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1.  Simulated effect of calcification feedback on atmospheric CO2 and ocean acidification 
Scientific Reports  2016;6:20284.
Ocean uptake of anthropogenic CO2 reduces pH and saturation state of calcium carbonate materials of seawater, which could reduce the calcification rate of some marine organisms, triggering a negative feedback on the growth of atmospheric CO2. We quantify the effect of this CO2-calcification feedback by conducting a series of Earth system model simulations that incorporate different parameterization schemes describing the dependence of calcification rate on saturation state of CaCO3. In a scenario with SRES A2 CO2 emission until 2100 and zero emission afterwards, by year 3500, in the simulation without CO2-calcification feedback, model projects an accumulated ocean CO2 uptake of 1462 PgC, atmospheric CO2 of 612 ppm, and surface pH of 7.9. Inclusion of CO2-calcification feedback increases ocean CO2 uptake by 9 to 285 PgC, reduces atmospheric CO2 by 4 to 70 ppm, and mitigates the reduction in surface pH by 0.003 to 0.06, depending on the form of parameterization scheme used. It is also found that the effect of CO2-calcification feedback on ocean carbon uptake is comparable and could be much larger than the effect from CO2-induced warming. Our results highlight the potentially important role CO2-calcification feedback plays in ocean carbon cycle and projections of future atmospheric CO2 concentrations.
doi:10.1038/srep20284
PMCID: PMC4738325  PMID: 26838480
3.  STK33 promotes hepatocellular carcinoma through binding to c-Myc 
Gut  2014;65(1):124-133.
Objective
STK33 has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in hepatocellular carcinoma (HCC) and its underlying mechanisms.
Design
251 patients with HCC were analysed for association between STK33 expression and clinical stage and survival rate. Tamoxifen (TAM)-inducible, hepatocyte-specific STK33 transgenic and knockout mice models were used to study the role of STK33 in liver tumorigenesis. HCC cell lines were used to study the role of STK33 in cell proliferation in vitro and in vivo.
Results
STK33 expression was found to be frequently upregulated in patients with HCC. Significant associations were found between increased expression of STK33 and advanced HCC staging and shorter disease-free survival of patients. Overexpression of STK33 increased HCC cell proliferation both in vitro and in vivo, whereas suppression of STK33 inhibited this effect. Using a TAM-inducible, hepatocyte-specific STK33 transgenic mouse model, we found that overexpression of STK33 resulted in increased hepatocyte proliferation, leading to tumour cell burst. Using a TAM-inducible, hepatocyte-specific STK33 knockout mouse model, we found that, when subjected to the diethylnitrosamine (DEN) liver cancer bioassay, STK33KOflox/flox, Alb-ERT2-Cre mice exhibited a markedly lower incidence of tumour formation compared with control mice. The underlying mechanism may be that STK33 binds directly to c-Myc and increases its transcriptional activity. In particular, the C-terminus of STK33 blocks STK33/c-Myc association, downregulates HCC cell proliferation, and reduces DEN-induced liver tumour cell number and tumour size.
Conclusions
STK33 plays an essential role in hepatocellular proliferation and liver tumorigenesis. The C-terminus of STK33 could be a potential therapeutic target in the treatment of patients with STK33-overexpressed HCC.
doi:10.1136/gutjnl-2014-307545
PMCID: PMC4717356  PMID: 25398772
HEPATOCELLULAR CARCINOMA; CANCER; CELL BIOLOGY; HEPATOCYTE
4.  The COX-2-Selective Antagonist (NS-398) Inhibits Choroidal Neovascularization and Subretinal Fibrosis 
PLoS ONE  2016;11(1):e0146808.
