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1.  Ratio of C-Reactive Protein/Albumin is An Inflammatory Prognostic Score for Predicting Overall Survival of Patients with Small-cell Lung Cancer 
Scientific Reports  2015;5:10481.
Recent studies have indicated that the C-reactive protein/ albumin (CRP/Alb) ratio is associated with clinical outcomes in patients with hepatocellular carcinoma (HCC). We examined the prognostic value of this ratio in patients with small-cell lung cancer (SCLC). In this retrospective study, a total of 367 eligible SCLC patients were analyzed and the correlation between the pretreatment CRP/Alb ratio and overall survival (OS) was investigated. The optimal cutoff level of CRP/Alb ratio was at 0.441. A low and high CRP/Alb ratio was assigned to 65.1% and 34.9% of patients, respectively. The median OS of patients with a high CRP/Alb ratio was worse than those in the low group (13.70 vs 18.90 months HR, 1.34; p = 0.005). Disease stage (p < 0.001), performance status (PS) (p < 0.001) and pretreatment LDH (p < 0.001) were also significant predictors of OS. Multivariate analyses showed that the CRP/Alb ratio is an independent prognostic factor (p = 0.025). This study demonstrated that the CRP/Alb ratio could independently predict OS in patients with SCLC, and had comparable prognostic value to other known prognostic markers. Therefore, the CRP/Alb ratio could have prognostic value and be a measurable biomarker in patients with SCLC.
doi:10.1038/srep10481
PMCID: PMC4471724  PMID: 26084991
2.  Occupational Hearing Loss among Chinese Municipal Solid Waste Landfill Workers: A Cross-Sectional Study 
PLoS ONE  2015;10(6):e0128719.
Background
Occupational hearing loss is an increasingly prevalent occupational condition worldwide, and has been reported to occur in a wide range of workplaces; however, its prevalence among workers from municipal solid waste landfills (MSWLs) remains less clear. This study aimed to investigate the occupational hearing loss among Chinese MSWL workers.
Methods
A cross-sectional study of 247 workers from 4 Chinese MSWLs was conducted. Noise and total volatile organic compounds (TVOCs) levels at worksites were determined. We conducted hearing examinations to determine hearing thresholds. A worker was identified as having hearing loss if the mean threshold at 2000, 3000 and 4000 Hz in either ear was equal to or greater than 25 dB. Prevalence of occupational hearing loss was then evaluated. Using unconditional Logistic regression models, we estimated the odds ratios (ORs) of MSWL work associated with hearing loss.
Results
According to the job title for each worker, the study subjects were divided into 3 groups, including group 1 of 63 workers without MSWL occupational hazards exposure (control group), group 2 of 84 workers with a few or short-period MSWL occupational hazards exposure, and group 3 of 100 workers with continuous MSWL occupational hazards exposure. Both noise and TVOCs levels were significantly higher at worksites for group 3. Significantly poorer hearing thresholds at frequencies of 2000, 3000 and 4000 Hz were found in group 3, compared with that in group 1 and group 2. The overall prevalence rate of hearing loss was 23. 5%, with the highest in group 3 (36.0%). The OR of MSWL work associated with hearing loss was 3.39 (95% confidence interval [CI]: 1.28-8.96).
Conclusion
The results of this study suggest significantly higher prevalence of hearing loss among MSWL workers. Further studies are needed to explore possible exposure-response relationship between MSWL occupational hazards exposure and hearing loss.
doi:10.1371/journal.pone.0128719
PMCID: PMC4455999  PMID: 26042421
3.  Effects of Climate Change on Plant Population Growth Rate and Community Composition Change 
PLoS ONE  2015;10(6):e0126228.
