We evaluated the contribution of three genetic alterations (p53 knockdown, K-RAS V12 , and mutant EGFR) to lung tumorigenesis using human bronchial epithelial cells (HBEC) immortalized with telomerase and Cdk4-mediated p16 bypass. RNA interference p53 knockdown or oncogenic K-RAS V12 resulted in enhanced anchorage-independent growth and increased saturation density of HBECs. The combination of p53 knockdown and K-RAS V12 further enhanced the tumorigenic phenotype with increased growth in soft agar and an invasive phenotype in three-dimensional organotypic cultures but failed to cause HBECs to form tumors in nude mice. Growth of HBECs was highly dependent on epidermal growth factor (EGF) and completely inhibited by EGF receptor (EGFR) tyrosine kinase inhibitors, which induced G 1 arrest. Introduction of EGFR mutations E746-A750 del and L858R progressed HBECs toward malignancy as measured by soft agar growth, including EGF-independent growth, but failed to induce tumor formation. Mutant EGFRs were associated with higher levels of phospho-Akt, phospho-signal transducers and activators of transcription 3 [but not phospho-extracellular signal-regulated kinase (ERK) 1/2], and increased expression of DUSP6/MKP-3 phosphatase (an inhibitor of phospho-ERK1/2). These results indicate that (a) the HBEC model system is a powerful new approach to assess the contribution of individual and combinations of genetic alterations to lung cancer pathogenesis; (b) a combination of four genetic alterations, including human telomerase reverse transcriptase overexpression, bypass of p16/RB and p53 pathways, and mutant K-RAS V12 or mutant EGFR, is still not sufficient for HBECs to completely transform to cancer; and (c) EGFR tyrosine kinase inhibitors inhibit the growth of preneoplastic HBEC cells, suggesting their potential for chemoprevention.
We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.
Among 3 biomarkers, AFP showed the best performance in discriminating HCC cases from controls. AFP and AFP-L3 combination adopting their novel cutoff values (5 ng/mL and 4%, respectively) significantly improved the sensitivity for detecting HCC at very early stage. This article is protected by copyright. All rights reserved.
The filamentary nature and dynamics of edge-localized modes (ELMs) in the KSTAR high-confinement mode plasmas have been visualized in 2D via electron cyclotron emission imaging. The ELM filaments rotating with a net poloidal velocity are observed to evolve in three distinctive stages: initial linear growth, interim quasisteady state, and final crash. The crash is initiated by a narrow fingerlike perturbation growing radially from a poloidally elongated filament. The filament bursts through this finger, leading to fast and collective heat convection from the edge region into the scrape-off layer, i.e., ELM crash.
The ECE imaging ͑ECEI͒ diagnostic tested on the TEXTOR tokamak revealed the sawtooth reconnection physics in unprecedented detail, including the first observation of high-field-side crash and collective heat transport ͓H. K. Park, N. C. Luhmann, Jr., A. J. H. Donné et al., Phys. Rev. Lett. 96, 195003 ͑2006͔͒. An improved ECEI system capable of visualizing both high-and low-field sides simultaneously with considerably better spatial coverage has been developed for the KSTAR tokamak in order to capture the full picture of core MHD dynamics. Direct 2D imaging of other MHD phenomena such as tearing modes, edge localized modes, and even Alfvén eigenmodes is expected to be feasible. Use of ECE images of the optically thin edge region to recover 2D electron density changes during L/H mode transitions is also envisioned, providing powerful information about the underlying physics. The influence of density fluctuations on optically thin ECE is discussed.
Noninvasive blood glucose monitoring has been a long-standing dream in diabetes management. The use of Raman spectroscopy, with its molecular specificity, has been investigated in this regard over the past decade. Previous studies reported on glucose sensing based on indirect evidence such as statistical correlation to the reference glucose concentration. However, these claims fail to demonstrate glucose Raman peaks, which has raised questions regarding the effectiveness of Raman spectroscopy for glucose sensing. Here, we demonstrate the first direct observation of glucose Raman peaks from in vivo skin. The signal intensities varied proportional to the reference glucose concentrations in three live swine glucose clamping experiments. Tracking spectral intensity based on linearity enabled accurate prospective prediction in within-subject and intersubject models. Our direct demonstration of glucose signal may quiet the long debate about whether glucose Raman spectra can be measured in vivo in transcutaneous glucose sensing.
The effect of static n ¼ 1 resonant magnetic perturbation (RMP) on the spatial structure and temporal dynamics of edge-localized modes (ELMs) and edge turbulence in tokamak plasma has been investigated. Two-dimensional images measured by a millimeter-wave camera on the KSTAR tokamak revealed that the coherent filamentary modes (i.e., ELMs) are still present in the edge region when the usual large scale collapse of the edge confinement, i.e., the ELM crash, is completely suppressed by n ¼ 1 RMP. Cross-correlation analyses on the 2D images show that (1) the RMP enhances turbulent fluctuations in the edge toward the ELM-crash-suppression phase, (2) the induced turbulence has a clear dispersion relation for wide ranges of wave number and frequency, and (3) the turbulence involves a net radially outward energy transport. Nonlinear interactions of the turbulent eddies with the coexisting ELMs are clearly observed by bispectral analysis, which implies that the exchange of energy between them may be the key to the prevention of large scale crashes.
Purpose:To establish the reference range for hepatic attenuation minus splenic attenuation difference (CT L 2 S ) values on nonenhanced computed tomographic (CT) images obtained in adults with a biopsy-proved nonsteatotic liver and determine the CT L 2 S criterion for diagnosing hepatic steatosis. Materials and Methods:This retrospective study was institutional review board approved, and all subjects had provided written informed consent. The CT L 2 S was measured in 315 liver donor candidates (207 men, 108 women; mean age, 31.5 years 6 10.1 [standard deviation]) who underwent nonenhanced CT of the liver and subsequent ultrasonographically guided liver biopsy on the same day. Nonenhanced liver CT was performed with a 16-section multidetector scanner in 154 individuals and with a 64-section multidetector scanner in 161 individuals. Biopsy specimens were analyzed for degree of hepatic steatosis and iron deposition. The CT L 2 S reference range was determined according to Clinical and Laboratory Standards Institute guideline C28-A3 in individuals with a histologically proved nonsteatotic liver. The sensitivity of nonenhanced CT for the diagnosis of 5% or greater and 30% or greater hepatic steatosis with use of the lower limit of the reference range as the diagnostic cutoff was determined. The effects of subject age and sex, CT scanner type, and hepatic iron on the CT L 2 S were evaluated by using multiple linear regression analysis. Results:Ninety-six subjects (48 men, 48 women) were found to have a histologically proved nonsteatotic liver, with an estimated reference range for CT L 2 S values of 1-18 HU. With a CT L 2 S of less than 1 HU as the criterion for hepatic steatosis, the sensitivities of nonenhanced CT for 5% or greater and 30% or greater hepatic steatosis were 18.6% (29 of 156 subjects) and 67 % (26 of 39 subjects), respectively. Subject age had a signifi cant but negligible effect on CT L 2 S (0.076-HU increase per year of age, P = .009), subject sex and scanner type had no effects on CT L 2 S , and hepatic iron deposition signifi cantly increased the CT L 2 S (1.434-HU increase per increase in iron deposition grade, P = .011). Conclusion:The histologically proved reference range of CT L 2 S values for nonsteatotic livers was 1-18 HU. A CT L 2 S of less than 1 HU could be used as a conservative criterion for diagnosing hepatic steatosis with nonenhanced CT more consistently.q RSNA, 2011
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