Choroidal neovascularization (CNV) is an important pathologic component of neovascular age-related macular degeneration (AMD), and CNV lesions later develop into fibrous scars, which contribute to the loss of central vision. Nowadays, the precise molecular and cellular mechanisms underlying CNV and subretinal fibrosis have yet to be fully elucidated. Cyclooxygenase-2 (COX-2) has previously been implicated in angiogenesis and fibrosis. However, the role of COX-2 in the pathogenesis of CNV and subretinal fibrosis is poorly understood. The present study reveals several important findings concerning the relationship of COX-2 signaling with CNV and subretinal fibrosis. Experimental CNV lesions were attenuated by the administration of NS-398, a COX-2-selective antagonist. NS-398-induced CNV suppression was found to be mediated by the attenuation of macrophage infiltration and down-regulation of VEGF in the retinal pigment epithelium–choroid complex. Additionally, NS-398 attenuated subretinal fibrosis, in an experimental model of subretinal scarring observed in neovascular AMD, by down-regulation of TGF-β2 in the retinal pigment epithelium–choroid complex. Moreover, we cultured mouse RPE cells and found that NS-398 decreased the secretion of VEGF and TGF-β2 in mouse RPE cells. The results of the present study provide new findings regarding the molecular basis of CNV and subretinal fibrosis, and provide a proof-of-concept approach for the efficacy of COX-2 inhibition in treating subretinal fibrosis.
doi:10.1371/journal.pone.0146808
PMCID: PMC4711821  PMID: 26760305
5.  A robust association test for detecting genetic variants with heterogeneous effects 
One common strategy for detecting disease-associated genetic markers is to compare the genotype distributions between cases and controls, where cases have been diagnosed as having the disease condition. In a study of a complex disease with a heterogeneous etiology, the sampled case group most likely consists of people having different disease subtypes. If we conduct an association test by treating all cases as a single group, we maximize our chance of finding genetic risk factors with a homogeneous effect, regardless of the underlying disease etiology. However, this strategy might diminish the power for detecting risk factors whose effect size varies by disease subtype. We propose a robust statistical procedure to identify genetic risk factors that have either a uniform effect for all disease subtypes or heterogeneous effects across different subtypes, in situations where the subtypes are not predefined but can be characterized roughly by a set of clinical and/or pathologic markers. We demonstrate the advantage of the new procedure through numeric simulation studies and an application to a breast cancer study.
doi:10.1093/biostatistics/kxu036
PMCID: PMC4263227  PMID: 25057183
Breast cancer; Etiology heterogeneity; Genetic association study; Multiple-comparison adjustment; Tree-based model
7.  Activation of the Mammalian Target of Rapamycin in the Rostral Ventromedial Medulla Contributes to the Maintenance of Nerve Injury-Induced Neuropathic Pain in Rat 
Neural Plasticity  2015;2015:394820.
The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, integrates extracellular signals, thereby modulating several physiological and pathological processes, including pain. Previous studies have suggested that rapamycin (an mTOR inhibitor) can attenuate nociceptive behaviors in many pain models, most likely at the spinal cord level. However, the mechanisms of mTOR at the supraspinal level, particularly at the level of the rostral ventromedial medulla (RVM), remain unclear. Thus, the aim of this study was to elucidate the role of mTOR in the RVM, a key relay region for the descending pain control pathway, under neuropathic pain conditions. Phosphorylated mTOR was mainly expressed in serotonergic spinally projecting neurons and was significantly increased in the RVM after spared nerve injury- (SNI-) induced neuropathic pain. Moreover, in SNI rat brain slices, rapamycin infusion both decreased the amplitude instead of the frequency of spontaneous excitatory postsynaptic currents and reduced the numbers of action potentials in serotonergic neurons. Finally, intra-RVM microinjection of rapamycin effectively alleviated established mechanical allodynia but failed to affect the development of neuropathic pain. In conclusion, our data provide strong evidence for the role of mTOR in the RVM in nerve injury-induced neuropathic pain, indicating a novel mechanism of mTOR inhibitor-induced analgesia.
doi:10.1155/2015/394820
PMCID: PMC4684879  PMID: 26770837
8.  1,25-hydroxyvitamin D relieves colitis in rats via down-regulation of toll-like receptor 9 expression 
Croatian Medical Journal  2015;56(6):515-524.
