 and June 2013, 110 consecutive patients with malignant hyperthermia following severe traumatic brain injury were treated using mild hypothermia (35–36°C) associated with small doses of sedative and muscle relaxant. Physiological parameters and intracranial pressure were monitored, and the patients slowly rewarmed following the maintenance of mild hypothermia for 3–12 days. Consecutive patients who had undergone normothermia therapy were retrospectively analyzed as the control. In the mild hypothermia group, the recovery rate was 54.5%, the mortality rate was 22.7%, and the severe and mild disability rates were 11.8 and 10.9%, respectively. The mortality rate of the patients, particularly that of patients with a Glasgow Coma Scale (GCS) score of between 3 and 5 differed significantly between the hypothermia group and the normothermia group (P<0.05). The mortality of patients with a GCS score of between 6 and 8 was not significantly different between the two groups (P> 0.05). The therapy using mild hypothermia with a combination of sedative and muscle relaxant was beneficial in decreasing the mortality of patients with malignant hyperthermia following severe traumatic brain injury, particularly in patients with a GCS score within the range 3–5 on admission. The therapy was found to be safe, effective and convenient. However, rigorous clinical trials are required to provide evidence of the effectiveness of ‘cool and quiet’ therapy for hyperthermia.
PMCID: PMC4280981  PMID: 25574217
traumatic brain injury; malignant hyperthermia; mild hypothermia; ‘cool and quiet’ therapy
10.  Analysis of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy 
World Journal of Gastroenterology : WJG  2014;20(46):17491-17497.
AIM: To explore the morbidity and risk factors of postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy.
METHODS: The data from 196 consecutive patients who underwent pancreaticoduodenectomy, performed by different surgeons, in the General Hospital of the People’s Liberation Army between January 1st, 2013 and December 31st, 2013 were retrospectively collected for analysis. The diagnoses of POPF and clinically relevant (CR)-POPF following pancreaticoduodenectomy were judged strictly by the International Study Group on Pancreatic Fistula Definition. Univariate analysis was performed to analyze the following factors: patient age, sex, body mass index (BMI), hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pancreatic duct diameter, pylorus preserving pancreaticoduodenectomy, pancreatic drainage and pancreaticojejunostomy. Multivariate logistic regression analysis was used to determine the main independent risk factors for POPF.
RESULTS: POPF occurred in 126 (64.3%) of the patients, and the incidence of CR-POPF was 32.7% (64/196). Patient characteristics of age, sex, BMI, hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pylorus preserving pancreaticoduodenectomy and pancreaticojejunostomy showed no statistical difference related to the morbidity of POPF or CR-POPF. Pancreatic duct diameter was found to be significantly correlated with POPF rates by univariate analysis and multivariate regression analysis, with a pancreatic duct diameter ≤ 3 mm being an independent risk factor for POPF (OR = 0.291; P = 0.000) and CR-POPF (OR = 0.399; P = 0.004). The CR-POPF rate was higher in patients without external pancreatic stenting, which was found to be an independent risk factor for CR-POPF (OR = 0.394; P = 0.012). Among the entire patient series, there were three postoperative deaths, giving a total mortality rate of 1.5% (3/196), and the mortality associated with pancreatic fistula was 2.4% (3/126).
CONCLUSION: A pancreatic duct diameter ≤ 3 mm is an independent risk factor for POPF. External stent drainage of pancreatic secretion may reduce CR-POPF mortality and POPF severity.
PMCID: PMC4265610  PMID: 25516663
Pancreaticoduodenectomy; Pancreatic fistula; Complication; Pancreatic duct
11.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
12.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
13.  Transcriptome-wide signatures of tumor stage in kidney renal clear cell carcinoma: connecting copy number variation, methylation and transcription factor activity 
Genome Medicine  2014;6(12):117.
Comparative analysis of expression profiles between early and late stage cancers can help to understand cancer progression and metastasis mechanisms and to predict the clinical aggressiveness of cancer. The observed stage-dependent expression changes can be explained by genetic and epigenetic alterations as well as transcription dysregulation. Unlike genetic and epigenetic alterations, however, activity changes of transcription factors, generally occurring at the post-transcriptional or post-translational level, are hard to detect and quantify.
Here we developed a statistical framework to infer the activity changes of transcription factors by simultaneously taking into account the contributions of genetic and epigenetic alterations to mRNA expression variations.
Applied to kidney renal clear cell carcinoma (KIRC), the model underscored the role of methylation as a significant contributor to stage-dependent expression alterations and identified key transcription factors as potential drivers of cancer progression.
