gebhart/patrepeval huggingface dataset:
Abstract 3518: Preclinical pharmacology of the novel, potent & selective CHK1 inhibitor SAR-020106 (2010)

Abstract Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromized G1/S checkpoint control. This has led to the hypothesis that S and G2/M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53 deficient background, as normal cells would be rescued at the G1/S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage linked S and G2/M checkpoint control. SAR-020106 (the structure will be shown on the poster) is an ATP competitive, potent and selective CHK1 inhibitor with an IC50 of 13.3nM on the isolated human enzyme. This compound abrogates an etoposide-induced G2 arrest with an IC50 of 55nM in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0 to 29-fold in a number of colon tumor lines in vitro and in a p53 dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug induced autophosphorylation of CHK1 at S296 and blocks phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased γH2AX and PARP cleavage consistent with SAR-020106 enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. Orally bioavailable analogues of SAR-02106 are currently under development. In conclusion SAR-020106 represents a novel class of CHK1 inhibitors which can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3518.
Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids (2006)

Exosomes are small membrane vesicles found in cell culture supernatants and in different biological fluids. Exosomes form in a particular population of endosomes, called multivesicular bodies (MVBs), by inward budding into the lumen of the compartment. Upon fusion of MVBs with the plasma membrane, these internal vesicles are secreted. Exosomes possess a defined set of membrane and cytosolic proteins. The physiological function of exosomes is still a matter of debate, but increasing results in various experimental systems suggest their involvement in multiple biological processes. Because both cell-culture supernatants and biological fluids contain different types of lipid membranes, it is critical to perform high-quality exosome purification. This unit describes different approaches for exosome purification from various sources, and discusses methods to evaluate the purity and homogeneity of the purified exosome preparations.
Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway (2011)

Sclerostin is a product of mature osteocytes embedded in mineralised bone and is a negative regulator of bone mass and osteoblast differentiation. While evidence suggests that sclerostin has an anti-anabolic role, the possibility also exists that sclerostin has catabolic activity. To test this we treated human primary pre-osteocyte cultures, cells we have found are exquisitely sensitive to sclerostin, or mouse osteocyte-like MLO-Y4 cells, with recombinant human sclerostin (rhSCL) and measured effects on pro-catabolic gene expression. Sclerostin dose-dependently up-regulated the expression of receptor activator of nuclear factor kappa B (RANKL) mRNA and down-regulated that of osteoprotegerin (OPG) mRNA, causing an increase in the RANK:OPG mRNA ratio. To examine the effects of rhSCL on resulting osteoclastic activity, MLO-Y4 cells plated onto a bone-like substrate were primed with rhSCL for 3 days and then either mouse splenocytes or human peripheral blood mononuclear cells (PBMC) were added. This resulted in cultures with elevated osteoclastic resorption (approximately 7-fold) compared to untreated co-cultures. The increased resorption was abolished by co-addition of recombinant OPG. In co-cultures of MLO-Y4 cells with PBMC, SCL also increased the number and size of the TRAP-positive multinucleated cells formed. Importantly, rhSCL had no effect on TRAP-positive cell formation from monocultures of either splenocytes or PBMC. Further, rhSCL did not induce apoptosis of MLO-Y4 cells, as determined by caspase activity assays, demonstrating that the osteoclastic response was not driven by dying osteocytes. Together, these results suggest that sclerostin may have a catabolic action through promotion of osteoclast formation and activity by osteocytes, in a RANKL-dependent manner.
Innovative Voltage Driving Pixel Circuit Using Organic Thin-Film Transistor for AMOLEDs (2009)

