| 1. |
- Zhang, Ruyang, et al.
(författare)
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Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects
- 2020
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Ingår i: Chest. - : Elsevier BV. - 0012-3692. ; 158:2, s. 808-819
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Tidskriftsartikel (refereegranskat)abstract
- Background: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions. Research Question: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis? Study Design and Methods: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated. Results: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10–17) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10–18) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC3 year, 0.88 [95% CI, 0.83-0.93]; and AUC5 year, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively. Interpretation: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.
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| 2. |
- Abraham, Roshan Mammen, et al.
(författare)
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Tau neutrinos in the next decade : from GeV to EeV
- 2022
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Ingår i: Journal of Physics G. - : Institute of Physics Publishing (IOPP). - 0954-3899 .- 1361-6471. ; 49:11
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Tidskriftsartikel (refereegranskat)abstract
- Tau neutrinos are the least studied particle in the standard model. This whitepaper discusses the current and expected upcoming status of tau neutrino physics with attention to the broad experimental and theoretical landscape spanning long-baseline, beam-dump, collider, and astrophysical experiments. This whitepaper was prepared as a part of the NuTau2021 Workshop.
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| 3. |
- Al-Saffar, Anas, 1969-, et al.
(författare)
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Parallel Changes in Harvey-Bradshaw Index, TNFα, and Intestinal Fatty Acid Binding Protein in Response to Infliximab in Crohn’s Disease
- 2017
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Ingår i: Gastroenterology Research and Practice. - Egypt : Hindawi Publishing Corporation. - 1687-6121 .- 1687-630X. ; , s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity. Aims: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNF alpha antibody (infliximab) induced lowering of TNF alpha and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNF alpha were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNF alpha was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNF alpha. Parallel infliximab effects on TNF alpha, HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.
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| 4. |
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| 5. |
- Deng, Qihong, et al.
(författare)
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Early life exposure to traffic-related air pollution and allergic rhinitis in preschool children
- 2016
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 121, s. 67-73
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence linking long-term exposure to outdoor air pollution with allergic rhinitis (AR) in children is scare, and the role of components of air pollution and timing of exposure remains unclear. Objective: To assess the association of pre- and post-natal exposure to air pollution with life-time prevalence of AR in preschool children. Methods: We conducted a cohort study of 2598 children aged 3-6 years in Changsha, China. The lifetime prevalence of AR was assessed by a questionnaire administered by parents. Children's exposures to dioxide nitrogen (NO2), sulfur dioxide (SO2) and particulate matter with an aerodynamic diameter <= 10 mu m (PM10) during different pre-and post-natal timing windows were estimated using the measured concentrations at monitoring stations. The odds ratio (OR) and 95% confidence interval (CI) of childhood AR for exposure to different air pollutants during different timing windows were assessed by logistic regression model in terms of an interquartile range (IQR) increase in exposure level. Results: Life-time prevalence of AR in preschool children (7.3%) was associated with both pre-and postnatal exposure to traffic-related air pollution (TRAP), but only significant during the third trimester of pregnancy with adjusted OR = 1.40 (95% CI: 1.08-1.82) for a 15 mu g/m(3) increase in NO2 and during the first-year of life with adjusted OR = 1.36 (95% CI: 1.03-1.78) and 1.54 (95% CI: 1.07-2.21) respectively for 11 and 12 mu g/m(3) increase in NO2 and PM10. The association of early life exposure to TRAP with childhood AR was robust by adjusting for other air pollutants and timing windows. Sensitivity analysis indicated that the association was higher in the children who are male, young, with genetic predisposition by parental atopy, and living in damp houses. Conclusion: Early life exposure to traffic-related air pollutant during pregnancy and first-year of life may contribute to childhood AR.
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| 6. |
- El-Sayed, Ramy, et al.
(författare)
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Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6 beta-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.
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| 7. |
- Guo, Yichen, et al.
