gebhart/patrepeval huggingface dataset:
Abstract 4848: Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma (2016)

Abstract We previously discovered a novel 2-aryl-4-benzoyl-imidazole (ABI) scaffold exerts its potent anti-proliferative effects through interacting with the colchicine binding site in tubulin. Extensive structure-activity relationship (SAR) studies of this novel scaffold showed that the best analog in this series, ABI-231, has an average IC50 = 5.2 nM against panels of melanoma and prostate cancer cell lines, is orally bioavailable, and strongly suppress melanoma tumors in vivo. Analyses of the potential binding pose of ABI-231 at the colchicine binding pocket suggested small substitutions to the indole moiety in ABI-231 could further increase its interactions to tubulin. Based this hypothesis, we have established an efficient synthetic method for the synthesis of ABI-231 analogs by either rotating the indole ring or introducing substituents on the indole of ABI-231. Using this method, we synthesized and tested 27 analogs of ABI-231. Several of the compounds show excellent potency against a panel of melanoma cancer cell lines with a diverse genomic background (mutations in BRAF, TP53, CDKN2A and PTEN) that are frequently encountered in clinical metastatic melanoma tumors. Additionally, they are not substrates for the P-glycoprotein (Pgp) efflux pump and therefore strongly inhibited the multidrug resistant cell lines. The potency of the compounds was further verified by their potent growth inhibition of cancer cell colonies. Results from cell cycle analysis, apoptosis evaluation and tubulin polymerization inhibition are consistent with their expected mechanisms of action. Potential off-target analyses performed by Eurofins Cerep-Panlabs SafetyScreen 44 indicated that they are clean and does not inihibt any of the tested off-targets at 100 fold of its IC50 value in melanoma cells, suggesting the good safety profile for this compound and the probably these scaffold in general. We are currently performing in vivo efficacy studies for the most potent analogs. These compounds hold great promise as a new generation of orally available tubulin inhibitors. Citation Format: Wang Qinghui, Arnst E. Kinsie, Duane D. Miller, Wei Li. Discovery of ABI-231 analogs targeting the colchicine site in tubulin for advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4848.
Designing Carbon Crystals for Nanotechnology Applications (2001)

Recent discovery of graphite polyhedral crystals, having shapes of faceted needles, rods, rings, barrels, and double-tipped pyramids with 7-fold, 9-fold, or more complex morphological symmetry, suggests the possibility of growing complex crystal shapes on nanoscale and microscale. Appropriate crystal design may result in more diverse and better controlled morphologies grown “to size” from the material that best suits the application.
The preparation and characterization of some N-chloro-2- and N-chloro-4-pyridones (1984)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe preparation and characterization of some N-chloro-2- and N-chloro-4-pyridonesAlan R. Katritzky, Ghulam R. Khan, David E. Leahy, and Michael De RosaCite this: J. Org. Chem. 1984, 49, 25, 4784–4786Publication Date (Print):December 1, 1984Publication History Published online1 May 2002Published inissue 1 December 1984https://pubs.acs.org/doi/10.1021/jo00199a008https://doi.org/10.1021/jo00199a008research-articleACS PublicationsRequest reuse permissionsArticle Views623Altmetric-Citations13LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Lung Injury Edema in Dogs (1986)

A B S T R A C T Increased vascular permeability characterizes lung injury pulmonary edema and renders fluid balance in the injured lung especially sensitive to changes in hydrostatic pressure. Pulmonary edema is often associated with increased sympathetic nervous system activity which can lead to pulmonary venoconstriction. This postcapillary venoconstriction could raise microvascular pressure and might therefore increase edema in the injured lung. We produced lung injury edema in dogs with oleic acid and directly measured small (<2 mm) pulmonary vein pressure. We found that the small pulmonary vein pressure was increased from 9.8±0.5 mmHg to 12.6±0.5 mmHg (n = 10) by oleic acid injury edema. The increase was not due to a rise in left atrial pressure since the small pulmonary vein-left atrial pressure gradient also increased. To test if this increase in the postcapillary pressure gradient was sympathetically mediated, we either unilaterally ablated the stellate ganglion or produced unilateral alpha adrenergic blockade with phenoxybenzamine before giving oleic acid. Both of these interventions prevented the increase in pulmonary vein pressure caused by oleic acid edema in the protected lung but not in the intact contralateral lung. These interventions produced a 30±6.8% reduction in the amount of edema caused by oleic acid. Restoring the increase in small vein pressure by inflating a balloon in the left atrium of dogs with bilateral stellate ganglion ablations abolished the reduction in edema produced by antisympathetic treatment. However, the decrease in edema was not significantly correlated with the reduction in pulmonary vein pressure. Thus, the mechanism of the effects of these antisympathetic interventions remains unclear. We conclude that lung injury edema causes sympathetically mediated pul
Macrophage-Lymphocyte Synergy in the Production of Osteoclast Activating Factor (1974)