In this work, we propose a novel active-matrix organic light-emitting diode displays (AMOLED) pixel circuit based on organic thin-film transistor (OTFT) architecture, which consisted of four switches, one driving transistor, and a capacitor. The pentacene-based OTFT device possesses a field-effect mobility of 0.1 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> /V ldr s, a threshold voltage of -1.5 V, subthreshold slope of 1.8 V/decade and an on/off current ratio 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sup> . The resultant voltage-driving pixel circuit, named ldquocomplementary voltage-induced coupling drivingrdquo (CVICD), is different from the current-driving scheme and can appropriately operate at low gray level for the low-mobility OTFT circuitry. The current non-uniformity less than 2.9% is achieved for data voltage ranging from 1 to 17 V by SPICE simulation work. In addition, the new external driving method can effectively reduce the complexity of OLED pixel circuitry.
Synthesis of Fluorinated Polythienothiophene-co-benzodithiophenes and Effect of Fluorination on the Photovoltaic Properties (2011)

Herein, we describe the synthesis of fluorinated polythienothiophene-co-benzodithiophenes (PTBFs) and the characterization of their physical properties, especially their performance in solar cells. Fluorination of the polymer backbone lowered both the HOMO and LUMO energy levels and simultaneously widened the energy bandgap of the polymer (0.1-0.2 eV). Incorporation of fluorine into the various positions of the polymer backbone significantly affected the solar cells' power conversion efficiency from 2.3% to 7.2%. Detailed studies revealed that the polymer containing mono-fluorinated thienothiophene gave the best solar cell performance. Perfluorination of the polymer backbone led to poor compatibility with PC(71)BM molecules, thus poor solar energy conversion efficiency. This is possibly due to the enhanced self-organization properties of the polymer chains and the fluorophobicity effect. Furthermore, it was found that perfluorination of the polymer backbone resulted in poor photochemical stability against singlet oxygen attack. Theoretical studies indicated that the internal polarization caused enhancement of the negative charge density on thienothiophene rings, which rendered them vulnerable to [2+4] cycloaddition reaction with singlet oxygen.
Jitter transfer analysis of tracked oversampling techniques for multigigabit clock and data recovery (2003)

Bang-bang controlled clock-recovery is widely used in serial link applications as it offers ideal matching between the timing and data samplers and is amenable to fast digital implementation. However, the bang-bang phase detection discards the magnitude information of the timing error and results in inconsistent loop dynamics that vary with the input-noise characteristics. This paper analyzes the jitter-dependent behavior of the tracked oversampling clock-recovery loop, by introducing the concept of effective phase detector gain. Three methods to stabilize the loop bandwidth against jitter variation are described and compared: adapting the loop gain, increasing the oversampling ratio, and adjusting the sampling points. The analyses are then verified with the jitter transfer characteristics obtained from time-step behavioral simulation.
Tissue refractometry using Hilbert phase microscopy (2007)

We present, for the first time to our knowledge, quantitative phase images associated with unstained 5 mum thick tissue slices of mouse brain, spleen, and liver. The refractive properties of the tissue are retrieved in terms of the average refractive index and its spatial variation. We find that the average refractive index varies significantly with tissue type, such that the brain is characterized by the lowest value and the liver by the highest. The spatial power spectra of the phase images reveal power law behavior with different exponents for each tissue type. This approach opens a new possibility for stain-free characterization of tissues, where the diagnostic power is provided by the intrinsic refractive properties of the biological structure. We present results obtained for liver tissue affected by a lysosomal storage disease and show that our technique can quantify structural changes during this disease development.
High-power (&gt;10 W) continuous-wave operation from 100-μm-aperture 0.97-μm-emitting Al-free diode lasers (1998)