The impacts of climate change on forest community composition are still not well known. Although directional trends in climate change and community composition change were reported in recent years, further quantitative analyses are urgently needed. Previous studies focused on measuring population growth rates in a single time period, neglecting the development of the populations. Here we aimed to compose a method for calculating the community composition change, and to testify the impacts of climate change on community composition change within a relatively short period (several decades) based on long-term monitoring data from two plots—Dinghushan Biosphere Reserve, China (DBR) and Barro Colorado Island, Panama (BCI)—that are located in tropical and subtropical regions. We proposed a relatively more concise index, Slnλ, which refers to an overall population growth rate based on the dominant species in a community. The results indicated that the population growth rate of a majority of populations has decreased over the past few decades. This decrease was mainly caused by population development. The increasing temperature had a positive effect on population growth rates and community change rates. Our results promote understanding and explaining variations in population growth rates and community composition rates, and are helpful to predict population dynamics and population responses to climate change.
doi:10.1371/journal.pone.0126228
PMCID: PMC4454569  PMID: 26039073
4.  The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0127306.
Background
The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients.
Methods
We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients.
Results
Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02).
Conclusions
This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy.
doi:10.1371/journal.pone.0127306
PMCID: PMC4452723  PMID: 26034985
5.  A Novel Peptide-Binding Motifs Inference Approach to Understand Deoxynivalenol Molecular Toxicity 
Toxins  2015;7(6):1989-2005.
Deoxynivalenol (DON) is a type B trichothecene mycotoxin that is commonly detected in cereals and grains world-wide. The low-tolerated levels of this mycotoxin, especially in mono-gastric animals, reflect its bio-potency. The toxicity of DON is conventionally attributed to its ability to inhibit ribosomal protein biosynthesis, but recent advances in molecular tools have elucidated novel mechanisms that further explain DON’s toxicological profile, complementing the diverse symptoms associated with its exposure. This article summarizes the recent findings related to novel mechanisms of DON toxicity as well as how structural modifications to DON alter its potency. In addition, it explores feasible ways of expanding our understating of DON-cellular targets and their roles in DON toxicity, clearance, and detoxification through the utilization of computational biology approaches.
doi:10.3390/toxins7061989
PMCID: PMC4488686  PMID: 26043274
deoxynivalenol; toxicity; modification; enzyme; computational biology
6.  Clinical analysis of 50 Eastern Asian patients with primary pulmonary large-cell neuroendocrine carcinoma 
OncoTargets and therapy  2015;8:1219-1227.
Background
To understand the clinicopathological features of patients with primary pulmonary large-cell neuroendocrine carcinoma (LCNEC), including the frequency of epidermal growth factor receptor (EGFR) mutation, and to explore prognostic factors.
Methods
We investigated a cohort of 50 individuals from our center database who were diagnosed with operable pulmonary LCNEC and treated in Sun Yat-sen University Cancer Center. Serum albumin (ALB) and neuron-specific enolase (NSE) were also collected. Survival curves were obtained with the Kaplan–Meier method, and the differences between groups in survival were tested by the log-rank test.
Results
The median age was 59 years (range, 40–80 years). Fourteen patients underwent mutational analysis of EGFR; of these, 12 had wild-type EGFR and the remaining two had EGFR mutations in exons. The median disease-free survival (DFS) of pulmonary LCNEC was 49.3 months and that of overall survival (OS) was not reached. DFS and OS were shorter for patients with decreased serum ALB than for patients with normal serum ALB (P=0.003 and P=0.004, respectively). Meanwhile, a high level of NSE was also significantly associated with short DFS and OS (P=0.005 and P=0.000, respectively). Multivariate analysis showed that decrease in serum ALB was an independent prognostic factor for OS (P=0.046).
Conclusion
The frequency of EGFR mutation in LCNEC patients is low. Serum ALB and NSE levels are valuable prognostic factors for LCNEC patients.
doi:10.2147/OTT.S83347
PMCID: PMC4454215  PMID: 26060407
pulmonary large cell neuroendocrine carcinoma; ALB; NSE; EGFR; prognosis
7.  Genome Assemblies of Three Soil-Associated Devosia species: D. insulae, D. limi, and D. soli 
Genome Announcements  2015;3(3):e00514-15.