Aim
To investigate the therapeutic and immunoregulatory effects of 1,25-dihydroxyvitamin D (1,25(OH)D3) on 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced colitis in rats.
Methods
Experimental colitis induced by enema administration of TNBS plus ethanol was treated with 5-aminosalicylic acid (5-ASA) and/or 1,25(OH)D3. Disease activity was measured using the disease activation index (DAI), colon macroscopic damage index (CMDI), histological colonic damage score, and myeloperoxidase (MPO) activity. The expression of toll-like receptor 9 (TLR9) in the colon was determined by reverse transcription-polymerase chain reaction and immunohistochemistry.
Results
Rats with TNBS-induced colitis had significantly elevated DAI, CMDI, histological colonic damage score, and MPO activity (all P < 0.001) compared to rats without colitis. Treatment with 5-ASA or 1,25(OH)D3 ameliorated colitis by lowering CMDI (P = 0.049, P = 0.040, respectively), histological colonic damage score (P = 0.010, P = 0.005, respectively), and MPO activity (P = 0.0003, P = 0.0013, respectively) compared with the TNBS group. Combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased MPO activity (P = 0.003). 1,25(OH)D3 attenuated colitis without causing hypercalcemia or renal insufficiency. TNBS significantly increased the number of TLR9 positive cells compared to control (P < 0.010), while 5-ASA, 1,25(OH)D3, and combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased it compared to TNBS group (all P < 0.010). In TNBS group a moderate correlation was observed between MPO activity and the number of TLR9-positive cells (r = 0.654, P < 0.001).
Conclusion
TLR9 expression correlates with the extent of inflammation in TNBS-induced colitis. 1,25(OH)D3 relieves this inflammation possibly by decreasing TLR9 expression.
doi:10.3325/cmj.2015.56.515
PMCID: PMC4707923  PMID: 26718757
9.  Game Theoretical Analysis on Cooperation Stability and Incentive Effectiveness in Community Networks 
PLoS ONE  2015;10(11):e0141755.
Community networks, the distinguishing feature of which is membership admittance, appear on P2P networks, social networks, and conventional Web networks. Joining the network costs money, time or network bandwidth, but the individuals get access to special resources owned by the community in return. The prosperity and stability of the community are determined by both the policy of admittance and the attraction of the privileges gained by joining. However, some misbehaving users can get the dedicated resources with some illicit and low-cost approaches, which introduce instability into the community, a phenomenon that will destroy the membership policy. In this paper, we analyze on the stability using game theory on such a phenomenon. We propose a game-theoretical model of stability analysis in community networks and provide conditions for a stable community. We then extend the model to analyze the effectiveness of different incentive policies, which could be used when the community cannot maintain its members in certain situations. Then we verify those models through a simulation. Finally, we discuss several ways to promote community network’s stability by adjusting the network’s properties and give some proposal on the designs of these types of networks from the points of game theory and stability.
doi:10.1371/journal.pone.0141755
PMCID: PMC4638359  PMID: 26551649
10.  Broadband and enhanced nonlinear optical response of MoS2/graphene nanocomposites for ultrafast photonics applications 
Scientific Reports  2015;5:16372.
Due to their relatively high compatibility with specific photonic structures, strong light-matter interactions and unique nonlinear optical response, two-dimensional (2D) materials, such as graphene and transition metal dichalcogenides, are attractive for ultrafast photonics applications. Here, we fabricate MoS2/graphene nanocomposites by a typical hydrothermal method. In addition, we systematically investigate their nonlinear optical responses. Our experiments indicate that the combined advantages of ultrafast relaxation, a broadband response from graphene, and the strong light-matter interaction from MoS2, can be integrated together by composition. The optical properties in terms of carrier relaxation dynamics, saturation intensity and modulation depth suggest great potential for the MoS2/graphene nanocomposites in photonics applications. We have further fabricated 2D nanocomposites based optical saturable absorbers and integrated them into a 1.5 μm Erbium-doped fiber laser to demonstrate Q-switched and mode-locked pulse generation. The fabrication of 2D nanocomposites assembled from different types of 2D materials, via this simple and scalable growth approach, paves the way for the formation and tuning of new 2D materials with desirable photonic properties and applications.
doi:10.1038/srep16372
PMCID: PMC4637866  PMID: 26549813
12.  Two Susceptibility Loci Identified for Prostate Cancer Aggressiveness 
Nature communications  2015;6:6889.
