258 research outputs found
Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells
Abstract
Background
Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells.
Methods
To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system.
Results
Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines.
Conclusions
Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes.http://deepblue.lib.umich.edu/bitstream/2027.42/112625/1/12885_2012_Article_3866.pd
Statistical study of dust properties in LMC molecular clouds
The objective of this paper is to construct a catalog providing the dust
properties and the star formation efficiency (SFE) of the molecular clouds in
the Large Magellanic Cloud (LMC). We use the infrared (IR) data obtained with
the Spitzer telescope as part of the ``Surveying the Agents of a Galaxy's
Evolution'' (SAGE) Legacy survey as well as the IRAS data. We also work with
extinction (Av) maps of the LMC. A total of 272 molecular clouds have been
detected in the LMC in a previous molecular survey, accounting for 230 giant
molecular clouds and 42 smaller clouds. We perform correlations between the IR
emission/extinction, and atomic and molecular gas tracers. We compare the
atomic gas that surrounds the molecular cloud with the molecular gas in the
cloud. Using a dust emission model, we derive the physical properties of dust
in and outside the clouds: equilibrium temperature, emissivity and extinction.
We also determine the luminosity of the interstellar radiation field
intercepted by the cloud, and the total IR luminosity. Statistically, we do not
find any significant difference in the dust properties between the atomic and
the molecular phases. In particular we do not find evidence for a systematic
decrease of the dust temperature in the molecular phase, with respect to the
surrounding, presumably atomic gas. This is probably because giant molecular
clouds are the sites of star formation, which heat the dust, while the smallest
clouds are unresolved. The ratio between the IR luminosity and the cloud mass
(LDust/Mgas) does not seem to correlate with Mgas. The highest value of the
ratio we derived is 18.1 Lsol/Msol in the 30 Doradus region, which is known to
be the most prominent star formation region of the LMC, while the most likely
value is 0.5 and is representative of quiescent clouds. We provide a
prescription to associate the various stages of star formation with its
LDust/Mgas.Comment: Accepted for publication in A
Downregulation of the CCL2/CCR2 and CXCL10/CXCR3 axes contributes to antitumor effects in a mouse model of malignant glioma
Glioblastoma multiforme involves glioma stem cells (GSCs) that are resistant to various therapeutic approaches. Here, we studied the importance of paracrine signaling in the glioma microenvironment by focusing on the celecoxib-mediated role of chemokines C–C motif ligand 2 (CCL2), C-X-C ligand 10 (CXCL10), and their receptors, CCR2 and CXCR3, in GSCs and a GSC-bearing malignant glioma model. C57BL/6 mice were injected with orthotopic GSCs intracranially and divided into groups administered either 10 or 30 mg/kg celecoxib, or saline to examine the antitumor effects associated with chemokine expression. In GSCs, we analyzed cell viability and expression of chemokines and their receptors in the presence/absence of celecoxib. In the malignant glioma model, celecoxib exhibited antitumor effects in a dose dependent manner and decreased protein and mRNA levels of Ccl2 and CxcL10 and Cxcr3 but not of Ccr2. CCL2 and CXCL10 co-localized with Nestin+ stem cells, CD16+ or CD163+ macrophages and Iba-1+ microglia. In GSCs, celecoxib inhibited Ccl2 and Cxcr3 expression in a nuclear factor-kappa B-dependent manner but not Ccr2 and CxcL10. Moreover, Ccl2 silencing resulted in decreased GSC viability. These results suggest that celecoxib-mediated regulation of the CCL2/CCR2 and CXCL10/ CXCR3 axes may partially contribute to glioma-specific antitumor effects
The Type Ic Hypernova SN 2002ap
Photometric and spectroscopic data of the energetic Type Ic supernova (SN)
2002ap are presented, and the properties of the SN are investigated through
models of its spectral evolution and its light curve. The SN is
spectroscopically similar to the "hypernova" SN 1997ef. However, its kinetic
energy [ erg] and the mass ejected (2.5-5
) are smaller, resulting in a faster-evolving light curve. The SN
synthesized of Ni, and its peak luminosity was
similar to that of normal SNe. Brightness alone should not be used to define a
hypernova, whose defining character, namely very broad spectral features, is
the result of a high kinetic energy. The likely main-sequence mass of the
progenitor star was 20-25 , which is also lower than that of both
hypernovae SNe 1997ef and 1998bw. SN 2002ap appears to lie at the low-energy
and low-mass end of the hypernova sequence as it is known so far. Observations
of the nebular spectrum, which is expected to dominate by summer 2002, are
necessary to confirm these values.Comment: 10 pages, 4 figures, accepted for publication in ApJL, 30 April 2002
(minor changes to match the accepted version, with figures being colored
The Orbiting Carbon Observatory (OCO-2) Tracks 2-3 Peta-Gram Increase in Carbon Release to the Atmosphere During the 2014-2016 El Nino