Abstract Supernatants from cultures of activated normal human peripheral blood leukocytes contain a factor which stimulates osteoclastic bone resorption in vitro. The present study indicates that osteoclast activating factor (OAF) is produced by phytohemagglutinin-activated mononuclear cells within 6 hr of activation, and that peak production is associated with increased amino acid incorporation into protein but precedes increased thymidine incorporation into DNA. Granulocytes, platelets, and red cells were not necessary for the production of OAF, since mononuclear cells purified on Ficoll-Hypaque gradients and devoid of these elements produced as much OAF as unseparated leukocytes. Granulocyte extracts did not show bone-resorbing activity. The production of OAF by mononuclear cells was impaired by irradiation, suggesting that it is made by radiosensitive lymphocytes rather than radioresistant macrophages. However, OAF was not produced by lymphocytes purified on glass-bead columns although these cells could respond to phytohemagglutinin with increased thymidine and amino acid incorporation. Purified macrophages also failed to produce substantial bone-resorbing activity. However, when a small number of irradiated but viable macrophages (5 × 104 cells/ml) was added to glass bead-purified lymphocytes (2 × 106 cells/ml), OAF production was as great as with unseparated mononuclear cell populations. These results suggest that OAF is produced by lymphocytes, but that its production is dependent on macrophage-lymphocyte interaction. OAF is a unique bone-resorbing factor which may play an important role in bone lesions associated with chronic inflammation and neoplasia. The cellular mechanisms for its production participate in the pathogenesis of these disorders.
Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats (2005)

Recombinant AAV vectors containing a dimerizer-inducible system of transcriptional activation provide a strategy for control of therapeutic gene expression in the CNS. Here we explored this system for regulated expression of human aromatic l-amino acid decarboxylase (hAADC) in a rodent model of Parkinson disease. Expression of hAADC, the enzyme that converts l-dopa to dopamine, was dependent on reconstitution of a functional transcription factor (TF) by the dimerizer rapamycin. Two vectors, AAV-CMV-TF and AAV-Z12-hAADC, were infused into striata of 6-OHDA-lesioned rats. Rapamycin-induced increases in expression of hAADC repeatedly produced robust rotational behavior in response to low doses of l-dopa. Seven weeks after vector infusion, AADC expression in brain was quantitated by both stereology and Western blot analysis following the final rapamycin treatment. While a low level of hAADC was observed in rats that were not induced with rapamycin, this basal expression was not significant enough to elicit a rotational response to l-dopa. This study demonstrated a robust behavioral response of parkinsonian rats to regulated hAADC expression. Recombinant AAV vectors controlled by rapamycin or its analogs show promise as candidates for CNS therapies in which regulation of the transgene is desired.
Investigation of a novel subarray nullsteering technique for distributed random arrays (2016)

This paper presents a new approach to phased array null-steering using randomly distributed antenna arrays. Classically, null-steering is done by applying adaptive amplitude tapers along individual phased array elements; however, this can be difficult and cumbersome to apply in a distributed system. To achieve the same effect, we propose a novel method which employs parasitic subarrays of circular topologies to precisely place nulls in specified directions of interest. Unlike typical adaptive beamforming algorithms, this process does not require the estimation of second order statistical metrics or knowledge of precise element placement; rather, it utilizes a shared aperture approach to generate null beams simultaneously. The analysis that proceeds examines the mean radiation pattern and mean distributions from finite element models to demonstrate the steering capability. The results show that shell annular and circular annular subarrays of the spherical random array composed of monopole elements steer deep nulls in precise increments.
The role of let-7 in cell differentiation and cancer (2009)

MicroRNAs (miRNAs or miRs) are small noncoding RNAs capable of regulating gene expression at the translational level. Current evidence suggests that a significant portion of the human genome is regulated by microRNAs, and many reports have demonstrated that microRNA expression is deregulated in human cancer. The let-7 family of microRNAs, first discovered in Caenorhabditis elegans, is functionally conserved from worms to humans. The human let-7 family contains 13 members located on nine different chromosomes, and many human cancers have deregulated let-7 expression. A growing body of evidence suggests that restoration of let-7 expression may be a useful therapeutic option in cancers, where its expression has been lost. In this review, we discuss the role of let-7 in normal development and differentiation, and provide an overview of the relationship between deregulated let-7 expression and tumorigenesis. The regulation of let-7 expression, cancer-relevant let-7 targets, and the relationship between let-7 and drug sensitivity are highlighted.
Intraneuronal Site of Action for Imipramine in Rat Striatal Slices (1980)

