Identification of Anti-Malarial Compounds as Novel Antagonists to Chemokine Receptor CXCR4 in Pancreatic Cancer Cells

Despite recent advances in targeted therapies, patients with pancreatic adenocarcinoma continue to have poor survival highlighting the urgency to identify novel therapeutic targets. Our previous investigations have implicated chemokine receptor CXCR4 and its selective ligand CXCL12 in the pathogenesis and progression of pancreatic intraepithelial neoplasia and invasive pancreatic cancer; hence, CXCR4 is a promising target for suppression of pancreatic cancer growth. Here, we combined in silico structural modeling of CXCR4 to screen for candidate anti-CXCR4 compounds with in vitro cell line assays and identified NSC56612 from the National Cancer Institute's (NCI) Open Chemical Repository Collection as an inhibitor of activated CXCR4. Next, we identified that NSC56612 is structurally similar to the established anti-malarial drugs chloroquine and hydroxychloroquine. We evaluated these compounds in pancreatic cancer cells in vitro and observed specific antagonism of CXCR4-mediated signaling and cell proliferation. Recent in vivo therapeutic applications of chloroquine in pancreatic cancer mouse models have demonstrated decreased tumor growth and improved survival. Our results thus provide a molecular target and basis for further evaluation of chloroquine and hydroxychloroquine in pancreatic cancer. Historically safe in humans, chloroquine and hydroxychloroquine appear to be promising agents to safely and effectively target CXCR4 in patients with pancreatic cancer

1/f gate tunneling current noise model of ultrathin oxide MOSFETs

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Mismatch Measure Improvement Using Kelvin Test Structures in Transistor Pair Configuration in Sub-Hundred Nanometer MOSFET Technology

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Pockets engineering impact on mismatch performance on 45nm MOSFET technologies

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Response of Correlated Double Sampling CMOS Imager Circuit to Random Telegraph Signal Noise

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Impact of Random Telegraph Signal in CMOS Image Sensors for Low-Light Levels

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Laboratory study of odour emissions from areal sources: evaluation of a sampling system

International audienceOdour emissions from various sources are of increasing concern to the public. Considering areal sources, there is need for the development of reliable methods for the measurement of odour emissions because none is yet accepted as a standard.In this work, a wind tunnel was first developed as a tool to measure odour emission from areal sources. A laboratory study on concentrations above the liquid surface was carried out to characterise the emission. Edge and fetch influence was shown as well as the presence of concentration gradients.Then, a dynamic flux chamber was developed as a sampling emission rate system. Tests in the wind tunnel showed good accuracy and precision

RGK GTPase-dependent CaV2.1 Ca2+ channel inhibition is independent of CaVbeta-subunit-induced current potentiation.

International audienceRGK (Rad-Gem-Rem) GTPases have been described as potent negative regulators of the Ca(2+) influx via high-threshold voltage-activated Ca(2+) channels. Recent work, mostly performed on Ca(V)1.2 Ca(2+) channels, has highlighted the crucial role played by the channel auxiliary Ca(V)beta subunits and identified several GTPase and beta-subunit protein domains involved in this regulation. We now extend these conclusions by producing the first complete characterization of the effects of Gem, Rem, and Rem2 on the neuronal Ca(V)2.1 Ca(2+) channels expressed with Ca(V)beta(1) or Ca(V)beta(2) subunits. Current inhibition is limited to a decrease in amplitude with no modification in the voltage dependence or kinetics of the current. We demonstrate that this inhibition can occur for Ca(V)beta constructs with impaired capacity to induce current potentiation, but that it is lost for Ca(V)beta constructs deleted for their beta-interaction domain. The RGK C-terminal last approximately 80 amino acids are sufficient to allow potent current inhibition and in vivo beta-subunit/Gem interaction. Interestingly, although Gem and Gem carboxy-terminus induce a completely different pattern of beta-subunit cellular localization, they both potently inhibit Ca(V)2.1 channels. These data therefore set the status of neuronal Ca(V)2.1 Ca(2+) channel inhibition by RGK GTPases, emphasizing the role of short amino acid sequences of both proteins in beta-subunit binding and channel inhibition and revealing a new mechanism for channel inhibition

Low frequency Noise Measurements as an investigation tool of pixel flickering in cooled Hg0,7Cd0,3Te focal plane arrays

International audienceWe report on electrical noise measurements on both Hg0.7Cd0.3Te test patterns and hybrid 320 x 256 focal plane array in order to explain the low-frequency pixel flickering physical origin. Dark and under infrared Illumination test patterns characterization highlights that the detector chip is not responsible for the flickering phenomenon. Taking into account the silicon readout chip influence when the full infrared complementary metal-oxyd semiconductor (IRCMOS) infrared detector is investigated, the indium bump based interconnecting system is finally pointed out as a potential excess noise source

About the physical origin of pixel flickering in cooled Hg0.7Cd0.3Te infrared photodetectors

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