The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of ...epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.
The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain ...barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-(11)C-verapamil PET/MR imaging with cyclosporin A, a p-glycoprotein inhibitor.
Six patients with drug-resistant epilepsy, 5 patients with drug-sensitive epilepsy, and 8 healthy controls underwent dynamic (R)-(11)C-verapamil PET/MR imaging with an intravenous infusion of cyclosporin A. Asymmetry indices (Right Region - Left Region)/(Right Region + Left Region) × 200% of the standard uptake values in each of the paired lobes were calculated.
All patients with drug-resistant epilepsy had significantly different asymmetry from the healthy controls, whereas all patients with drug-sensitive epilepsy had asymmetry similar to that in healthy controls. In the temporal lobe, the asymmetry indices of patients with left temporal lobe drug-resistant epilepsy were more positive than those of healthy controls (healthy controls: 4.0413 ± 1.7452; patients: 7.2184 ± 1.8237; P = .048), and those of patients with right temporal drug-resistant epilepsy were more negative (patients: -1.6496 ± 3.4136; P = .044). In addition, specific regions that had significant asymmetry were different between the lateral and medial temporal lobe epilepsy groups. In the frontal lobe, the asymmetry index of patients with right frontal lobe drug-resistant epilepsy was more negative than that in healthy controls.
We confirmed that statistical parametric mapping analysis by using asymmetry indices of (R)-(11)C-verapamil PET/MR imaging with cyclosporin A could be used as a surrogate marker for drug-resistant epilepsy, and this approach might be helpful for localizing or lateralizing the epileptic zone.
Despite ionizing radiation (IR) is being widely used as a standard treatment for lung cancer, many evidences suggest that IR paradoxically promotes cancer malignancy. However, its molecular ...mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that exposure to fractionated radiation (2 Gy per day for 3 days) induces the secretion of granulocyte-colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. Intriguingly, radiation-induced G-CSF promoted the migratory and invasive properties by triggering the epithelial-mesenchymal cell transition (EMT) in non-small-cell lung cancer cells (NSCLCs). By irradiation, G-CSF was upregulated transcriptionally by β-catenin/TCF4 complex that binds to the promoter region of G-CSF as a transcription factor. Importantly, irradiation increased the stability of β-catenin through the activation of PI3K/AKT (phosphatidylinositol 3-kinase/AKT), thereby upregulating the expression of G-CSF. Radiation-induced G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3 (Janus kinase/signal transducers and activators of transcription), thereby triggering EMT program in NSCLCs. Taken together, our findings suggest that the application of G-CSF in cancer therapies to ameliorate neutropenia should be reconsidered owing to its effect on cancer progression, and G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy for the treatment of NSCLC.
Charge density wave (CDW) correlations have been shown to universally exist in cuprate superconductors. However, their nature at high fields inferred from nuclear magnetic resonance is distinct from ...that measured with x-ray scattering at zero and low fields. We combined a pulsed magnet with an x-ray free-electron laser to characterize the CDW in YBa2Cu3O6.67 via x-ray scattering in fields of up to 28 tesla. While the zero-field CDW order, which develops at temperatures below ~150 kelvin, is essentially two dimensional, at lower temperature and beyond 15 tesla, another three-dimensionally ordered CDW emerges. The field-induced CDW appears around the zero-field superconducting transition temperature; in contrast, the incommensurate in-plane ordering vector is field-independent. This implies that the two forms of CDW and high-temperature superconductivity are intimately linked.
Objectives. To determine whether osteopontin (OPN) is increased in patients with AS and to investigate its relationship to inflammatory disease activity and bone remodelling process. Methods. This ...cross-sectional study included 30 patients with AS and 23 age- and sex-matched healthy controls. We assessed clinical characteristics and laboratory parameters including the ESR, CRP, lipid profiles, the Bath AS disease activity index (BASDAI) and the Bath AS radiographic index (BASRI). To evaluate bone metabolism, we tested ALP, OCN and C-telopeptide of type I collagen (CTX-I). Plasma levels of OPN, TNF-α and IL-6 were measured by ELISA, and mRNA expression in peripheral blood mononuclear cells (PBMCs) was performed by RT–PCR. Changes in OPN level were also evaluated in eight patients after the treatment with a TNF-α blocker. Results. Patients with AS had significantly higher plasma OPN, TNF-α and IL-6 levels and more mRNA expression than healthy controls. Plasma OPN levels were correlated with serum ALP, OCN and CTX-I levels, but not with ESR, CRP, lipid profiles, BASDAI or BASRI. Treatment with a TNF-α blocker did not alter OPN levels, although it reduced the disease activity. Conclusions. Patients with AS had higher levels of OPN compared with controls. The plasma OPN level was correlated with serum ALP, OCN and CTX-I levels, but not with disease activity in AS. OPN might be involved in bone remodelling rather than in inflammation in AS.