Integrating copy number, methylation, and transcription factor activity signatures to explain stage-dependent expression alterations presented a precise and comprehensive view on the underlying mechanisms during KIRC progression.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0117-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4293006  PMID: 25648588
14.  Ad-p53 enhances the sensitivity of triple-negative breast cancer MDA-MB-468 cells to the EGFR inhibitor gefitinib 
Oncology Reports  2014;33(2):526-532.
Triple-negative breast cancer (TNBC) accounts for 20% of all molecular subtypes of breast cancer. Neither endocrine nor anti-HER2 molecular targeting treatment yield promising results. At present, epidermal growth factor receptor (EGFR) inhibitor, as a single agent, is unable to obtain encouraging results in the treatment of TNBC, even though most of these tumors overexpress EGFR. In the present study, we used recombinant human p53 adenovirus (Ad-p53) and EGFR inhibitor gefitinib to treat the TNBC cell line MDA-MB-468. The combined treatment of gefitinib and Ad-p53 synergistically inhibited the proliferation of MDA-MB-468 cells; it restrained colony formation, enhanced cellular apoptosis and arrested the cell cycle in vitro, and decreased tumor burden of xenografts in nude mice. Western blot analysis revealed that Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B (p-Akt) and upregulated caspase-9 and cleaved caspase-3, while there were minimal effects on the expression of extracellular signal-regulated kinase (ERK) and phosphorylation of ERK (p-ERK). These results suggest that Ad-p53 may block the PI3K/Akt pathway rather than the Raf/MEK/ERK pathway. Importantly, wild-type p53 was able to reverse the drug resistance of MDA-MB-468 cells to gefitinib through inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The apoptotic activity induced by this combined treatment may be regulated by caspase cascade-dependent activation.
PMCID: PMC4306269  PMID: 25501339
triple-negative breast cancer; MDA-MB-468 cells; p53; EGFR; targeted therapy; PI3K/Akt
15.  Comparative transcriptomic analyses revealed divergences of two agriculturally important aphid species 
BMC Genomics  2014;15(1):1023.
Grain aphid (Sitobion avenae F) and pea aphid (Acyrthosiphon pisum) are two agriculturally important pest species, which cause significant yield losses to crop plants each year by inflicting damage both through the direct effects of feeding and by vectoring debilitating plant viruses. Although a close phylogenetic relationship between grain aphid and pea aphid was proposed, the biological variations between these two aphid species are obvious. While the host ranges of grain aphid is restricted to cereal crops and in particular wheat, that of pea aphid is wider, mainly colonizing leguminous plant species. Until now, the genetic factors underlying the divergence between grain aphid and pea aphid still remain unclear due to the limited genomic data of grain aphid available in public databases.
Based on a set of transcriptome data of grain aphid generated by using Roche 454 GS-FLX pyrosequencing, comparative analysis between this set of transcriptome data of grain aphid and mRNA sequences of pea aphid available in the public databases was performed. Compared with mRNA sequences of pea aphid, 4,857 unigenes were found to be specifically presented in the transcriptome of grain aphid under the rearing conditions described in this study. Furthermore, 3,368 orthologous pairs which could be calculated with both nonsynonymous (Ka) and synonymous (Ks) substitutions were used to infer their sequence divergences. The average differences in the coding, 5′ and 3′ untranslated regions of these orthologs were 10.53%, 21.29% and 18.96%, respectively. Moreover, of 340 orthologs which were identified to have evolved in response to positive selection based on the rates of Ka and Ks substitutions, 186 were predicted to be involved in secondary metabolism and xenobiotic metabolisms which might contribute to the divergence of these two aphid species.
The comprehensive transcriptome divergent sequence analysis between grain aphid and pea aphid provides an invaluable resource for the investigation of genes involved in host plant adaptation and evolution. Moreover, the demonstration of divergent transcriptome sequences between grain aphid and pea aphid pave the way for the investigation of the molecular mechanisms underpinning the biological variations of these two agriculturally important aphid species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1023) contains supplementary material, which is available to authorized users.
PMCID: PMC4301665  PMID: 25424897
Grain aphid; Pea aphid; Transcriptome; Comparative transcriptomic analysis; Divergence
16.  Spatiotemporal Transmission Dynamics of Hemorrhagic Fever with Renal Syndrome in China, 2005–2012 
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures.
Data on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff's space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences.
A total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran's I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties.