Most men diagnosed with prostate cancer will experience indolent disease; hence discovering genetic variants that distinguish aggressive from non-aggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49×10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18×10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85×10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
doi:10.1038/ncomms7889
PMCID: PMC4422072  PMID: 25939597
13.  Statistical Approach to Decreasing the Error Rate of Noninvasive Prenatal Aneuploid Detection caused by Maternal Copy Number Variation 
Scientific Reports  2015;5:16106.
Analyses of cell-free fetal DNA (cff-DNA) from maternal plasma using massively parallel sequencing enable the noninvasive detection of feto-placental chromosome aneuploidy; this technique has been widely used in clinics worldwide. Noninvasive prenatal tests (NIPT) based on cff-DNA have achieved very high accuracy; however, they suffer from maternal copy-number variations (CNV) that may cause false positives and false negatives. In this study, we developed an algorithm to exclude the effect of maternal CNV and refined the Z-score that is used to determine fetal aneuploidy. The simulation results showed that the algorithm is robust against variations of fetal concentration and maternal CNV size. We also introduced a method based on the discrepancy between feto-placental concentrations to help reduce the false-positive ratio. A total of 6615 pregnant women were enrolled in a prospective study to validate the accuracy of our method. All 106 fetuses with T21, 20 with T18, and three with T13 were tested using our method, with sensitivity of 100% and specificity of 99.97%. In the results, two cases with maternal duplications in chromosome 21, which were falsely predicted as T21 by the previous NIPT method, were correctly classified as normal by our algorithm, which demonstrated the effectiveness of our approach.
doi:10.1038/srep16106
PMCID: PMC4632076  PMID: 26534864
14.  Percutaneous Coronary Intervention after Fibrinolysis for ST-Segment Elevation Myocardial Infarction Patients: An Updated Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(11):e0141855.
Background
Percutaneous coronary intervention (PCI), fibrinolysis and the combination of both methods are current therapeutic options for patients with ST-segment elevation myocardial infarction (STEMI).
Methods
We searched PubMed, EMBASE, Google scholar and Cochrane Controlled Trials Register for randomized controlled trials (RCTs) evaluating the efficacy and safety of PCI after fibrinolysis within 24 hours, which was compared with primary PCI alone and ischemia-guided or delayed PCI. Meta-analysis was conducted using Review Manager 5.30 following the methods described by the Cochrane library.
Results
A total of 16 studies including 10,034 patients were enrolled. As compared with primary PCI alone group, the short-term mortality (5.8% vs 4.5%, RR 1.29, 95% confidence interval [CI] 1.00–1.65) and re-infarction rate (4.1% vs 2.7%, RR 1.46, 95%CI 1.05–2.03) were higher in the immediate PCI group (median/mean time ≤ 2 h after fibrinolysis). However, the short-term mortality and re-infarction rate showed no statistically significant differences in the early PCI group (2–24 hours after fibrinolysis). The rate of major bleeding events was higher both in the immediate PCI (6.3% vs 4.4%, RR 1.43, 95%CI 1.11–1.85) and the early PCI group (6.4% vs 4.4%, RR 1.46, 95%CI 1.03–2.06) as compared with primary PCI alone group. As compared with ischemia-guided or delayed PCI, early PCI was associated with significantly reduced re-infarction (2.4% vs 4.0%, RR 0.61, 95%CI 0.41–0.92) and recurrent ischemia (1.5% vs 5.3%, RR 0.29, 95%CI 0.12–0.70) at short-term. And the reduced re-infarction rate was also observed at long-term.
