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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Brenner, Darren R, et al.
(författare)
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Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 36:11, s. 1314-1326
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
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| 4. |
- Chen, Ying, et al.
(författare)
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Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice.
- 2015
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Ingår i: Molecular Cancer Therapeutics. - 1538-8514. ; 14:1, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and is previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. beta-catenin was determined by immunohistochemistry, PAF levels by ELISA and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared to WT mice. While all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared to WT mice, cytosol expression of beta-catenin was significantly decreased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion lack of alk-SMase markedly increases AOM/DSS induced colonic tumorigenesis associated with decreased ceramide and increased sphingosine-1-phosphate and PAF levels.
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| 5. |
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| 6. |
- Dong, Xuesi, et al.
(författare)
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Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma
- 2019
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 11:16, s. 6312-6335
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Tidskriftsartikel (refereegranskat)abstract
- Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71×10-3). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.
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| 7. |
- Lee, Dong Geon, et al.
(författare)
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Effect of Metal Electrodes on Aging-Induced Performance Recovery in Perovskite Solar Cells
- 2019
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Ingår i: ACS Applied Materials and Interfaces. - : AMER CHEMICAL SOC. - 1944-8244 .- 1944-8252. ; 11:51, s. 48497-48504
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Tidskriftsartikel (refereegranskat)abstract
- For commercialization of perovskite solar cells (PSCs), it is important to substitute the alternative electrode for Au to decrease the unit cost. From the early stage, Ag exhibits a potential to be a good counter electrode in PSCs; however, there is an abnormal s-shaped J-V curve with the Ag electrode, and it is recovered as time passes. The perception of the aging-induced recovery process and refutation of the raised stability issues are required for commercial application of Ag electrodes. Herein, we compared the aging effect of PSCs with Ag and Au electrodes and found that only devices with Ag electrodes have a dramatical aging-induced recovery process. We observed the change of photoelectronic properties only in the devices with Ag electrodes as time passes, which mainly contributes to recovery of the s-shaped J-V curve. We verified the work function change of an aged Ag electrode and its mechanism by photoelectron spectroscopy analysis. By comparing the light stability under 1 sun intensity illumination, we can assure the practical stability of Ag electrodes in case of being encapsulated. This work suggests the profound understanding of the aging-induced recovery process of PSCs and the possibility of commercial application of Ag electrodes.
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| 8. |
- Li, Zhao, et al.
(författare)
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Non-uniform seasonal warming regulates vegetation greening and atmospheric CO2 amplification over northern lands
- 2018
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- The enhanced vegetation growth by climate warming plays a pivotal role in amplifying the seasonal cycle of atmospheric CO2 at northern lands (>50° N) since 1960s. However, the correlation between vegetation growth, temperature and seasonal amplitude of atmospheric CO2 concentration have become elusive with the slowed increasing trend of vegetation growth and weakened temperature control on CO2 uptake since late 1990s. Here, based on in situ atmospheric CO2 concentration records from the Barrow observatory site, we found a slowdown in the increasing trend of the atmospheric CO2 amplitude from 1990s to mid-2000s. This phenomenon was associated with the paused decrease in the minimum CO2 concentration ([CO2]min), which was significantly correlated with the slowdown of vegetation greening and growing-season length extension. We then showed that both the vegetation greenness and growing-season length were positively correlated with spring but not autumn temperature over the northern lands. Furthermore, such asymmetric dependences of vegetation growth upon spring and autumn temperature cannot be captured by the state-of-art terrestrial biosphere models. These findings indicate that the responses of vegetation growth to spring and autumn warming are asymmetric, and highlight the need of improving autumn phenology in the models for predicting seasonal cycle of atmospheric CO2 concentration.
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| 9. |
- Liu, Yong, et al.
(författare)
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Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-kappa B activity
- 2017
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of L-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor kappa B (NF-kappa B) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-kappa B activation and less release of TNF-alpha and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
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| 10. |
- Qin, Haihong, et al.