This study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne viral disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem and accounts for 90% of the reported cases in the world. We examined the spatiotemporal dynamics of HFRS cases in China during 2005–2012 and compared characteristics between cases from high-risk and low-risk counties. Several distinct HFRS cluster areas were identified, concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties. These findings suggest preventative strategies for HFRS should be focused on the identified clusters in order to achieve the most cost-effective outcomes.
PMCID: PMC4239011  PMID: 25412324
17.  Impact of Roles Assignation on Heterogeneous Populations in Evolutionary Dictator Game 
Scientific Reports  2014;4:6937.
The evolution of cooperation is a hot and challenging topic in the field of evolutionary game theory. Altruistic behavior, as a particular form of cooperation, has been widely studied by the ultimatum game but not by the dictator game, which provides a more elegant way to identify the altruistic component of behaviors. In this paper, the evolutionary dictator game is applied to model the real motivations of altruism. A degree-based regime is utilized to assess the impact of the assignation of roles on evolutionary outcome in populations of heterogeneous structure with two kinds of strategic updating mechanisms, which are based on Darwin's theory of evolution and punctuated equilibrium, respectively. The results show that the evolutionary outcome is affected by the role assignation and that this impact also depends on the strategic updating mechanisms, the function used to evaluate players' success, and the structure of populations.
PMCID: PMC4223679  PMID: 25377303
18.  Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma 
Scientific Reports  2014;4:6855.
The insulin-like growth factor type 1 receptor (IGF-1R) plays an essential role in the development of numerous cancers. Figitumumab (CP) is not only a monocloncal antibody, it also has agonist activity on IGF-1R. The antitumor activity of CP in esophageal squamous cell carcinoma (ESCC) is still unclear. In our study, we identified IGF-1R as an independent prognostic factor in ESCC patients, and investigated the antitumor effects of CP in ESCC cell lines. CP suppressed tumor growth and sensitized cells to chemotherapeutic drugs. In addition, CP inhibited cell proliferation, migration, colony forming activity and anti-apoptosis induced by IGF-1. Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R. Inhibition of ERK1/2 enhanced the antitumor activity of CP. Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation. Thus, we demonstrated antitumor activities of CP on ESCC, and as a biased agonist, CP induced ERK1/2 activation and receptor down-regulation required β-arrestin1 and GRKs, suggesting a promising role for targeting IGF-1R in ESCC.
PMCID: PMC4215295  PMID: 25358597
19.  Evaluation of Preoperative Hematologic Markers as Prognostic Factors and Establishment of Novel Risk Stratification in Resected pN0 Non-Small-Cell Lung Cancer 
PLoS ONE  2014;9(10):e111494.
The aims of this study were to investigate whether the preoperative hematologic markers, the neutrophil-lymphocyte ratio (NLR) or the platelet-lymphocyte ratio (PLR) were prognostic indicators and to develop a novel risk stratification model in pN0 non-small-cell lung cancer (NSCLC).
We performed a retrospective analysis of 400 consecutive pN0 NSCLC patients. Prognostic values were evaluated by Cox proportional hazard model analyses and patients were stratified according to relative risks for patients’ survival.
During the follow-up, 117 patients had cancer recurrence, and 86 patients died. In univariate analysis, age, gender, smoke status and tumor size as well as WBC, NEU, LYM, PLR and NLR were significantly associated with patients’ prognosis. In multivariate analysis, age, tumor size and NLR were independent predictors for patients’ overall survival (P = 0.024, 0.001, and 0.002 respectively). PLR didn’t associated with patients’ survival in multivariate analysis. Patients were stratified into 3 risk groups and the differences among the groups were significant according to disease free survival and overall survival (P = 0.000 and 0.000 respectively).
We confirmed that NLR other than PLR was an independent prognostic factor. Combination of NLR, age and tumor size could stratify pN0 NSCLC patients into 3 risk groups and enabled us to develop a novel risk stratification model.
PMCID: PMC4216075  PMID: 25360716
20.  The Evolutionary History and Spatiotemporal Dynamics of the Fever, Thrombocytopenia and Leukocytopenia Syndrome Virus (FTLSV) in China 
In 2007, a novel bunyavirus was found in Henan Province, China and named fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV); since then, FTLSV has been found in ticks and animals in many Chinese provinces. Human-to-human transmission has been documented, indicating that FTLSV should be considered a potential public health threat. Determining the historical spread of FTLSV could help curtail its spread and prevent future movement of this virus.