Conclusions
Early PCI after fibrinolysis, with a relatively broader time for PCI preparation, can bring the similar effects with primary PCI alone and is better than ischemia-guided or delayed PCI in STEMI patients with symptom onset < 12 h who cannot receive timely PCI. However, immediate PCI after fibrinolysis is detrimental.
doi:10.1371/journal.pone.0141855
PMCID: PMC4629904  PMID: 26523834
15.  Borneol Depresses P-Glycoprotein Function by a NF-κB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model 
P-glycoprotein (P-gp) on brain microvascular endothelial cells (BMECs) that form the blood brain barrier (BBB), influences transportation of substances between blood and brain. The objective of this study was to characterize the effects of borneol on P-gp efflux function on BBB and explore the potential mechanisms. We established an in vitro BBB model comprised of rat BMECs and astrocytes to measure the effects of borneol on the known P-gp substrates transport across BBB, and examined the function and expression of P-gp in BMECs and the signaling pathways regulating P-gp expression. Borneol increased intracellular accumulation of Rhodamine 123, enhanced verapamil and digoxin across the BBB in vitro model, and depressed mdr1a mRNA and P-gp expression. Borneol could activate nuclear factor-κB (NF-κB) and inhibition of NF-κB with MG132 (carbobenzoxy-Leu-Leu-leucinal) and SN50 (an inhibitory peptide) obscuring the P-gp decreases induced by borneol. These data suggested that borneol depresses P-gp function in BMECs by a NF-κB signaling medicated mechanism in a BBB in vitro model.
doi:10.3390/ijms161126051
PMCID: PMC4661909  PMID: 26593909
borneol; P-glycoprotein; brain microvascular endothelial cells; NF-κB; blood brain barrier
16.  Myeloid-derived suppressor cells inhibit T cell proliferation in human extranodal NK/T cell lymphoma: a novel prognostic indicator 
Cancer Immunology, Immunotherapy  2015;64(12):1587-1599.
The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR−CD33+CD11b+ MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14+ monocytic (Mo-MDSCs, >60 %) and CD15+ granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFβ and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFβ secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR−CD33+CD11b+ cells and CD14+ Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-015-1765-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00262-015-1765-6
PMCID: PMC4643115  PMID: 26497849
Prognosis; Immunosuppression; Hematopoietic malignancy; MDSCs; NK/T cell lymphoma
17.  Correlation of PET-CT nodal SUVmax with p16 positivity in oropharyngeal squamous cell carcinoma 
Background
The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been rising in recent years. Given the clinical impact of HPV/p16 positivity in OPSCC, identifying surrogate markers of this disease early in the diagnostic work-up of these patients could improve patient care.
Methods
Demographic, pathologic, staging and PET-CT data from patients diagnosed with OPSCC from 2009–2014 were obtained from a prospectively collected provincial cancer registry. Tumor HPV/p16 status was correlated to the maximum standard uptake value (SUVmax) of the primary tumor and cervical nodes. Comparisons of means and multinomial regression models were used to determine associations between p16 status and SUVmax. A diagnostic odds ratio was calculated using a cut off value for predicting HPV/p16 positivity based on nodal SUVmax.
Results
PET-CT and HPV/p16 data was obtained for 65 patients treated surgically for OPSCC. Significantly higher nodal SUVmax was associated with HPV/p16 positive nodes (SUVmax 10.8 vs 7.9). No significant differences were seen between HPV/p16 positive vs negative primary tumor SUVmax (10.3 vs 13.7). In combination with other clinical parameters, higher nodal SUVmax was highly correlated with HPV/p16 positivity.
Conclusion
Elevated nodal SUVmax is a significant predictor of HPV/p16 positive disease.
doi:10.1186/s40463-015-0091-5
PMCID: PMC4570692  PMID: 26374294
Oropharyngeal cancer; Positron emission tomography; Standard uptake value; p16; Human papillomavirus
18.  Optimal detection of hypothyroidism in early stage laryngeal cancer treated with radiotherapy 
Background
Hypothyroidism following radiation therapy (RT) for treatment of Head and Neck Cancer (HNC) is a common occurrence. Rates of hypothyroidism following RT for Early Stage Laryngeal Squamous Cell Carcinoma (ES-LSCC) are among the highest. Although routine screening for hypothyroidism is recommended; its optimal schedule has not yet been established. We aim to determine the prevalence and optimal timing of testing for hypothyroidism in ES-LSCC treated with RT.