By incorporating a broad transverse waveguide (1.3 μm) in 0.97-μm-emitting InGaAs(P)/InGaP/GaAs separate-confinement-heterostructure quantum-well diode-laser structures we obtain record-high continuous-wave (cw) output powers for any type of InGaAs-active diode lasers: 10.6–11.0 W from 100-μm-wide-aperture devices at 10 °C heatsink temperature, mounted on either diamond or Cu heatsinks. Built-in discrimination against the second-order transverse mode allows pure fundamental-transverse-mode operation (θ⊥=36°) to at least 20-W-peak pulsed power, at 68×threshold. The internal optical power density at catastrophic optical mirror damage (COMD) P̄COMD is found to be 18–18.5 MW/cm2 for these conventionally facet-passivated diodes. The lasers are 2-mm-long with 5%/95% reflectivity for front/back facet coating. A low internal loss coefficient (αi=1 cm−1) allows for high external differential quantum efficiency ηd (85%). The characteristic temperatures for the threshold current T0 and the differential quantum efficiency T1 are 210 and 1800 K, respectively. Low differential series resistance Rs: 26 mΩ; leads to electrical-to-optical power conversion efficiency values in excess of 40% from 1 W up to 10.6 W cw output power, and as much as 50% higher than those of 0.97-μm-emitting Al-containing devices.
Kinetics of acylglycerol sequential hydrolysis by human milk bile salt activated lipase and effect of taurocholate as fatty acid acceptor (1988)

The simplest reaction scheme for the conversion of trioleoylglycerol to glycerol catalyzed by human milk bile salt activated lipase can be described by consecutive first-order reactions: triacylglycerol k1----diacylglycerol k2----monoacylglycerol k3----glycerol. In these equations, k1, k2, and k3 represent the pseudo-first-order rate constants for the indicated reactions. The results from this study show that although the relative ratio of k2/k1 or k3/k1 may change somewhat, depending on the reaction conditions, the enzyme has a reactivity with the order of dioleoylglycerol greater than trioleoylglycerol greater than monooleoylglycerol. The incomplete equilibration of the intermediary diacylglycerol and monoacylglycerol with the bulk of the substrate during sequential lipolysis of triacylglycerol provides a means for their efficient lipolysis and minimizes the effect of partial acylglycerol as competitive substrates for intact triacylglycerol lipolysis. Taurocholate functions both as an activator of the enzyme and also as fatty acid acceptor to relieve product inhibition. In the presence of sufficient taurocholate, bovine serum albumin is no longer required as a fatty acid acceptor for the in vitro lipolysis.
Generation of Higher Fullerenes in Flames (1997)

The presence of fullerenes up to C116 was observed in condensable material from a benzene/oxygen flame. The flame material was Soxhlet-extracted with toluene for 363 h, fractionationed by means of a silica-based semipreparative HPLC column, and analyzed by HPLC coupled to a mass spectrometer via a heated nebulizer interface using a 2-(1-pyrenyl)ethylsilica stationary phase. UV−vis spectra were measured for C60, C60O, C60·CH4, C70, C70O, C76, C78, C80, C84, a C84 adduct, C86, C88, C90, C92, C94, C96, C98, C100, C102, and C108. Isomers could be discerned for C78, C90, and C94. A calibration using external standards was performed for C60, C70, C76, C78, and C84. For all other species the relative abundances were estimated based on HPLC peak integration results. Electric arc soot was extracted under similar conditions and the quantification of fullerenes compared to the data obtained with flame-generated condensable material. Except for C60 and C76, the abundances were significantly higher in the case of flame-generated condensable material. Also, striking differences between the two fullerene production methods are seen in the relative abundances of C78 isomers. Considering the present results and the ease with which the experimental setup could be scaled up, flame-generated condensable material represents an excellent starting material for the preparative isolation of higher fullerenes.
Effect of ghrelin and growth hormone‐releasing peptide 6 on septic ileus in mice (2004)