Agricultural soils constitute highly diverse ecosystems with very rich bacterial populations. Recent studies employing next-generation sequencing techniques have begun to explore the dynamics of bacterial species of such soils and utilized metagenomics approaches to understand how the diversity in soil microorganisms is affected or modified by agricultural practices. Understanding any microorganism’s environmental adaptability in the genomic era starts by fully appreciating their encoding genome. Here, we report the draft genome sequences of three Devosia species based on three type strains that originated from soil samples: D. insulae strain DS-56, D. limi strain DSM17137, and D. soli strain GH2-10.
doi:10.1128/genomeA.00514-15
PMCID: PMC4440970  PMID: 25999556
8.  Effect of the Interplay between Trauma Severity and Trait Neuroticism on Posttraumatic Stress Disorder Symptoms among Adolescents Exposed to a Pipeline Explosion 
PLoS ONE  2015;10(3):e0120493.
Background
While numerous studies have explored relevant factors of posttraumatic stress disorder (PTSD) symptoms, there have been few joint investigations of trauma severity and trait neuroticism on the development of PTSD symptoms. This study aims to assess the involvement and interrelationship of trauma severity and neuroticism in the expression of PTSD symptoms among adolescents exposed to an accidental explosion.
Methods
Six hundred and sixty-two adolescents were recruited from a junior middle school closest to the 2013 pipeline explosion site in China and were assessed using the Explosion Exposure Questionnaire, the NEO Five Factor Inventory-Neuroticism Subscale (FFI-N), and the PTSD Checklist-Civilian (PCL-C). A battery of hierarchical multiple regression analyses and two-way ANOVAs were performed to examine the effect of trauma severity and trait neuroticism on adolescent PTSD symptoms.
Results
Eighty-seven adolescents (13.1%) showed PTSD symptoms after the pipeline explosion. Correlation analysis showed that all the factors of explosion exposure and trait neuroticism were positively associated with adolescent PTSD symptoms. Being male and younger was linked to lower risk for PTSD symptoms. The regression models identified explosion exposure and neuroticism as independent risk factors for PTSD symptoms, and the interactions between trait neuroticism and trauma exposure (personal casualty, degree of influence, total traumatic severity) were related to PTSD symptoms.
Conclusions
The results highlight the role of trauma exposure and trait neuroticism as risk factors for PTSD symptoms. Therefore, the combination of these two factors should be investigated in clinical settings due to an augmented risk for more severe PTSD symptoms.
doi:10.1371/journal.pone.0120493
PMCID: PMC4368575  PMID: 25793606
9.  Biodiversity of Jinggangshan Mountain: The Importance of Topography and Geographical Location in Supporting Higher Biodiversity 
PLoS ONE  2015;10(3):e0120208.
Diversity is mainly determined by climate and environment. In addition, topography is a complex factor, and the relationship between topography and biodiversity is still poorly understood. To understand the role of topography, i.e., altitude and slope, in biodiversity, we selected Jinggangshan Mountain (JGM), an area with unique topography, as the study area. We surveyed plant and animal species richness of JGM and compared the biodiversity and the main geographic characteristics of JGM with the adjacent 4 mountains. Gleason’s richness index was calculated to assess the diversity of species. In total, 2958 spermatophyte species, 418 bryophyte species, 355 pteridophyte species and 493 species of vertebrate animals were recorded in this survey. In general, the JGM biodiversity was higher than that of the adjacent mountains. Regarding topographic characteristics, 77% of JGM’s area was in the mid-altitude region and approximately 40% of JGM’s area was in the 10°–20° slope range, which may support more vegetation types in JGM area and make it a biodiversity hotspot. It should be noted that although the impact of topography on biodiversity was substantial, climate is still a more general factor driving the formation and maintenance of higher biodiversity. Topographic conditions can create microclimates, and both climatic and topographic conditions contribute to the formation of high biodiversity in JGM.
doi:10.1371/journal.pone.0120208
PMCID: PMC4357464  PMID: 25763820
10.  The Lipid-lowering Effects of R-bambuterol in Healthy Chinese Volunteers: A Randomized Phase I Clinical Study 
EBioMedicine  2015;2(4):356-364.