Method/Principal Findings
To examine the pattern of FTLSV evolution and the origin of outbreak strains, as well to examine the rate of evolution, the genome of 12 FTLSV strains were sequenced and a phylogenetic and Bayesian phylogeographic analysis of all available FTLSV sequences in China were performed. Analysis based on the FTLSV L segment suggests that the virus likely originated somewhere in Huaiyangshan circa 1790 (95% highest probability density interval: 1756–1817) and began spreading around 1806 (95% highest probability density interval: 1773–1834). Analysis also indicates that when FTLSV arrived in Jiangsu province from Huaiyangshan, Jiangsu Province became another source for the spread of the disease. Bayesian factor test analysis identified three major transmission routes: Huaiyangshan to Jiangsu, Jiangsu to Liaoning, and Jiangsu to Shandong. The speed of FTLSV movement has increased in recent decades, likely facilitated by modern human activity and ecosystem changes. In addition, evidence of RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force in the evolution of this virus.
Results presented in the manuscript suggest that the Huaiyangshan area is likely be the origin of FTLSV in China and identified probable viral migration routes. These results provide new insights into the origin and spread of FTLSV in China, and provide a foundation for future virological surveillance and control.
Author Summary
FTLSV is novel bunyavirus belonging to genus Phlebovirus and was first found in Huaiyangshan area. The epidemiology and pathogenesis of FTLSV remain poorly understood. This lack of information underscores the importance of analyzing the movement and genetic history of FTLSV in China. Recent advances in Bayesian coalescent phylogenetic analyses have resulted in more sophisticated methods being available for determining the relative age of emerging pathogens. In this study, a phylogenetic and Bayesian phylogeographic analysis was performed for FTLSV whole genomic sequences isolated from China. Results identified the Huaiyangshan area as the most probable origin of FTLSV and suggested migrating routes of the virus. These results offer the first description of the movement and history of FTLSV in China. RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force driving the evolution of this virus. The results of this study could be used to facilitate the development of new strategies for controlling FTLSV.
PMCID: PMC4199521  PMID: 25329580
21.  GroupRank: Rank Candidate Genes in PPI Network by Differentially Expressed Gene Groups 
PLoS ONE  2014;9(10):e110406.
Many cell activities are organized as a network, and genes are clustered into co-expressed groups if they have the same or closely related biological function or they are co-regulated. In this study, based on an assumption that a strong candidate disease gene is more likely close to gene groups in which all members coordinately differentially express than individual genes with differential expression, we developed a novel disease gene prioritization method GroupRank by integrating gene co-expression and differential expression information generated from microarray data as well as PPI network. A candidate gene is ranked high using GroupRank if it is differentially expressed in disease and control or is close to differentially co-expressed groups in PPI network. We tested our method on data sets of lung, kidney, leukemia and breast cancer. The results revealed GroupRank could efficiently prioritize disease genes with significantly improved AUC value in comparison to the previous method with no consideration of co-exprssed gene groups in PPI network. Moreover, the functional analyses of the major contributing gene group in gene prioritization of kidney cancer verified that our algorithm GroupRank not only ranks disease genes efficiently but also could help us identify and understand possible mechanisms in important physiological and pathological processes of disease.
PMCID: PMC4199715  PMID: 25330105
22.  miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the Oxidative Stress pathway 
Molecular Cancer  2014;13(1):234.
Chemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer.
From the detailed studies of a multi-chemosensitive (5637) versus a chemoresistant (H-bc) bladder cancer cell lines, we showed that miR-193a-3p [GenBank: NR_029710.1] promotes the multi-chemoresistance of bladder cancer cells. We further demonstrated that lysyl oxidase-like 4 (LOXL4) gene [GenBank: NM_032211.6] is a direct target of miR-193a-3p and executes the former’s impact on bladder cancer chemoresistance. The Oxidative Stress pathway activity is drastically affected by a forced reversal of miR-193a-3p or LOXL4 levels in cell and may act at the downstream of LOXL4 gene to relay the miR-193a-3p’s impact on the multi-chemoresistance in both cultured cells and the tumor xenografts in nude mice.
In addition to a new mechanistic insight, our results provide a set of the essential genes in this newly identified miR-193a-3p/LOXL4/Oxidative Stress axis as the diagnostic targets for a guided anti-bladder cancer chemotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-4598-13-234) contains supplementary material, which is available to authorized users.