(författare)
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DNA Methylation of LRRC3B : A Biomarker for Survival of Early-Stage Non-Small Cell Lung Cancer Patients
- 2018
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Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 27:12, s. 1527-1535
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies support a tumor-suppressor role for LRRC3B across various types of cancers. We aimed to investigate the association between DNA methylation of LRRC3B and overall survival (OS) for patients with early-stage non-small cell lung cancer (NSCLC).Methods: This study included 1,230 patients with early-stage NSCLC. DNA was extracted from lung tumor tissues and DNA methylation was measured using Illumina Infinium HumanMethylation450 BeadChips. The association between DNA methylation and OS was first tested using Cox regression on a discovery cohort and then validated in an independent cohort. Next, the association between DNA methylation and gene expression was investigated in two independent cohorts. Finally, the association between gene expression and OS was investigated in three independent groups of patients.Results: Three novel DNA methylation sites in LRRC3B were significantly associated with OS in two groups of patients. Patients with hypermethylation in the DNA methylation sites had significantly longer survival than the others in both the discovery cohort (HR, 0.62; P = 2.02 × 10-05) and validation cohort (HR, 0.55; P = 4.44 × 10-04). The three DNA methylation sites were significantly associated with LRRC3B expression, which was also associated with OS.Conclusions: Using clinical data from a large population, we illustrated the association between DNA methylation of LRRC3B and OS of early-stage NSCLC.Impact: We provide evidence of plausibility for building biomarkers on DNA methylation of LRRC3B for OS of early-stage NSCLC, thus filling a gap between previous in vitro studies and clinical applications. Cancer Epidemiol Biomarkers Prev; 27(12); 1-9. ©2018 AACR.
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| 8. |
- Jin, Yukun, et al.
(författare)
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Mixed Insulating State for van der Waals CoPS3
- 2022
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Ingår i: Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 13:45, s. 10486-10493
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale high-quality van der Waals CoPS3single crystals are synthesized using a chemical vapor transport (CVT) method. The crystallographic structure and electronic properties of this layered material are systematically studied using different spectroscopic methods (XPS, NEXAFS, and resonant photoelectron spectroscopy) accompanied by density functional theory (DFT) calculations. All experimental and theoretical data allow assignment of this material to the class of mixed Mott-Hubbard/charge-transfer insulator with Udd≅ Δ. All obtained results can enrich the information on the new class of van der Waals materials, transition metal phosphorus trichalcogenides, and help to further effectively exploit their electronic, optical, and transport properties, which are important for adopting this kind of materials into different application areas, such as spintronics and catalysis.
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| 9. |
- Li, Zhuona, et al.
(författare)
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Effects of polycyclic musks HHCB and AHTN on steroidogenesis in H295R cells
- 2013
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 90:3, s. 1227-1235
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Tidskriftsartikel (refereegranskat)abstract
- 1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-(γ)-2-benzopyran (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) are widely used in personal care products. Previous studies showed that HHCB and AHTN can be found in various environmental matrices and have potential endocrine disrupting effects. However, the effects on adrenocortical function of HHCB and AHTN are not fully understood. This study evaluated the influences of HHCB and AHTN on seven steroid hormones (progesterone, aldosterone, cortisol, 17α-OH-progesterone, androstenedione, 17β-estradiol, and testosterone) and 10 genes involved in steroidogenic pathways (HMGR, StAR, CYP11A1, 3βHSD2, CYP17, CYP21, CYP11B1, CYP11B2, 17βHSD, and CYP19) using the H295R cell line in the absence and presence of 8-Br-cAMP. MC2R transcription on the cell membrane was also examined to further investigate the effects of HHCB and AHTN on adrenal steroidogenesis. The results demonstrated that HHCB and AHTN could inhibit progesterone and cortisol production mainly by the suppression of 3βHSD2 and CYP21. Meanwhile, high concentrations of AHTN can affect the sensitivity of H295R cells to ACTH by disrupting MC2R transcription. Overall, the results indicate that high concentrations of HHCB and AHTN can affect steroidogenesis in vitro using the H295R cell line.
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| 10. |
- Lobov, Gleb, et al.