Ghrelin is an orexigenic peptide with prokinetic effects in the rat. We investigated the effect of ghrelin and growth hormone-releasing hormone 6 (GHRP-6) on gastric emptying and transit in control and septic mice. Mice were injected i.p. with lipopolysaccharides (LPS) or saline (control). After 16-17 h mice were pretreated with saline, ghrelin or GHRP-6 1 h before intragastric administration of Evans blue. Fifteen minutes later, after assessment of the behaviour scale, mice were killed and gastric emptying, transit and rectal temperature were measured. In control mice, ghrelin (100 microg kg(-1)) and GHRP-6 (20-100 microg kg(-1)) accelerated gastric emptying, whereas ghrelin and GHRP-6 failed to increase transit significantly. Septic mice developed a delay in gastric emptying and transit, hypothermia and a deterioration of the behaviour scale. In septic mice, ghrelin (20 microg kg(-1)) accelerated gastric emptying without effect on transit while GHRP-6 significantly accelerated gastric emptying dose-dependently and failed to increase transit significantly. Ghrelin and GHRP-6 had no effect on the endotoxin-induced hypothermia or deterioration of behaviour scale. Therefore, the beneficial prokinetic effect of ghrelin but mainly of GHRP-6 offers potential therapeutic options in the treatment of septic gastric ileus.
Targeting of tumor cells and DNA by a chlorambucil-spermidine conjugate. (1992)

Many tumor cells, including murine ADJ/PC6 plasmacytoma cells, possess an active energy dependent polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds. We have attempted to target the cytotoxic drug chlorambucil to a tumor possessing this uptake system by conjugating it to the polyamine spermidine. Furthermore, since polyamines have a high affinity for DNA, the attachment of spermidine to chlorambucil should also facilitate its targeting to DNA. This was supported by the observation that the chlorambucil-spermidine conjugate was approximately 10,000-fold more active than chlorambucil at forming interstrand crosslinks with naked DNA. In vitro cytotoxicity and in vivo antitumor studies were carried out using the ADJ/PC6 plasmacytoma. In vitro, using [3H]thymidine incorporation to assess cell viability following a 1-h exposure to control and polyamine depleted ADJ/PC6 cells, chlorambucil-spermidine was 35- and 225-fold, respectively, more toxic than chlorambucil. The increased toxicity of the conjugate compared to chlorambucil was possibly due to enhanced DNA binding and/or facilitated uptake via the polyamine uptake system. The enhanced toxicity of the conjugate but not chlorambucil by prior polyamine depletion with difluoromethylornithine, together with the observation that the conjugate but not chlorambucil competitively inhibited spermidine uptake into tumor cells, supported the suggestion that the conjugate utilized the polyamine uptake system. In vivo following a single i.p. dose, the conjugate was 4-fold more potent than chlorambucil in its ability to inhibit ADJ/PC6 tumor growth in BALB/c mice. However, the therapeutic index was not increased. Our results support the hypothesis that polyamines linked to cytotoxics facilitate their entry into tumor cells possessing a polyamine uptake system and increase their selectivity to DNA. This may have therapeutic application in the delivery of cytotoxic agents linked to polyamines to certain tumors.
Distinguishing the Contribution of Type 1 Pili from That of Other QseB-Misregulated Factors when QseC Is Absent during Urinary Tract Infection (2012)

Urinary tract infections (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), are one of the leading bacterial infections due to their high frequency and rate of recurrence. Both type 1 pilus adhesive organelles (fim) and the QseC sensor kinase have been implicated in UPEC virulence during UTI and have been individually reported to be promising drug targets. Deletion of qseC leads to pleiotropic effects due to unregulated activation of the cognate response regulator QseB, influencing conserved metabolic processes and diminishing expression of virulence genes, including type 1 pili. Here, we discern the type 1 pilus-dependent and -independent effects that contribute to the virulence attenuation of a UPEC qseC deletion mutant in a murine model of experimental UTI. We show that although a ΔqseC mutant restored for type 1 pilus expression regains the ability to colonize the host and initiate acute infection up to 16 h postinfection, it is rapidly outcompeted during acute infection when coinoculated with a wild-type strain. As a result, this strain has a diminished capacity to establish chronic infection. A prophylactic oral dose of a FimH small-molecular-weight antagonist (ZFH-02056) further reduced the ability of the qseC mutant to establish chronic infection. Thus, loss of QseC significantly enhances the efficacy of ZFH-02056. Collectively, our work indicates that type 1 pili and QseC become critical in different infection stages, and that dual targeting of these factors has an additive effect on ablating UPEC virulence.
Safety and convenience of a mechanical injector pump for coronary angiography (1989)