Method
We conducted a population-based cohort study. Data was extracted from a prospective provincial head and neck cancer database. Demographic, survival data, and pre- and post-treatment thyroid stimulating hormone (TSH) levels were obtained for patients diagnosed with ES-LSCC from 2008–2012. Inclusion criteria consisted of patients diagnosed clinically with ES-LSCC (T1 or 2, N0, M0) treated with curative intent. Patients were excluded if there was a history of hypothyroidism before the treatment or any previous history of head and neck cancers.
Results
Ninety-five patients were included in this study. Mean age was 66.1 years (range: 44.0–88.0 years) and 82.3 % of patients were male. Glottis was the most common subsite at 77.9 % and the average follow-up was 40 months (Range: 12–56 months). Five-year overall survival generated using the Kaplan-Meier method was 79 %. Incidence of hypothyroidism after RT was found to be 46.9 %. The greatest frequency of developing hypothyroidism was at 12 months.
Conclusions
We found a high prevalence of hypothyroidism for ES-LSCC treated with RT, with the highest rate at 12 months. Consequently, we recommend possible routine screening for hypothyroidism using TSH level starting at 12 months. To our knowledge, this is the first study to suggest the optimal timing for the detection of hypothyroidism.
doi:10.1186/s40463-015-0085-3
PMCID: PMC4567796  PMID: 26362315
Hypothyroidism; Early stage laryngeal squamous cell carcinoma; Radiation therapy
19.  Duodenal gangliocytic paraganglioma: report of two cases and review of literature 
We report two cases of Gangliocytic paraganglioma (GP), one of which was accompanied by lymph node metastasis. Histologically, the tumor was composed of three morphologically distinct cell populations: spindle cells, ganglion-like cells and epithelioid cells. The epithelioid cells were positive for cytokeratin (AE1/AE3), synaptophysin (Syn), chromogranin A (CgA), CD56 and progesterone receptor (PR). Ganglion-like cell types showed positive reactivity for Syn and CD56. In contrast, the spindle-shaped cells showed positive reactivity for S-100. The patient with lymph node metastasis has a good prognosis. Nonetheless, close surveillance is still necessary for patients with GP because a few cases of GP with regional lymph node metastasis and even distant metastasis have been published, including a malignant case of GP showing a lethal course.
PMCID: PMC4637770  PMID: 26617685
Gangliocytic paraganglioma; synaptophysin; chromogranin A; CD117
20.  Exploring Dynamic Brain Functional Networks Using Continuous “State-Related” Functional MRI 
BioMed Research International  2015;2015:824710.
We applied a “temporal decomposition” method, which decomposed a single brain functional network into several “modes”; each of them dominated a short temporal period, on a continuous, “state-” related, “finger-force feedback” functional magnetic resonance imaging experiment. With the hypothesis that attention and internal/external information processing interaction could be manipulated by different (real and sham) feedback conditions, we investigated functional network dynamics of the “default mode,” “executive control,” and sensorimotor networks. They were decomposed into several modes. During real feedback, the occurrence of “default mode-executive control competition-related” mode was higher than that during sham feedback (P = 0.0003); the “default mode-visual facilitation-related” mode more frequently appeared during sham than real feedback (P = 0.0004). However, the dynamics of the sensorimotor network did not change significantly between two conditions (P > 0.05). Our results indicated that the visual-guided motor feedback involves higher cognitive functional networks rather than primary motor network. The dynamics monitoring of inner and outside environment and multisensory integration could be the mechanisms. This study is an extension of our previous region-specific and static-styled study of our brain functional architecture.