(författare)
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Dynamic manipulation of optical anisotropy of suspended Poly-3-hexylthiophene nanofibers
- 2016
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Ingår i: Advanced Optical Materials. - : Wiley. - 2162-7568 .- 2195-1071. ; 4:10, s. 1651-1656
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Tidskriftsartikel (refereegranskat)abstract
- Poly-3-hexylthiophene (P3HT) nanofibers are 1D crystalline semiconducting nanostructures, which are known for their application in photovoltaics. Due to the internal arrangement, P3HT nanofibers possess optical anisotropy, which can be enhanced on a macroscale if nanofibers are aligned. Alternating electric field, applied to a solution with dispersed nanofibers, causes their alignment and serves as a method to produce solid layers with ordered nanofibers. The transmission ellipsometry measurements demonstrate the dichroic absorption and birefringence of ordered nanofibers in a wide spectral range of 400–1700 nm. Moreover, the length of nanofibers has a crucial impact on their degree of alignment. Using electric birefringence technique, it is shown that external electric field applied to the solution with P3HT nanofibers can cause direct birefringence modulation. Dynamic alignment of dispersed nanofibers changes the refractive index of the solution and, therefore, the polarization of transmitted light. A reversible reorientation of nanofibers is organized by using a quadrupole configuration of poling electrodes. With further development, the described method can be used in the area of active optical fiber components, lab-on-chip or sensors. It also reveals the potential of 1D conducting polymeric structures as objects whose highly anisotropic properties can be implemented in electro-optical applications..
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| 11. |
- Lobov, Gleb, et al.
(författare)
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Optical birefringence from P3HT nanofibers in alternating electric field
- 2016
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Ingår i: Optics InfoBase Conference Papers. - : OSA - The Optical Society. - 9781943580194
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Konferensbidrag (refereegranskat)abstract
- AC poling allowing to control the orientation of P3HT nanofibers, result in strong optical birefringence with promising implementation in a novel type of optical modulator, without necessary embedding into any hosting matrix, e.g. liquid crystal.
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| 12. |
- Lobov, Gleb S., et al.
(författare)
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Electric field induced optical anisotropy of P3HT nanofibers in a liquid solution
- 2015
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Ingår i: Optical Materials Express. - : Optical Society of America. - 2159-3930 .- 2159-3930. ; 5:11, s. 2642-2647
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Tidskriftsartikel (refereegranskat)abstract
- The nanofiber morphology of regioregular Poly-3- hexylthiophene (P3HT) is a 1D crystalline structure organized by π - π stacking of the backbone chains. In this study, we report the impact of electric field on the orientation and optical properties of P3HT nanofibers dispersed in liquid solution. We demonstrate that alternating electric field aligns nanofibers, whereas static electric field forces them to migrate towards the cathode. The alignment of nanofibers introduces anisotropic optical properties, which can be dynamically manipulated until the solvent has evaporated. Time resolved spectroscopic measurements revealed that the electro-optical response time decreases significantly with the magnitude of applied electric field. Thus, for electric field 1.3 V ·μm-1 the response time was measured as low as 20 ms, while for 0.65 V ·μm-1 it was 110-150 ms. Observed phenomenon is the first mention of P3HT supramolecules associated with electrooptical effect. Proposed method provides real time control over the orientation of nanofibers, which is a starting point for a novel practical implementation. With further development P3HT nanofibers can be used individually as an anisotropic solution or as an active component in a guest-host system.
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| 13. |
- Lobov, Gleb S., et al.
(författare)
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Electro-optical response of P3HT nanofibers in liquid solution
- 2015
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Ingår i: Asia Communications and Photonics Conference, ACPC 2015. - Washington, D.C. : OSA. - 9781943580064
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Konferensbidrag (refereegranskat)abstract
- AC electric poling introduces in P3HT nanofibers anisotropic electro-optical response and birefringence. Along with birefringence, such material exhibits strong amplitude modulation which makes it more efficient alternative to liquid crystals.
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| 14. |
- Lobov, Gleb S., et al.
(författare)
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Electro-optical response of P3HT nanofibers in liquid solution
- 2015
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Ingår i: Asia Communications and Photonics Conference 2015. - : Optical Society of America. - 9781943580064
-
Konferensbidrag (refereegranskat)abstract
- AC electric poling introduces in P3HT nanofibers anisotropic electro-optical response and birefringence. Along with birefringence, such material exhibits strong amplitude modulation which makes it more efficient alternative to liquid crystals.
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| 15. |
- Lobov, Gleb S., et al.