(författare)
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A digital-controlled SiC-based solid state circuit breaker with soft switch-off method for DC power system
- 2019
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Ingår i: Electronics (Switzerland). - : MDPI AG. - 2079-9292. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Due to the lower on-state resistance, direct current (DC) solid state circuit breakers (SSCBs) based on silicon-carbide (SiC) metal-oxide-semiconductor field-effect transistors (MOSFETs) can reduce on-state losses and the investment of the cooling system when compared to breakers based on silicon (Si) MOSFETs. However, SiC MOSFETs, with smaller die area and higher current density, lead to weaker short-circuit ability, shorter short-circuit withstand time and higher protection requirements. To improve the reliability and short-circuit capability of SiC-based DC solid state circuit breakers, the short-circuit fault mechanisms of Si MOSFETs and SiC MOSFETs are revealed. Combined with the desaturation detection (DESAT), a “soft turn-off” short-circuit protection method based on source parasitic inductor is proposed. When the DESAT protection is activated, the “soft turn-off” method can protect the MOSFET against short-circuit and overcurrent. The proposed SSCB, combined with the flexibility of the DSP, has the μs-scale ultrafast response time to overcurrent detection. Finally, the effectiveness of the proposed method is validated by the experimental platform. The method can reduce the voltage stress of the power device, and it can also suppress the short-circuit current.
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| 11. |
- Wang, Min, et al.
(författare)
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Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways
- 2019
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Ingår i: Molecular Medicine Reports. - 1791-2997. ; 19:2, s. 1272-1283
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Spandidos Publications. All rights reserved. Apolipoprotein M (ApoM) is a type of apolipoprotein. It is well known that high-density lipoprotein (HDL) decreases inflammatory responses via the apoM-sphingosine-1-phosphate (S1P) pathway. The present study further investigated the importance of ApoM in the inhibitory effects of HDL on inflammation. Mice with an apoM gene deficiency (apoM-/-) were employed to investigate the effects of ApoM on the expression of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), S1P receptor-1 (S1PR1) and 3β-hydroxysterol Δ-24-reductase (DHCR24), as compared with in wild-type mice (apoM+/+). Furthermore, cell culture experiments were performed using a permanent human hybrid endothelial cell line (EA.hy926). Cells were cultured in the presence of recombinant human apoM (rec-apoM) or were induced to overexpress apoM (apoMTg); subsequently, cells were treated with tumor necrosis factor-α (TNF-α), in order to investigate the effects of ApoM on IL-1β and MCP-1. The results demonstrated that the mRNA expression levels of IL-1β and MCP-1 were significantly higher in the liver following administration of lipopolysaccharide in apoM-/- mice compared with in apoM+/+ mice. In cell culture experiments, when cells were pre-cultured with rec-apoM or were engineered to overexpress apoM (apoMTg), they exhibited decreased expression levels of IL-1β and MCP-1 following TNF-α treatment compared with in normal apoM-expressing cells (apoMTgN). Furthermore, the mRNA expression levels of IL-1β and MCP-1 were significantly elevated following addition of the S1PR1 inhibitor W146, but not by the scavenger receptor class B type I inhibitor, block lipid transport-1 (BLT-1), in apoMTg cells prior to TNF-α treatment. Conversely, there were no differences in these inflammatory biomarkers under the same conditions in apoMTgN cells. The mRNA expression levels of DHCR24 were significantly reduced by the addition of BLT-1 prior to TNF-α treatment in apoMTg cells; however, there was no difference in the expression of this inflammatory biomarker in apoMTgN cells. In conclusion, ApoM displayed inhibitory effects against the inflammatory response in vivo and in vitro; these effects may be induced via the S1PR1 and DHCR24 pathways.
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| 12. |
- Zhang, Ping, et al.