The powerful El Nio event of 2015-2016 - the third most intense since the 1950s - has exerted a large impact on the Earth's natural climate system. The column-averaged CO2 dry-air mole fraction (XCO2) observations from satellites and ground based networks are analyzed together with in situ observations for the period of September 2014 to October 2016. From the differences between satellite (OCO-2) observations and simulations using an atmospheric chemistry-transport model, we estimate that, relative to the mean annual fluxes for 2014, the most recent El Nio has contributed to an excess CO2 emission from the Earth's surface (land+ocean) to the atmosphere in the range of 2.4+/-0.2 PgC (1 Pg = 10(exp 15) g) over the period of July 2015 to June 2016. The excess CO2 flux is resulted primarily from reduction in vegetation uptake due to drought, and to a lesser degree from increased biomass burning. It is about the half of the CO2 flux anomaly (range: 4.4-6.7 PgC) estimated for the 1997/1998 El Nio. The annual total sink is estimated to be 3.9+/-0.2 PgC for the assumed fossil fuel emission of 10.1 PgC. The major uncertainty in attribution arise from error in anthropogenic emission trends, satellite data and atmospheric transport
腫瘍細胞由来のVEGFを慢性的に阻害すると大腸がん細胞の悪性形質化を増強する
Background: Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells.
Methods: To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system.
Results: Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function (s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines.
Conclusions: Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes
Readministration of gefitinib in a responder after treatment discontinuation due to gefinitib-related interstitial lung disease: a case report
<p>Abstract</p> <p>Introduction</p> <p>Gefitinib is a new molecular-targeted agent for the treatment of patients with advanced non-small cell lung cancer that fail to respond to conventional chemotherapy. Gefitinib is considered to be well tolerated and less toxic compared with conventional cytotoxic drugs. However, interstitial lung disease (ILD) has been reported as a serious adverse effect. The precise management of a gefitinib responder having severe adverse events remains unknown.</p> <p>Case Presentation</p> <p>We report the case of gefitinib readministration in a patient with lung adenocarcinoma who had once responded but in whom treatment had to be discontinued owing to gefinitib-related ILD. A dramatic response was achieved both at the time of initial treatment (250 mg/day) and at readministration of gefitinib (125 mg/day). The effectiveness of gefitinib therapy in our patient could be explained in part by the presence of an activating mutation of epidermal growth factor receptor (<it>EGFR</it>) gene, L858R in exon 21, which was identified in the primary tumor.</p> <p>Conclusion</p> <p>A reduced dose of gefitinib might be sufficient for patients having tumors with <it>EGFR </it>gene mutations, and that the currently approved dose may be excessively potent in some of these patients, thus resulting in the onset of adverse events.</p
GibbsST: a Gibbs sampling method for motif discovery with enhanced resistance to local optima
BACKGROUND: Computational discovery of transcription factor binding sites (TFBS) is a challenging but important problem of bioinformatics. In this study, improvement of a Gibbs sampling based technique for TFBS discovery is attempted through an approach that is widely known, but which has never been investigated before: reduction of the effect of local optima. RESULTS: To alleviate the vulnerability of Gibbs sampling to local optima trapping, we propose to combine a thermodynamic method, called simulated tempering, with Gibbs sampling. The resultant algorithm, GibbsST, is then validated using synthetic data and actual promoter sequences extracted from Saccharomyces cerevisiae. It is noteworthy that the marked improvement of the efficiency presented in this paper is attributable solely to the improvement of the search method. CONCLUSION: Simulated tempering is a powerful solution for local optima problems found in pattern discovery. Extended application of simulated tempering for various bioinformatic problems is promising as a robust solution against local optima problems
Enhanced Logic Performance with Semiconducting Bilayer Graphene Channels
Realization of logic circuits in graphene with an energy gap (EG) remains one
of the main challenges for graphene electronics. We found that large transport
EGs (>100 meV) can be fulfilled in dual-gated bilayer graphene underneath a
simple alumina passivation top gate stack, which directly contacts the graphene
channels without an inserted buffer layer. With the presence of EGs, the
electrical properties of the graphene transistors are significantly enhanced,
as manifested by enhanced on/off current ratio, subthreshold slope and current
saturation. For the first time, complementary-like semiconducting logic
graphene inverters are demonstrated that show a large improvement over their
metallic counterparts. This result may open the way for logic applications of
gap-engineered graphene.Comment: Accepted by ACS Nan
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