(författare)
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Size Impact of Ordered P3HT Nanofibers on Optical Anisotropy
- 2016
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Ingår i: Macromolecular Chemistry and Physics. - : John Wiley & Sons. - 1022-1352 .- 1521-3935. ; 217:9, s. 1089-1095
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Tidskriftsartikel (refereegranskat)abstract
- Poly-3-hexylthiophene (P3HT) nanofibers are 1D crystalline structures with semiconductor properties. When P3HT nanofi bers are dispersed in nonconducting solvent, they react to external alternate electric field by aligning along the field lines. This can be used to create layers of ordered nanofi bers and is referred to as alternating current poling method. P3HT nanofi bers with three different size distributions are fabricated, using self-assembly mechanism in marginal solvents, and used for the alignment studies. Anisotropic absorption of oriented 2 mu m long nanofi bers exponentially increases with the magnitude of applied field to a certain asymptotic limit at 0.8 V mu m(-1), while 100-500 nm long nanofi bers respond to electric field negligibly. Effective optical birefringence of oriented 2 mu m long nanofi bers is calculated, based on the phase shift at 633 nm and the average layer thickness, to be 0.41. These results combined with further studies on real-time control over orientation of P3HT nanofi bers in liquid solution or host system are promising in terms of exploiting them in electroabsorptive and electrorefractive applications.
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| 16. |
- Ning, Rui, et al.
(författare)
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Assessing progression limits in different grades of keratoconus from a novel perspective : precision of measurements of the corneal epithelium
- 2024
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Ingår i: Eye and Vision. - 2326-0254. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess repeatability and reproducibility of corneal epithelium thickness (ET) measured by a spectral-domain optical coherence tomographer (SD-OCT)/Placido topographer (MS-39, CSO, Florence, Italy) in keratoconus (KC) population at different stages, as well as to determine the progression limits for evaluating KC progression. Methods: A total of 149 eyes were enrolled in this study, with 29 eyes in the forme fruste keratoconus (FFKC) group, 34 eyes in the mild KC group, 40 eyes in the moderate KC group, and 46 eyes in the severe KC group. Employing the within-subject standard deviation (Sw), test-retest variability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC) to evaluate intraoperator repeatability and interoperator reproducibility. Results: The repeatability and reproducibility of MS-39 in patients with KC were acceptable, according to ICC values ranging from 0.732 to 0.954. However, patients with more severe KC and progressive peripheralization of the measurement points had higher TRTs but a thinning trend. The current study tended to set the cut-off values of mild KC, moderate KC, and severe KC to 4.9 µm, 5.2 µm, and 7.4 µm for thinnest epithelium thickness (TET). When differences between follow-ups are higher than those values, progression of the disease is possible. As for center epithelium thickness (CET), cut-off values for mild KC, moderate KC, and severe KC should be 2.8 µm, 4.4 µm, and 5.3 µm. This might be useful in the follow-up and diagnosis of keratoconus. Conclusions: This study demonstrated that the precision of MS-39 was reduced in measuring more severe KC patients and more peripheral corneal points. In determining disease progression, values should be differentiated between disease-related real changes and measurement inaccuracies. Due to the large difference in ET measured by MS-39 between various stages of disease progression, it is necessary to accurately grade KC patients to avoid errors in KC clinical decision-making.
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| 17. |
- Shen, Sipeng, et al.
(författare)
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A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer
- 2018
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:6, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51-2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.
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| 18. |
- Sugunan, Abhilash, et al.
(författare)
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Synthesis of tetrahedral quasi-type-II CdSe-CdS core-shell quantum dots
- 2011
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Ingår i: Nanotechnology. - : IOP Publishing. - 0957-4484 .- 1361-6528. ; 22:42, s. 425202-
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Tidskriftsartikel (refereegranskat)abstract
- Synthesis of colloidal nanocrystals of II-VI semiconductor materials has been refined in recent decades and their size dependent optoelectronic properties have been well established. Here we report a facile synthesis of CdSe-CdS core-shell heterostructures using a two-step hot injection process. Red-shifts in absorption and photoluminescence spectra show that the obtained quantum dots have quasi-type-II alignment of energy levels. The obtained nanocrystals have a heterostructure with a large and highly faceted tetrahedral CdS shell grown epitaxially over a spherical CdSe core. The obtained morphology as well as high resolution electron microscopy confirms that the tetrahedral shell have a zinc blende crystal structure. A phenomenological mechanism for the growth and morphology of the nanocrystals is discussed.