Background
Existing treatments are inadequate for patients at high risk of coronary heart disease caused by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C). Bambuterol is a prodrug of β2-agonist commonly used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) with the advantage of once daily dosing and favorable side effect profile. The potential lipid-lowering effects of bambuterol were unclear, possibly due to the racemic bambuterol (rac-bambuterol) that was used in previous studies.
Methods
The lipid-lowering effects of R-bambuterol were examined in a randomized phase I trial in 48 healthy Chinese volunteers aged 18–45 years. Participants were randomly assigned to five groups to receive a single dose (2.5 mg, 5 mg or 10 mg) or multiple doses (5 mg) of oral medications of R-bambuterol, or a single dose of rac-bambuterol (10 mg). Plasma lipid levels were measured at baseline, time to peak concentration (Tmax) and 24 h after the treatment.
Findings
Administration of a single-dose of R-bambuterol resulted in dose-dependent reductions in the levels of plasma LDL-C, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) at Tmax. Levels of LDL-C exhibited the most reductions, which were statistically significant in all three single-dose R-bambuterol groups (all P values < 0.05). R-bambuterol was more potent in LDL-C lowering compared to rac-bambuterol at Tmax (P = 0.08). At 24 h after dosing, the significant lipid lowering effects of R-bambuterol sustained for LDL-C (P = 0.01), ApoB (P = 0.001) and ApoA1 (P = 0.03), but not for HDL-C. The ratio of ApoA1/ApoB was marginally increased (P = 0.06). In the multiple-dose group, LDL-C levels again were significantly reduced (all P values < 0.05), whereas the ratios of ApoA1/ApoB were marginally increased.
Interpretation
R-bambuterol can lower the plasma levels of LDL-C, and marginally raise the ratio of ApoA1/ApoB (indicator of HDL-C/LDL-C) with both a single dose and multiple doses. R-bambuterol was more potent in LDL-C lowering than rac-bambuterol.
Highlights
•Oral administration of R-bambuterol, a long-acting bronchodilator, can significantly lower LDL cholesterol in healthy Chinese volunteers.•R-bambuterol was more potent than rac-bambuterol in lowering LDL-C and raising the ratio of ApoA1/ApoB.•It may provide an alternative for treating high cholesterol, especially for those also suffering from COPD.
doi:10.1016/j.ebiom.2015.02.006
PMCID: PMC4485901  PMID: 26137575
β2-Agonist; R-bambuterol; Cholesterol; LDL-C
11.  Tanshinone IIA Inhibits HIF-1α and VEGF Expression in Breast Cancer Cells via mTOR/p70S6K/RPS6/4E-BP1 Signaling Pathway 
PLoS ONE  2015;10(2):e0117440.
Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.
doi:10.1371/journal.pone.0117440
PMCID: PMC4320086  PMID: 25659153
12.  Human olfactory receptor responses to odorants 
Scientific Data  2015;2:150002.
Although the human olfactory system is capable of discriminating a vast number of odors, we do not currently understand what chemical features are encoded by olfactory receptors. In large part this is due to a paucity of data in a search space covering the interactions of hundreds of receptors with billions of odorous molecules. Of the approximately 400 intact human odorant receptors, only 10% have a published ligand. Here we used a heterologous luciferase assay to screen 73 odorants against a clone library of 511 human olfactory receptors. This dataset will allow other researchers to interrogate the combinatorial nature of olfactory coding.