The uptake of 3H-labeled imipramine ([3H]IMI) in rat carpus striatum slices was found to be strongly temperature-dependent. The accumulation was shown to be saturable and two apparent Km's were found: 2.2 x 10(-8) and 3.5 x 10(-7) M. Once incorporated, the labeled drug was released from superfused slices by K+ (55 mM) depolarization in the presence of calcium ions. Imipramine was also studied for its ability to induce the release of [3H]dopamine ([2H]DA) which had been previously accumulated by striatal slices. It was found that striatal slices superfused during 1 or 6 min with imipramine (10(-6) - 10(-4) M) release substantial amounts of radioactive dopamine, independently of the presence of Ca2+ in the medium. This release is completely abolished after reserpine pretreatment. It is proposed that imipramine enters the dopaminergic storage vesicles and displaces dopamine. An intraneuronal mechanism of action for imipramine is discussed.
Comparison of the production and phenotypic properties of altered hepatocyte foci in rats initiated with diethylnitrosamine neonatally or after partial hepatectomy in early adulthood (1989)

The production and phenotypic properties of altered hepatocyte foci that appear prior to hepatic tumor formation were compared in rats initiated with a single low dose of diethylnitrosamine (DEN, 4 micrograms/g body weight), either neonatally or 24 h after partial hepatectomy at 57 days of age, and subsequently promoted with 0.05% dietary phenobarbital. All rats were killed at 100 days after initiation and their livers were examined for foci exhibiting between one and six histochemical markers as well as for cytomorphological changes detected by hematoxylin and eosin staining. Those foci that were detectable solely by histochemical means were designated hist(+)/morph({minus}) foci and those that also showed cytomorphological aberrations were classified as hist(+)/morph(+) foci. Frequencies, sizes, and histochemical phenotypes of foci in each of the two classes were determined by computer-assisted image analysis of stained serial sections from frozen livers. The results showed that the foci generated by the neonatal initiation protocol were substantially larger and more abundant than those produced by initiation after partial hepatectomy. Moreover, the focus populations generated by the two initiation systems differed in terms of their histochemical and cytomorphological properties, with the foci from the neonatal initiation protocol exhibiting greater evidence of deviation from normalcy (i.e., having higher proportions of foci with more histochemical markers and cytomorphological changes) than the foci from the partial hepatectomy protocol. 18 refs., 3 tabs.
Abscisic acid is not necessarily required for the induction of patchy stomatal closure (1998)

Patchy stomatal closure was observed in leaves of transgenic plants of Nicotiana plumbaginifolia producing antibodies that block the action of abscisic acid. Stomatal patchiness was induced by leaf detachment and subsequent water loss. Stomatal closure was followed by an irreversible reduction of maximal chlorophyll fluorescence. The degree of deviation from the A/ci-curve is correlated with steady-state diffusion conductance before leaf detachment. It is concluded that a heterogeneous sensitivity of stomata to abscisic acid is not directly involved in the induction of patchy stomatal closure.
Effect of KBr on the FTIR Spectra of NO3−LDHs (Layered Double Hydroxides) (2009)

Abstract Anion exchange of NO3−LDH with Br− of KBr, which leads to the formation of Br−LDH and NO3−-doped KBr, was found to occur during the preparation of KBr pellets for FTIR measurement, and the obtained spectra were composed of characteristic features of NO3− bands in NO3−LDH and in NO3−-doped KBr mixed in variable proportions depending on pellet preparation conditions.
L1 Report for the Enhanced Surveillance Campaign Experimental Benchmarking of Pu Electronic Structure (2006)

The objective of this work is to develop and/or apply advanced diagnostics to the understanding of aging of Pu. Advanced characterization techniques such as photoelectron and x-ray absorption spectroscopy will provide fundamental data on the electronic structure of Pu phases. These data are crucial for the validation of the electronic structure methods. The fundamental goal of this project is to narrow the parameter space for the theoretical modeling of Pu aging. The short-term goal is to perform experiments to validate electronic structure calculations of Pu. The long-term goal is to determine the effects of aging upon the electronic structure of Pu. Many of the input parameters for aging models are not directly measurable. These parameters will need to be calculated or estimated. Thus a First Principles-Approach Theory is needed, but it is unclear what terms are important in the Hamiltonian (H{Psi} = E{Psi}). Therefore, experimental data concerning the 5f electronic structure are needed, to determine which terms in the Hamiltonian are important. The data obtained in this task are crucial for reducing the uncertainty of Task LL-01-developed models and predictions. The data impact the validation of electronic structure methods, the calculation of defect properties, the evaluation of helium diffusion, and the validation of void nucleation models. The importance of these activities increases if difficulties develop with the accelerating aging alloy approach.
Reversible exposure of the pseudosubstrate domain of protein kinase C by phosphatidylserine and diacylglycerol. (1992)