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| 19. |
- Tang, Yong, et al.
(författare)
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Combustion of aluminum nanoparticle agglomerates : From mild oxidation to microexplosion
- 2017
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Ingår i: Proceedings of the Combustion Institute. - : Elsevier BV. - 1540-7489. ; , s. 2325-2332
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Tidskriftsartikel (refereegranskat)abstract
- While the nano-sized energetic materials are featured with ultra-high energy density, the ubiquitous agglomeration in their combustion is still unexplored. In this paper, the combustion characteristics of aluminum nanoparticle agglomerates in the size range of 4-20μm are investigated on a modified Hencken burner with different temperature (800-1800K) and oxygen concentration (0.5-5.5mol/m3). Due to the heat accumulation effect of the designed porous structures, the nanoparticle agglomerates even maintain the advantages of combustion process of single nanoparticle in terms of a low ignition temperature (∼800K) and a fast energy release rate. Further, the combustion of agglomerates is numerically studied by a newly-developed model, which accurately predicts both burn time and temperature of agglomerate of the mild combustion process. The microexplosion phenomenon occurs when the oxygen concentration exceeds 3.5mol/m3. Measurements of particle temperature, burn time, emission spectra and morphologies indicate that this explosion is driven by the vaporization of unreacted aluminum core, which results in huge stresses to tear the Al/Al2O3 particle into many smaller, dispersed clusters. Thus a melt/vapor dispersion mechanism (MVDM) based on melt dispersion mechanism is proposed to cover the microexplosion and subsequent accelerated oxidation reactions.
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| 20. |
- Tsioras, Konstantinos, et al.
(författare)
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Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis
- 2023
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 42:10
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.
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| 21. |
- Wei, Yongyue, et al.
(författare)
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Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC
- 2018
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: KDMlysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations inKDMgenes and their roles in lung cancer survival.Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites inKDMgenes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.Results: DNA methylation at sites cg11637544 inKDM2Aand cg26662347 inKDM1Awere in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50,P = 1.1 × 10-4;HRcg26662347 = 1.88, 95%CI, 1.37-2.60,P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 forKDM2A,P = 1.3 × 10-10; cg26662347 forKDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.Conclusions: These findings highlight the association between somatic DNA methylation inKDMgenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.
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| 22. |
- Xu, Jiawei, et al.
(författare)
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Optoelectronic memristor model for optical synaptic circuit of spiking neural networks
- 2023
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Ingår i: 21st IEEE Interregional NEWCAS Conference, NEWCAS 2023. - : Institute of Electrical and Electronics Engineers (IEEE).
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Konferensbidrag (refereegranskat)abstract
- Optoelectronic memristors are suitable candidates for hardware implementation of optical synapses in spiking neural networks (SNNs), thanks to their electrical and optical characteristics. To study the feasibility of memristor-based optical synapses in SNNs, a behavior model for optoelectronic memristors is proposed in this paper, including electrical programming modeling and photocurrent read modeling. Based on the model, the behavior of a molecular ferroelectric (MF)/semiconductor interfacial memristor is simulated. This paper also proposes an optical synaptic circuit for trace-based spike-timing-dependent plasticity (STDP) learning rule. The electrical characteristics of the memristor are explored and exploited to emulate the trace in the pairwise nearest-neighbor STDP, while the optical characteristics are utilized for non-destructive readout and weight calculation. Synaptic-level simulation results show a 99.96% correlation coefficient (CC) and a 1.91% relative root mean square error (RRMSE) in the weight approximate computation. Extending the simulation to the network level, the optoelectronic memristor-based unsupervised STDP learning system can achieve a 92.07± 0.64% accuracy on the MNIST benchmark.
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| 23. |
- 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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| 24. |
- 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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| 25. |
- Zhong, Jia, et al.
(författare)
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B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:13, s. 3503-3508
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Tidskriftsartikel (refereegranskat)abstract
- Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m(3)) under placebo, and PM2.5 (250 μg/m(3)) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4(+) T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.
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