doi:10.1155/2015/824710
PMCID: PMC4564637  PMID: 26413546
21.  Anti-inflammatory effect of emodin on lipopolysaccharide-induced keratitis in Wistar rats 
Emodin, a major bioactive extract of several Chinese herbs, has been shown to have a number of biological activities including antiviral, anti-inflammatory, anti-tumor, anti-fibrosis etc. In the present study, we investigated the effects of emodin as an anti-inflammatory agent on lipopolysaccharide (LPS) induced keratitis in Wistar rats. Clinical score, slit-lamp microscope were used to determine corneal inflammatory response. Corneal structure was observed by hematoxylin-eosin staining and transmission electron microscopy. Messenger ribonucleic acid levels of tight junction protein and cytokines were determined by reverse transcription- polymerase chain reaction. The activation of nuclear factor-kappa B (NF-κB) was detected with Western blot. We found that disorganized corneal tissue and cellular structures were observed in keratitis rats and emodin could deduce inflammatory response and improve corneal structure. Pretreated with emodin could up-regulate and down-regulate the mRNA expression of occludin and Interleukin-6. The activation of NF-κB could be inhibited partly after emodin treatment. In conclusion, emodin reduced corneal inflammation in LPS-induced keratitis in Wistar rats due to its capability of inhibition in NF-κB activation.
PMCID: PMC4612833  PMID: 26550148
Chinese herb; lipopolysaccharides; nuclear factor-kappa B; inflammation
22.  Prognostic Value of Yes-Associated Protein 1 (YAP1) in Various Cancers: A Meta-Analysis 
PLoS ONE  2015;10(8):e0135119.
Background
Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which is critical for regulating organ size, cell proliferation and tumor growth in mammals. Many previous studies have explored the relationship between YAP1 and various types of cancer. However, these studies were limited by the small samples size and the findings were inconsistent among them. Therefore, a meta-analysis was conducted to assess the association between YAP1 and malignancies.
Methods
A systematic literature search was conducted for eligible studies in the PubMed, Corchane Library, Web of Knowledge, EMBASE and CBM disc databases from inception to August 1st 2014. After heterogeneity analysis, pooled harzad ratio (HR) with 95% confidence interval (95%CI) using both fixed and random effect models were estimated in STATA 10.0. Meta regression analysis, subgroup analysis and sensitivity analysis were performed to explore the potential sources of heterogeneity and to evaluate the robustness of the result. Publication bias was assessed by Egger’s test and funnel plot.
Results
A total of 21 unique articles from 2009 to 2014, comprising 2983 patients, were analyzed in the meta-analysis. The association of YAP1 expression and overall survival time (OS) was evaluated in 20 studies including 2067 patients. Positive YAP1 showed poorer OS (HR = 1.826; 95% CI = 1.465–2.275; p <0.002). For evaluating disease-free survival time (DFS), 10 studies with 1139 patients were analyzed. Positive YAP1 indicated worse DFS (HR = 2.114; 95%CI = 1.406–3.179; p <0.001). Subgroup analysis showed that both positive nuclear YAP1 (HR = 1.390, 95% CI: 0.810–2.400, p = 0.729) and up-regulation overall YAP1 (HR = 2.237, 95% CI: 1.548–3.232, p <0.001) had poorer OS for patients with malignancies. Similarly, both positive nuclear YAP1 (HR = 3.733, 95% CI: 1.469–9.483, p = 0.001) and up-regulation overall YAP1 (HR = 1.481, 95% CI: 1.163–1.886, p = 0.554) showed worse DFS. The patients with urogenital system cancer had the poorest OS (HR = 2.133, 95% CI: 1.549–2.937, p = 0.020). The patients with alimentary system cancer had the most significant impact on DFS (HR = 1.879, 95% CI: 1.537–2.297, p <0.001).
Conclusion
Both overall and nuclear YAP1 overexpression are intimately associated with adverse OS and DFS in numerous cancers, suggesting that YAP1 may act as a potential therapeutic targets of these malignancies in the future.
doi:10.1371/journal.pone.0135119
PMCID: PMC4532485  PMID: 26263504
23.  A fast and powerful tree-based association test for detecting complex joint effects in case–control studies 
Bioinformatics  2014;30(15):2171-2178.