(författare)
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Deficiency of alkaline SMase enhances dextran sulfate sodium-induced colitis in mice with upregulation of autotaxin
- 2018
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Ingår i: Journal of Lipid Research. - 1539-7262. ; 59:10, s. 1841-1850
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal alkaline SMase (Alk-SMase) cleaves phosphocholine from SM, platelet-activating factor (PAF), and lysophosphatidylcholine. We recently found that colitis-associated colon cancer was 4- to 5-fold enhanced in Alk-SMase KO mice. Here, we further studied the pathogenesis of colitis induced by dextran sulfate sodium (DSS) in WT and KO mice. Compared with WT mice, KO mice demonstrated greater body weight loss, more severe bloody diarrhea, broader inflammatory cell infiltration, and more serious epithelial injury. Higher levels of PAF and lower levels of interleukin (IL)10 were identified in KO mice 2 days after DSS treatment. A greater and progressive increase of lysophosphatidic acid (LPA) was identified. The change was associated with increased autotaxin expression in both small intestine and colon, which was identified by immunohistochemistry study, Western blot, and sandwich ELISA. The upregulation of autotaxin coincided with an early increase of PAF. IL6 and TNFα were increased in both WT and KO mice. At the later stage (day 8), significant decreases in IL6, IL10, and PAF were identified, and the decreases were greater in KO mice. In conclusion, deficiency of Alk-SMase enhances DSS-induced colitis by mechanisms related to increased autotaxin expression and LPA formation. The early increase of PAF might be a trigger for such reactions.
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| 13. |
- Zhang, Ruyang, et al.
(författare)
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EGLN2 DNA methylation and expression interact with HIF1A to affect survival of early-stage NSCLC
- 2019
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 14:2, s. 118-129
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia occurs frequently in human cancers and promotes stabilization and activation of hypoxia inducible factor (HIF). HIF-1α is specific for the hypoxia response, and its degradation mediated by three enzymes EGLN1, EGLN2 and EGLN3. Although EGLNs expression has been found to be related to prognosis of many cancers, few studies examined DNA methylation in EGLNs and its relationship to prognosis of early-stage non-small cell lung cancer (NSCLC). We analyzed EGLNs DNA methylation data from tumor tissue samples of 1,230 early-stage NSCLC patients, as well as gene expression data from The Cancer Genome Atlas. The sliding windows sequential forward feature selection method and weighted random forest were used to screen out the candidate CpG probes in lung adenocarcinomas (LUAD) and lung squamous cell carcinomas patients, respectively, in both discovery and validation phases. Then Cox regression was performed to evaluate the association between DNA methylation and overall survival. Among the 34 CpG probes in EGLNs, DNA methylation at cg25923056EGLN2 was identified to be significantly associated with LUAD survival (HR = 1.02, 95% CI: 1.01–1.03, P = 9.90 × 10–5), and correlated with EGLN2 expression (r =–0.36, P = 1.52 × 10–11). Meanwhile, EGLN2 expression was negatively correlated with HIF1A expression in tumor tissues (r =–0.30, P = 4.78 × 10–8) and significantly (P = 0.037) interacted with HIF1A expression on overall survival. Therefore, DNA methylation of EGLN2- HIF1A is a potential marker for LUAD prognosis and these genes are potential treatment targets for further development of HIF-1α inhibitors in lung cancer therapy.
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| 14. |
- Zhang, Ruyang, et al.
(författare)
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SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival : an epigenomic–smoking interaction analysis
- 2019
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:5, s. 1235-1248
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Tidskriftsartikel (refereegranskat)abstract
- Smoking cessation prolongs survival and decreases mortality of patients with non-small-cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome-wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two-stage study design to identify DNA methylation–smoking cessation interactions that affect overall survival for early-stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology-stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation–smoking cessation interaction terms. Interactions with false discovery rate-q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology-specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510 SIPA 1L3 ) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR) interaction = 1.12; 95% confidence interval (CI): 1.07–1.16; P = 4.30 × 10 –7 ]. Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510 SIPA 1L3 . Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34–0.82; P = 4.61 × 10 –3 ) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86–1.70; P = 0.266) of cg02268510 SIPA 1L3 . Moreover, there was an antagonistic interaction between elevated methylation of cg02268510 SIPA 1L3 and smoking cessation (HR interaction = 2.1835; 95% CI: 1.27–3.74; P = 4.46 × 10 −3 ). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510 SIPA 1L3 . The results have implications for not only smoking cessation after diagnosis, but also possible methylation-specific drug targeting.
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| 15. |
- Zhu, Ying, et al.
(författare)
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Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942
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Tidskriftsartikel (refereegranskat)abstract
- Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
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