The recent discovery of a gamma-ray burst (GRB) coincident with the gravitational-wave (GW) event GW170817 revealed the existence of a population of low-luminosity short duration gamma-ray transients ...produced by neutron star mergers in the nearby Universe. These events could be routinely detected by existing gamma-ray monitors, yet previous observations failed to identify them without the aid of GW triggers. Here we show that GRB150101B is an analogue of GRB170817A located at a cosmological distance. GRB150101B is a faint short burst characterized by a bright optical counterpart and a long-lived X-ray afterglow. These properties are unusual for standard short GRBs and are instead consistent with an explosion viewed off-axis: the optical light is produced by a luminous kilonova, while the observed X-rays trace the GRB afterglow viewed at an angle of ~13°. Our findings suggest that these properties could be common among future electromagnetic counterparts of GW sources.
This paper measures the impact of vertically integrated and exclusive software on industry structure and welfare in the sixth-generation of the US video game industry (2000-2005). I specify and ...estimate a dynamic model of both consumer demand for hardware and software products, and software demand for hardware platforms. I use estimates to simulate market outcomes had platforms been unable to own or contract exclusively with software. Driven by increased software compatibility, hardware and software sales would have increased by 7 percent and 58 percent and consumer welfare by $1.5 billion. Gains would be realized only by the incumbent, suggesting exclusivity favored the entrant platforms.
The code couples the electrical circuit with plasma focus (PF) dynamics, thermodynamics and radiation. It is energy-, charge- and mass-consistent and accounts for the effects of transit times of ...small disturbances and plasma self-absorption. It has been used in design and interpretation of Mather-type PF experiments and as a complementary facility to provide diagnostic reference numbers in all gases. Information computed includes axial and radial dynamics, SXR emission characteristics and yield for various applications including microelectronics lithography and optimization of machines. Plasma focus neutron yield calculations, current and neutron yield limitations, deterioration of neutron scaling (neutron saturation), radiative collapse, speed-enhanced PF, current-stepped PF and extraction of diagnostic and anomalous resistance data from current signals have been studied using the code; which also produces reference numbers for fluence, flux and energy of deuteron beams and ion beams for all gases. There has been no pause in its continuous evolution in three decades so much so that the model code has no formal source reference except
www.plasmafocus.net
. This review presents, for the first time a comprehensive up-to-date version of the 5-phase model code. The equations of each phase are derived. Those of the first two phases are normalized to reveal important scaling parameters. The focus pinch phase is discussed with radiation-coupled dynamics necessitating the computation of radiation terms moderated by plasma self-absorption. Neutron and ion beam yields are computed. The 5-phase model code appears to be adequate for all Mather-type PF, lacking only in one aspect that for high inductance PF (termed Type 2) the measured current waveform contains an extended dip which cannot be fitted by the 5-phase code; necessitating an extended 6-phase code. This sixth phase (termed phase 4a) is dominated by anomalous resistance, providing a way to extract valuable data on anomalous resistivity from the current trace.
Although surgical resection has been an important alternative treatment for patients with intractable epilepsy related to focal cortical dysplasia (FCD), the prognostic relevance of the degree of ...pathologic severity is controversial and there has been only limited information regarding the prognostic factors involved in the surgical treatment of refractory epilepsy in patients with FCD.
We undertook the present study to assess whether the pathologic subtypes of FCD affect surgical outcomes in patients with drug-resistant epilepsy. We also studied the prognostic roles of clinical factors and various diagnostic modalities in the surgical treatment.
A total of 166 consecutive patients were included. By univariate analysis, incomplete resection of epileptogenic area (p < 0.001), mild pathologic features (p = 0.01), and the presence of secondary tonic clonic seizures (2GTCS) (p = 0.05) were associated with poor surgical outcomes. There was a strong tendency for patients with severe pathologic features to have MRI abnormalities (p < 0.001). Incomplete resection of epileptogenic area (p < 0.001) and mild pathologic features (p = 0.02) were poor independent outcome predictors on multivariate analysis. The results of MRI, scalp EEG, fluorodeoxyglucose-PET, and ictal SPECT were not associated with surgical outcomes.
Our study shows that there is a strong tendency for patients with severe pathologic features to have MRI abnormalities, and patients with incomplete resection, mild pathologic features, or the presence of secondary tonic clonic seizures have a high chance of a poorer surgical outcome.
Solid waste management (SWM) is an integral part of an environmental management system. SWM approaches have been modified into a more practical and effective option to establish sustainability based ...on the “reduce”, “reuse”, and “recycle” (3R) principles. This review provides an overview of a wide range of existing SWM strategies with the following key objectives: (i) to comprehensively describe current technologies, strategic innovations, and monitoring tools, (ii) to provide an overview of prevailing waste management scenarios across different countries, (iii) to identify the roles of life cycle assessment (LCA) and other modeling tools in SWM, and (iv) to showcase feasible approaches for sustainable recycling and utilization of solid wastes. The current review finds that geographical positions and economic status of nations are important to dictate waste characteristics. A number of economic and LCA models have been described to facilitate future workers vis-à-vis organizations for the selection of appropriate waste management algorithms and for the evaluation of their eventual performance. In addition, this paper showcases various innovative solutions that have been reported for the achievement of smart and sustainable waste management plans in many countries.
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