doi:10.1038/sdata.2015.2
PMCID: PMC4412152  PMID: 25977809
13.  Anti-tumor effect and mechanism of cyclooxygenase-2 inhibitor through matrix metalloproteinase 14 pathway in PANC-1 cells 
Objective: To investigate whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can attenuate proliferation, migration, invasion and MMP-14 expression in pancreatic cancer cells PANC-1 and the possible anti-tumor mechanism of celecoxib. Methods: Human pancreatic cancer cell line PANC-1 cells were treated with diverse concentrations of celecoxib (20, 60, 100 μmol/L). Cell proliferation, invasion and migration capabilities were measured by MTT colorimetry, transwell invasion assay, and scratch assay separately. At the same time, the protein expression of COX-2 and MMP-14 was assessed by ELISA. Results: The capabilities of proliferation, invasion and migration in PANC-1 cells were attenuated in a concentration-dependent manner after treated with celecoxib, followed by the down-regulation of the protein expression of COX-2 and MMP-14. In addition, MMP-14 expression was significantly positively correlated with COX-2 expression. Conclusions: COX-2 inhibitor celecoxib can inhibit the proliferation, invasion and migration of PANC-1 cells via down-regulating the expression of MMP-14 in a concentration-dependent manner, thus contributing to its anti-tumor effect in pancreatic cancer.
PMCID: PMC4396316  PMID: 25973062
Pancreatic cancer; celecoxib; matrix metalloproteinase-14; cyclooxygenase-2
14.  The Effectiveness of RECIST on Survival in Patients with NSCLC Receiving Chemotherapy with or without Target Agents as First-Line Treatment 
Scientific Reports  2015;5:7683.
We analyzed the correlation between survival and antitumor effect evaluated by RECIST in advanced NSCLC patients with chemotherapy plus target therapy or not as first-line treatment, to examine the applicability of RECIST in this population. The patients were screened from 4 clinical trials (12621, 12006, FASTACT-I, and FASTACT-II), and those who received chemotherapy plus target therapy or chemotherapy alone were eligible. Among the 59 enrolled patients, 29 received combination therapy, while the other 30 received chemotherapy only. In the combination therapy group, patients with PR or SD had longer overall survival (OS) than those with PD (P < 0.001 and P = 0.002, respectively). However, in the chemotherapy alone group, compared with PD patients, either PR or SD group had no significant overall survival benefit (P = 0.690 and P = 0.528, respectively). In summary, for advanced NSCLC patients receiving chemotherapy plus target therapy as first-line treatment and evaluated by RECIST criteria, SD has the same overall survival benefit as PR, suggesting that antitumor effective evaluation by RECIST criteria cannot be translated to overall survival benefit especially for this kind of patients. Therefore, developing a more comprehensive evaluation method to perfect RECIST criteria is thus warranted for patients received target therapy in NSCLC.
doi:10.1038/srep07683
PMCID: PMC4286759  PMID: 25567662
15.  Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome 
Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS) is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair.
doi:10.3390/ijms16010966
PMCID: PMC4307285  PMID: 25569081
myelodysplastic syndrome; hematopoietic stem cells; DNA damage response/repair; aging
16.  Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis 
Oncotarget  2014;6(3):1834-1849.
Cofilin is a member of the actin-depolymerizing factor (ADF) family protein, which plays an essential role in regulation of the mitochondrial apoptosis. It remains unclear how cofilin regulates the mitochondrial apoptosis. Here, we report for the first time that natural compound 4-methylthiobutyl isothiocyanate (erucin) found in consumable cruciferous vegetables induces mitochondrial fission and apoptosis in human breast cancer cells through the mitochondrial translocation of cofilin. Importantly, cofilin regulates erucin-induced mitochondrial fission by interacting with dynamin-related protein (Drp1). Knockdown of cofilin or Drp1 markedly reduced erucin-mediated mitochondrial translocation and interaction of cofilin and Drp1, mitochondrial fission, and apoptosis. Only dephosphorylated cofilin (Ser 3) and Drp1 (Ser 637) are translocated to the mitochondria. Cofilin S3E and Drp1 S637D mutants, which mimick the phosphorylated forms, suppressed mitochondrial translocation, fission, and apoptosis. Moreover, both dephosphorylation and mitochondrial translocation of cofilin and Drp1 are dependent on ROCK1 activation. In vivo findings confirmed that erucin-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model is associated with the mitochondrial translocation of cofilin and Drp1, fission and apoptosis. Our study reveals a novel role of cofilin in regulation of mitochondrial fission and suggests erucin as a potential drug for treatment of breast cancer.