Motivation: Multivariate tests derived from the logistic regression model are widely used to assess the joint effect of multiple predictors on a disease outcome in case–control studies. These tests become less optimal if the joint effect cannot be approximated adequately by the additive model. The tree-structure model is an attractive alternative, as it is more apt to capture non-additive effects. However, the tree model is used most commonly for prediction and seldom for hypothesis testing, mainly because of the computational burden associated with the resampling-based procedure required for estimating the significance level.
Results: We designed a fast algorithm for building the tree-structure model and proposed a robust TREe-based Association Test (TREAT) that incorporates an adaptive model selection procedure to identify the optimal tree model representing the joint effect. We applied TREAT as a multilocus association test on >20 000 genes/regions in a study of esophageal squamous cell carcinoma (ESCC) and detected a highly significant novel association between the gene CDKN2B and ESCC (). We also demonstrated, through simulation studies, the power advantage of TREAT over other commonly used tests.
Availability and implementation: The package TREAT is freely available for download at http://www.hanzhang.name/softwares/treat, implemented in C++ and R and supported on 64-bit Linux and 64-bit MS Windows.
Contact:  yuka@mail.nih.gov
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu186
PMCID: PMC4103596  PMID: 24794927
24.  Grey zone in the Barcelona Clinic Liver Cancer Classification for hepatocellular carcinoma: Surgeons’ perspective 
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. The Barcelona Clinic Liver Cancer (BCLC) classification has been endorsed as the optimal staging system and treatment algorithm for HCC by the European Association for the Study of Liver Disease and the American Association for the Study of Liver Disease. However, in real life, the majority of patients who are not considered ideal candidates based on the BCLC guideline still were performed hepatic resection nowadays, which means many hepatic surgeons all around the world do not follow the BCLC guidelines. The accuracy and application of the BCLC classification has constantly been challenged by many clinicians. From the surgeons’ perspectives, we herein put forward some comments on the BCLC classification concerning subjectivity of the assessment criteria, comprehensiveness of the staging definition and accuracy of the therapeutic recommendations. We hope to further discuss with peers and colleagues with the aim to make the BCLC classification more applicable to clinical practice in the future.
doi:10.3748/wjg.v21.i27.8256
PMCID: PMC4507095  PMID: 26217077
Hepatocellular carcinoma; Staging system; Barcelona Clinic Liver Cancer Classification; Treatment; Hepatectomy; Prognosis
25.  Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury 
Scientific Reports  2015;5:12362.
Autophagy is essentially a metabolic process, but its in vivo role in nuclear radioprotection remains unexplored. We observed that ex vivo autophagy activation reversed the proliferation inhibition, apoptosis, and DNA damage in irradiated hematopoietic cells. In vivo autophagy activation improved bone marrow cellularity following nuclear radiation exposure. In contrast, defective autophagy in the hematopoietic conditional mouse model worsened the hematopoietic injury, reactive oxygen species (ROS) accumulation and DNA damage caused by nuclear radiation exposure. Strikingly, in vivo defective autophagy caused an absence or reduction in regulatory proteins critical to both homologous recombination (HR) and non-homologous end joining (NHEJ) DNA damage repair pathways, as well as a failure to induce these proteins in response to nuclear radiation. In contrast, in vivo autophagy activation increased most of these proteins in hematopoietic cells. DNA damage assays confirmed the role of in vivo autophagy in the resolution of double-stranded DNA breaks in total bone marrow cells as well as bone marrow stem and progenitor cells upon whole body irradiation. Hence, autophagy protects the hematopoietic system against nuclear radiation injury by conferring and intensifying the HR and NHEJ DNA damage repair pathways and by removing ROS and inhibiting apoptosis.
doi:10.1038/srep12362
PMCID: PMC4508834  PMID: 26197097

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