The lipid activators of protein kinase C, phosphatidylserine and diacylglycerol, induce a reversible conformational change that exposes the auto-inhibitory pseudosubstrate domain of the enzyme. The pseudosubstrate domain of beta-II protein kinase C is cleaved after the first residue, arginine 19, by the endoproteinase Arg-C only when the kinase is bound to the activating lipid phosphatidylserine. Exposure of this residue is markedly enhanced by diacylglycerol. In contrast, the pseudosubstrate domain is not cleaved in the absence of lipids, when protein kinase C is bound to non-activating acidic lipids, when the kinase has autophosphorylated on the amino terminus, or after dilution of the activating lipids. This work reveals specificity in the interaction of protein kinase C with phosphatidylserine since only this phospholipid causes the specific conformational change detected in the regulatory domain of the enzyme, and demonstrates that allosteric regulators expose the intramolecular auto-inhibitory domain of a kinase.
Marking-up Multiple Views Of A Text: Discourse And Reference (1998)

We describe an encoding scheme for discourse structure and reference, based on the TEI Guidelines and the recommendations of the Corpus Encoding Specification (CES). A central feature of the scheme is a CES-based data architecture enabling the encoding of and access to multiple views of a marked-up document. We describe a tool architecture that supports the encoding scheme, and then show how we have used the encoding scheme and the tools to perform a discourse analytic task in support of a model of global discourse cohesion called Veins Theory (Cristea, Ide and Romary, forthcoming). 1. Introduction Recent work on discourse processing has demonstrated the need for large corpora annotated for relational structures in discourse (Cristea and Webber, 1997; Marcu, 1997a). Although corpora marked for discourse structure are beginning to exist,1 they are typically marked using ad hoc encoding formats that are designed to accommodate a specific piece of software and/or research need. No cohere...
Structural Brain Abnormalities in Patients with Primary Open-Angle Glaucoma: A Study with 3T MR Imaging (2012)

In patients with POAG, three-dimensional MRI revealed widespread abnormalities in the central nervous system beyond the visual cortex.
Effect of ionic strength on the activation parameters of fast electron-transfer reactions (1976)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEffect of ionic strength on the activation parameters of fast electron-transfer reactionsA. Ekstrom, A. B. McLaren, and L. E. SmytheCite this: Inorg. Chem. 1976, 15, 11, 2853–2856Publication Date (Print):November 1, 1976Publication History Published online1 May 2002Published inissue 1 November 1976https://doi.org/10.1021/ic50165a059RIGHTS & PERMISSIONSArticle Views28Altmetric-Citations13LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (515 KB) Get e-Alerts Get e-Alerts
The Use of Hypothermia Therapy in Traumatic Ischemic/Reperfusional Brain Injury: Review of the Literatures (2011)

Therapeutic mild hypothermia has been used widely in brain injury. It has evaluated in numerous clinical trials, and there is strong evidence for the use of hypothermia in treating patients with several types of ischemic / reperfusional (I/R) injuries, examples being cardiac arrest and neonatal hypoxic-ischemic encephalopathy.In spite of many basic research projects demonstrating effectiveness, therapeutic hypothermia has not been proven effective for the heterogeneous group of traumatic brain injury patients in multicenter clinical trials. In the latest clinical trial, however, researchers were able to demonstrate the significant beneficial effects of hypothermia in one specific group; patients with mass evacuated lesions. This suggested that mild therapeutic hypothermia might be effective for I/R related traumatic brain injury.In this article we have reviewed much of the previous literature concerning the mechanisms of I/R injury to the protective effects of mild therapeutic hypothermia.
Evaluation of a Thin CaF2(Eu) Scintillator for Detecting Tritium (1987)

The primary objective of this project was to investigate the feasibility of using a CaF2(Eu) scintillator for detecting low-energy beta particles from tritium. A proof-of-principle detector was designed to flow tritium-spiked nitrogen gas across the surface of a thin scintillator, which was optically coupled between two low-noise photomultiplier tubes. Electronics for operating two photomultiplier tubes in coincidence eliminated most of the tube noise pulses and allowed detection of small pulses from the low-energy tritium beta particles.