PMCID: PMC4359335  PMID: 25595902
Cofilin; Drp1; mitochondrial fission; erucin; apoptosis
17.  Neural circuits containing olfactory neurons are involved in the prepulse inhibition of the startle reflex in rats 
Many neuropsychiatric disorders, such as schizophrenia, have been associated with olfactory dysfunction and abnormalities in the prepulse inhibition (PPI) response to a startle reflex. However, whether these two abnormalities could be related is unclear. The present investigations were designed to determine whether theblockage of olfactory sensory input by zinc sulfate infusion in the olfactory naris (0.5 ml, 0.17 M, ZnE) can disturb the PPI response. Furthermore, a bilateral microinjection of lidocaine/MK801 in the olfactory bulb (OB) was administered to examine whether the blockage of olfactory sensory input could impair the PPI response. To identify the neural projection between olfaction and PPI-related areas, trans-synaptic retrograde tracing with the recombinant pseudorabies virus (PRV) was used. Our results demonstrated that blockage of olfactory sensory input could disturb olfactory behavior. In the function studies, we demonstrated that blockage of olfactory sensory input could impair the pre-pulse inhibition of the startle response following decreased c-Fos expression in relevant brain regions during the PPI responses. Furthermore, similar and more robust findings indicated that blockage of olfactory sensory input by microinjection of lidocaine/MK801 in the OB could impair the PPI response. In the circuit-level studies, we demonstrated that trans-synaptic retrograde tracing with PRV exhibited a large portion of labeled neurons in several regions of the olfactory cortices from the pedunculopontine tegmental nucleus (PPTg). Thus, these data suggest that the olfactory system participates in the PPI regulating fields and plays a role in the pre-pulse inhibition of the startle response in rats.
doi:10.3389/fnbeh.2015.00074
PMCID: PMC4373374  PMID: 25859195
olfactory dysfunction; sensory stimulus; prepulse inhibition (PPI); NMDA receptor; neural trace
18.  A Large-scale Cross-sectional Study of ALK Rearrangements and EGFR Mutations in Non-small-cell Lung Cancer in Chinese Han Population 
Scientific Reports  2014;4:7268.
The predictive power of age at diagnosis and smoking history for ALK rearrangements and EGFR mutations in non-small-cell lung cancer (NSCLC) remains not fully understood. In this cross-sectional study, 1160 NSCLC patients were prospectively enrolled and genotyped for EML4-ALK rearrangements and EGFR mutations. Multivariate logistic regression analysis was performed to explore the association between clinicopathological features and these two genetic aberrations. Receiver operating characteristic (ROC) curves methodology was applied to evaluate the predictive value. We showed that younger age at diagnosis was the only independent variable associated with EML4-ALK rearrangements (odds ratio (OR) per 5 years' increment, 0.68; p < 0.001), while lower tobacco exposure (OR per 5 pack-years' increment, 0.88; p < 0.001), adenocarcinoma (OR, 6.61; p < 0.001), and moderate to high differentiation (OR, 2.05; p < 0.001) were independently associated with EGFR mutations. Age at diagnosis was a very strong predictor of ALK rearrangements but poorly predicted EGFR mutations, while smoking pack-years may predict the presence of EGFR mutations and ALK rearrangements but with rather limited power. These findings should assist clinicians in assessing the likelihood of EML4-ALK rearrangements and EGFR mutations and understanding their biological implications in NSCLC.
doi:10.1038/srep07268
PMCID: PMC4248273  PMID: 25434695
19.  EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy 
Oncotarget  2014;5(23):12189-12202.
PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-κB pathways. Besides, IFN-γ was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.
PMCID: PMC4322961  PMID: 25361008
Nasopharyngeal carcinoma (NPC); latent membrane protein 1 (LMP1); PD-L1; Epstein–Barr virus (EBV)
20.  Risk of treatment-related deaths with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis of 41 randomized controlled trials 
OncoTargets and therapy  2014;7:1851-1867.
Background
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have widely been used in advanced cancer. However, these drugs may also lead to serious adverse events. The present meta-analysis aimed to determine the overall incidence and risk of deaths due to VEGFR-TKIs with more detailed subgroup analysis.
Materials and methods
PubMed, Web of Science, and Cochrane databases were searched for randomized controlled trials (RCTs) that compared VEGFR-TKIs with non-VEGFR-TKIs in the treatment of solid cancer. Pooled incidence, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included trials.
Results
A total of 14,139 participants from 41 RCTs were enrolled. The pooled incidence of death due to VEGFR-TKIs was 1.9% (95% CI: 1.6%–2.3%) with an OR of 1.85 (95% CI: 1.33–2.58; P<0.01) when compared with control groups. On subgroup analysis, significantly increased risk of death was found in patients with nonsmall-cell lung cancer (OR: 2.37; 95% CI: 1.19–4.73; P=0.01) and colorectal cancer (OR: 2.84; 95% CI: 1.02–7.96; P=0.05). Among different VEGFR-TKIs, sorafenib and sunitinib had significant risk of death when compared with control arms, respectively. VEGFR-TKIs in combination with other antineoplastic agents, but not VEGFR-TKI monotherapy, significantly increased the risk of treatment-related deaths. No heterogeneity was noted across all the prespecified subgroups regarding ORs.
Conclusion
The present work pointed out a significantly increased risk of death due to VEGFR-TKIs. Close monitoring should be emphasized in patients receiving these drugs.
doi:10.2147/OTT.S68386
PMCID: PMC4199796  PMID: 25336977
cancer; tyrosine kinase inhibitors; treatment-related death; meta-analysis
21.  Draft Genome Sequences of Devosia sp. Strain 17-2-E-8 and Devosia riboflavina Strain IFO13584 
Genome Announcements  2014;2(5):e00994-14.
Here we report the draft genome of Devosia sp. strain 17-2-E-8, isolated from Ontario agricultural soil (Canada) with promising deoxynivalenol biotransformation capabilities. In addition, we report the draft genome of Devosia riboflavina strain IFO13584, used as a control strain in our studies aimed at highlighting unique gene clusters involved in deoxynivalenol epimerization.
doi:10.1128/genomeA.00994-14
PMCID: PMC4183881  PMID: 25278537
22.  Arctigenin enhances swimming endurance of sedentary rats partially by regulation of antioxidant pathways 
Acta Pharmacologica Sinica  2014;35(10):1274-1284.
Aim:
Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan found in traditional Chinese herbs, has been determined to exhibit a variety of pharmacological activities, including anti-tumor, anti-inflammation, neuroprotection, and endurance enhancement. In the present study, we investigated the antioxidation and anti-fatigue effects of arctigenin in rats.
Methods:
Rat L6 skeletal muscle cell line was exposed to H2O2 (700 μmol/L), and ROS level was assayed using DCFH-DA as a probe. Male SD rats were injected with arctigenin (15 mg·kg−1·d−1, ip) for 6 weeks, and then the weight-loaded forced swimming test (WFST) was performed to evaluate their endurance. The levels of antioxidant-related genes in L6 cells and the skeletal muscles of rats were analyzed using real-time RT-PCR and Western blotting.