Coronary angiography and left ventriculography was performed in 5,887 consecutive patients over a 5-year period using a mechanical injector pump activated by a foot switch. Five coronary dissections occurred, four of the right coronary artery and one of the left internal mammary artery, which had been grafted to the left anterior descending artery. One patient had angina following an air embolus; there were no significant intramyocardial injections of contrast agent. The pressure generated in the catheter by hand injection of contrast agent was compared with that generated by the injector pump. Contrast agent was injected through a 7F Judkins Right 4 and an 8F Sones catheter by hand at slow, medium, and fast rates by hand and by the injector pump at 2,3, and 4 ml/sec; maximum pressure generated was recorded. Although the pressures generated through a Sones catheter were similar using both methods, pressures with hand injection were much more variable. The pressures generated with hand injection through a Judkins catheter were lower than those with pump injection, but again the pressures showed much greater variability with hand injection. The pump was found to be safe, reliable, predictable, and convenient when used for coronary angiography with Sones and Judkins catheters. It eliminates the need for a trained assistant during the procedure of coronary angiography.
Plasmonics enhancement of a luminescent or Raman-active layer in a multilayered metallic nanoshell (2009)

Expressions for the enhancement of the far-field scattering cross section of a luminescent or Raman-active compound contained within a multilayered nanosphere are derived, where the active compound resides between an outer metallic shell and a metallic core. The quasi-static approximation is assumed for silver and gold particles using a Lorentz-Drude model of the dielectric function. An attempt has also been made to account for the effect of electron scattering from the boundaries of the shell on the enhancement calculation.
Promotion of B Cell Immune Responses via an Alum-Induced Myeloid Cell Population (2004)

Exposure of naïve B cells to the cytokine interleukin-4 (IL-4) and/or antigen leads to a state of "priming," in which subsequent aggregation of major histocompatibility complex class II molecules induces the mobilization of calcium ions and cell proliferation. However, it is not clear how critical this priming is for immune responses or how it is normally induced in vivo. Injection of mice with the commonly used adjuvant alum led to priming of splenic B cells and to the accumulation in the spleen of a previously unknown population of IL-4-producing, Gr1+ cells. These cells and IL-4 were both required for in vivo priming and expansion of antigen-specific B cells, as well as for optimal production of antibody. These studies reveal a key role for a previously unknown accessory myeloid cell population in the generation of humoral immune responses.
High-throughput transfection and engineering of primary cells and cultured cell lines – an invaluable tool for research as well as drug development (2007)

The manipulation of eukaryotic cells by introducing nucleic acids and other substrates using chemical, physical or viral methods is one of the ground-breaking tools in the life sciences. Changes in the molecular equipment of a cell induced by introducing different molecules not only enable the dissection of signal transduction and metabolic pathways, but also allow the exploitation of engineered cells as bio-factories for the production of proteins in the processes of target research and drug development. In addition to the application of engineered cells for modern cell-based assays, medically relevant engineered cells can be used in clinical settings for adoptive immunotherapy or gene therapy. With the advent of methods exploiting RNA interference (RNAi), gene identification and functional validation in eukaryotic cells have clearly become one of the most exciting methods in life sciences during the past few years. To accelerate research and development in these areas, high-quality, high-throughput approaches (i.e., using sample formats of at least 96 wells) for cell engineering are needed with increasing demand. Recent developments, especially in the field of electroporation, now allow the efficient, high-throughput engineering of virtually any cell type, including primary cells, many of which were previously considered difficult or even impossible to transfect. Primary cells freshly isolated from native tissues are gaining more and more interest, as data obtained with these cells are considered to be of higher physiological relevance than data obtained with immortalized cell lines that have been cultured for extensive periods. In this review, the various methods for cell engineering (with focus on higher eukaryotic cells) are summarized and their impact for high-throughput applications in research and drug development is discussed.