PMCID: PMC4200202  PMID: 25311867
LOXL4; miR-193a-3p; Chemoresistance; Bladder cancer; Oxidative stress pathway
23.  Prognostic Significance of Systemic Inflammation-Based Lymphocyte- Monocyte Ratio in Patients with Lung Cancer: Based on a Large Cohort Study 
PLoS ONE  2014;9(10):e108062.
Increasing evidence indicates cancer-related inflammatory biomarkers show great promise for predicting the outcome of cancer patients. The lymphocyte- monocyte ratio (LMR) was demonstrated to be independent prognostic factor mainly in hematologic tumor. The aim of the present study was to investigate the prognostic value of LMR in operable lung cancer. We retrospectively enrolled a large cohort of patients with primary lung cancer who underwent complete resection at our institution from 2006 to 2011. Inflammatory biomarkers including lymphocyte count and monocyte count were collected from routinely performed preoperative blood tests and the LMR was calculated. Survival analyses were calculated for overall survival (OS) and disease-free survival (DFS). A total of 1453 patients were enrolled in the study. The LMR was significantly associated with OS and DFS in multivariate analyses of the whole cohort (HR = 1.522, 95% CI: 1.275–1.816 for OS, and HR = 1.338, 95% CI: 1.152–1.556 for DFS). Univariate subgroup analyses disclosed that the prognostic value was limited to patients with non-small-cell lung cancer (NSCLC) (HR: 1.824, 95% CI: 1.520–2.190), in contrast to patients with small cell lung cancer (HR: 1.718, 95% CI: 0.946–3.122). Multivariate analyses demonstrated that LMR was still an independent prognostic factor in NSCLC. LMR can be considered as a useful independent prognostic marker in patients with NSCLC after complete resection. This will provide a reliable and convenient biomarker to stratify high risk of death in patients with operable NSCLC.
PMCID: PMC4183469  PMID: 25275631
24.  CLIP-EZ: a computational tool for HITS-CLIP data analysis 
BMC Bioinformatics  2014;15(Suppl 10):P1.
PMCID: PMC4196020
25.  A Bayesian Framework to Identify Methylcytosines from High-Throughput Bisulfite Sequencing Data 
PLoS Computational Biology  2014;10(9):e1003853.
High-throughput bisulfite sequencing technologies have provided a comprehensive and well-fitted way to investigate DNA methylation at single-base resolution. However, there are substantial bioinformatic challenges to distinguish precisely methylcytosines from unconverted cytosines based on bisulfite sequencing data. The challenges arise, at least in part, from cell heterozygosis caused by multicellular sequencing and the still limited number of statistical methods that are available for methylcytosine calling based on bisulfite sequencing data. Here, we present an algorithm, termed Bycom, a new Bayesian model that can perform methylcytosine calling with high accuracy. Bycom considers cell heterozygosis along with sequencing errors and bisulfite conversion efficiency to improve calling accuracy. Bycom performance was compared with the performance of Lister, the method most widely used to identify methylcytosines from bisulfite sequencing data. The results showed that the performance of Bycom was better than that of Lister for data with high methylation levels. Bycom also showed higher sensitivity and specificity for low methylation level samples (<1%) than Lister. A validation experiment based on reduced representation bisulfite sequencing data suggested that Bycom had a false positive rate of about 4% while maintaining an accuracy of close to 94%. This study demonstrated that Bycom had a low false calling rate at any methylation level and accurate methylcytosine calling at high methylation levels. Bycom will contribute significantly to studies aimed at recalibrating the methylation level of genomic regions based on the presence of methylcytosines.
Author Summary
High-throughput bisulfite sequencing (BS-seq) has advanced tremendously the study of DNA methylation and the determination of methylcytosines at single-base resolution. In BS-seq data analysis, sequencing errors, incomplete bisulfite conversion, and cell heterozygosis affect the accuracy of methylcytosine detection in quite a major way. Simple filtering methods using predefined thresholds have proved to have extremely low efficiency. The commonly used Lister uses binomial distribution to overcome the impacts of non-conversion rate and sequencing errors, but the impact of the cell heterozygosis is not considered. Here, we present Bycom, a novel algorithm based on the Bayesian inference model. To improve the accuracy of methylcytosine calling, Bycom considers sequencing errors, non-conversion rate, and cell heterozygosis integratively to identify methylcytosines from BS-seq data. We evaluated the performance of Bycom using different kinds of BS-seq data. Our results demonstrated that Bycom identified methylcytosines more accurately than Lister, especially in BS-seq data with extremely low genome-wide methylation levels.
PMCID: PMC4177668  PMID: 25255082

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