Results:
Incubation of L6 cells with arctigenin (1, 5, 20 μmol/L) dose-dependently decreased the H2O2-induced ROS production. WFST results demonstrated that chronic administration of arctigenin significantly enhanced the endurance of rats. Furthermore, molecular biology studies on L6 cells and skeletal muscles of the rats showed that arctigenin effectively increased the expression of the antioxidant-related genes, including superoxide dismutase (SOD), glutathione reductase (Gsr), glutathione peroxidase (GPX1), thioredoxin (Txn) and uncoupling protein 2 (UCP2), through regulation of two potential antioxidant pathways: AMPK/PGC-1α/PPARα in mitochondria and AMPK/p53/Nrf2 in the cell nucleus.
Conclusion:
Arctigenin efficiently enhances rat swimming endurance by elevation of the antioxidant capacity of the skeletal muscles, which has thereby highlighted the potential of this natural product as an antioxidant in the treatment of fatigue and related diseases.
doi:10.1038/aps.2014.70
PMCID: PMC4186987  PMID: 25152028
arctigenin; skeletal muscle; weight-loaded forced swimming test; fatigue; physical endurance; ROS; antioxidant; AMPK; PPARα; Nrf2
23.  Myelodysplastic Syndrome: an inability to appropriately respond to damaged DNA? 
Experimental hematology  2013;41(8):665-674.
Myelodysplastic syndrome (MDS) is considered a hematopoietic stem cell (HSC) disease, characterized by abnormal hematopoietic differentiation and a high propensity to develop acute myeloid leukemia (AML). It is mostly associated with advanced age, but also with prior anti-cancer therapy and inherited syndromes related to abnormalities in DNA repair. Recent technological advances have led to the identification of a myriad of frequently occurring genomic perturbations associated with MDS. These observations suggest that MDS and its progression to AML is a genomic instability disorder, resulting from a step-wise accumulation of genetic abnormalities. The notion is now emerging that the underlying mechanism of this disease may be a defect in one or more pathways that are involved in responding to or repairing damaged DNA. In this review, we will discuss these pathways in relationship to a large number of studies performed with MDS patient samples and MDS mouse models. Moreover, in view of our current understanding of how DNA damage response/repair pathways are affected by age in HSCs, we will also explore how this might relate to MDS development.
doi:10.1016/j.exphem.2013.04.008
PMCID: PMC3729593  PMID: 23643835
myelodysplastic syndromes; DNA damage response; hematopoietic stem cell
24.  Pharmacokinetics and Tissue Distribution Study of Chlorogenic Acid from Lonicerae Japonicae Flos Following Oral Administrations in Rats 
Chlorogenic acid (ChA) is proposed as the major bioactive compounds of Lonicerae Japonicae Flos (LJF). Forty-two Wistar rats were randomly divided into seven groups to investigate the pharmacokinetics and tissue distribution of ChA, via oral administration of LJF extract, using ibuprofen as internal standard, employing a high performance liquid chromatography in conjunction with tandem mass spectrometry. Analytes were extracted from plasma samples and tissue homogenate by liquid–liquid extraction with acetonitrile, separated on a C18 column by linear gradient elution, and detected by electrospray ionization mass spectrometry in negative selected multiple reaction monitoring mode. Our results successfully demonstrate that the method has satisfactory selectivity, linearity, extraction recovery, matrix effect, precision, accuracy, and stability. Using noncompartment model to study pharmacokinetics, profile revealed that ChA was rapidly absorbed and eliminated. Tissue study indicated that the highest level was observed in liver, followed by kidney, lung, heart, and spleen. In conclusion, this method was suitable for the study on pharmacokinetics and tissue distribution of ChA after oral administration.
doi:10.1155/2014/979414
PMCID: PMC4130225  PMID: 25140190
25.  The Missense of Smell: Functional Variability in the Human Odorant Receptor Repertoire 
Nature neuroscience  2013;17(1):114-120.
Humans have approximately 400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals differ functionally at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high affinity in vitro agonist guaiacol, but do not explain phenotypic variation for the lower affinity agonists vanillin and ethyl vanillin.
doi:10.1038/nn.3598
PMCID: PMC3990440  PMID: 24316890

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