gebhart/patrepeval huggingface dataset:
Enhanced antiproliferative effects of alkoxyalkyl esters of cidofovir in human cervical cancer cells in vitro (2006)

Nearly all cervical cancers are associated with the high-risk subtypes of human papillomavirus (HPV) expressing the E6 and E7 oncoproteins. The E6 and E7 oncoproteins reduce cellular levels of the p53 and the retinoblastoma (pRb) tumor suppressors, respectively, and represent an important component of the malignant phenotype. Several groups have shown that treatment with cidofovir suppresses levels of E6 and E7, restoring cellular p53 and pRb levels, in turn slowing cell replication and increasing the susceptibility of the cancer cells to radiation and apoptosis. Recently, our group synthesized alkoxyalkyl esters of cidofovir, which were found to be >100 times more active than unmodified cidofovir in vitro against various double-stranded DNA viruses, including cytomegalovirus, herpes simplex virus, adenoviruses, cowpox, vaccinia, and variola viruses. We compared the activity of octadecyloxyethyl-cidofovir (ODE-CDV) and oleyloxyethyl-cidofovir (OLE-CDV) with that of unmodified cidofovir against both HPV-negative and HPV-positive cervical cancer cells. We compared the antiproliferation activity in CaSki, HeLa, and Me-180 cells, prototypical HPV-positive cell lines bearing the HPV-16, HPV-18, and HPV-68 high-risk subtypes, with the activity in C33A cells, a cervical cancer cell line lacking HPV, and in nonmalignant primary human foreskin fibroblast cells. OLE-CDV and ODE-CDV were several logs more potent than cidofovir in CaSki, Me-180, HeLa, and C33A cervical cancer cells as determined by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt proliferation assay. Cell cycle analysis indicates that the cidofovir analogues interfere with passage of dividing cells through the S phase. ODE-CDV and OLE-CDV were 500 to 17,000 times more active than cidofovir in inhibiting the growth of cervical cancer cells. ODE-CDV and OLE-CDV showed selectivity for cervical cancer cells versus nonmalignant human foreskin fibroblast cells and warrant further investigation as potential therapies for cervical cancer.
Rejection of a nonimmunogenic melanoma by vaccination with natural melanoma peptides on engineered antigen-presenting cells (1997)

Naturally processed peptides, obtained by acid extraction of tumor cells, contain Ags able to activate specific CTL in vitro. We recently reported that the nonprofessional APC, RMA-S, expressing the B7.1 molecule (RMA-S/B7), pulsed with naturally processed peptides from the nonimmunogenic B16F1 melanoma (B16F1a.e.) primed syngenic CD8+ T cells against the tumor in vitro. Here, we show the rejection of B16F1 melanoma by C57BL/6 mice after immunization with RMA-S/B7 cells pulsed with B16F1a.e. This response is critically dependent on both CD4+ and CD8+ cells, but not on NK cells. However, only CD8+ T cells exert anti-B16F1 cytolitic activity in vitro. Moreover, RMA-S/B7 cells pulsed with B16F1a.e. can be used to prevent the growth of 24-h preestablished melanomas. These results may have important implications for the clinical use of natural peptide fractions of tumor cells as therapeutic cancer vaccines.
Androgen Receptor on the Move: Boarding the Microtubule Expressway to the Nucleus (2012)

Recent studies have shown that the microtubule-stabilizing drug paclitaxel, which is commonly used for the treatment of prostate cancer, inhibits signaling from the androgen receptor by inhibiting its nuclear accumulation downstream of microtubule stabilization. This mechanism is independent of paclitaxel-induced mitotic arrest and could provide an alternative mechanism of drug action that can explain its clinical activity. In this review, we highlight the importance of signaling and trafficking pathways that depend on intact and dynamic microtubules, and, as such, they represent downstream targets of microtubule inhibitors. We showcase prostate cancer, which is driven by the activity of the androgen receptor, as recent reports have revealed a connection between the microtubule-dependent trafficking of the androgen receptor and the clinical efficacy of taxanes. Identification and further elucidation of microtubule-dependent tumor-specific pathways will help us better understand the molecular basis of clinical taxane resistance as well as to identify individual patients more likely to respond to treatment.
Site-directed mutagenesis reveals functional contribution of Thr218, Lys220 and Asp304 in chymosin (1990)

The functional contributions of amino acid residues Thr218 and Asp304 of chymosin, both of which are highly conserved in the aspartic proteinases, are analysed by means of site-directed mutagenesis. The optimum pH values, milk-clotting (C) and proteolytic (P) activities and kinetic parameters for synthetic oligopeptides as substrates were examined for the mutant enzymes. The mutation Thr218Ser caused a marked increase in the C/P ratio, which seemed to be due to a change in substrate recognition. Although the negative charge of Asp304 had been expected to play a role in lowering the optimum pH values in the aspartic proteinases, this turned out not to be the case in chymosin because both the mutations Asp304Ala and Asp304Glu caused a similar shift of the optimum pH towards the acidic side. In addition, the mutation Lys220Leu, which we generated previously, was found to cause a decrease in the C/P ratio, mainly due to the increase in the proteolytic activity.
Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide (2015)

There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.
The vascular protective effects of estrogen (1996)

There is now strong epidemiological evidence that estrogen replacement therapy has a protective effect in postmenopausal women. The cardiovascular protective action of estrogen is reported to be mediated indirectly by an effect on lipoprotein metabolism and by a direct effect on the vessel wall itself. Estrogen is active both in vascular smooth muscle and endothelium. Functionally competent estrogen receptors have been identified in vascular smooth muscle cells, and specific binding sites have been demonstrated in endothelium. Estrogen administration promotes vasodilation both in human and experimental animals, in part by stimulating] prostacyclin and nitric oxide synthesis. Both the prostaglandin synthase and the constitutive nitric oxide synthase were recently reported to be induced by estrogen treatment. In vitro, estrogen exerts a direct inhibitory effect on the smooth muscle by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, estradiol-17 beta prevents neointimal thickening after balloon injury and in rabbit cardiac transplant allografts. These data are consistent with in vitro studies wherein estrogen inhibits [3H]thymidine uptake by arterial segments from porcine coronary artery as well as proliferation of rabbit aortic vascular smooth muscle cells induced by hyperlipedemic serum. Recent studies have also reported an effect of estrogen on directed vascular smooth muscle cell migration. Furthermore, like other steroids, the effect of estrogen on the vessel wall has a rapid nongenomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression. The nature of these estrogen response genes in the vessel wall and their relation to vasodilation and antiproliferation remain to be determined.
GM‐CSF promotes proliferation of human fetal and adult microglia in primary cultures (1994)

Proliferation of microglia/macrophages is a common finding in many central nervous system diseases. To identify mitogenic signals for human microglia, we examined primary cultures of human fetal and adult microglia after stimulation with cytokines, colony stimulating factors (CSFs), or LPS, using proliferating cell nuclear antigen (PCNA) expression as an index of cell proliferation. The results showed that both M-CSF and GM-CSF induced microglial proliferation in fetal and adult human cultures, but that GM-CSF provided a much stronger stimulus. At 96 h post-stimulation, the mean PCNA labeling index was 2.4 for M-CSF and 13.3 for GM-CSF in fetal microglia; in adult microglia, the PCNA labeling index was 4.7 for M-CSF and 9.0 for GM-CSF. The effect of GM-CSF on fetal microglia was dose dependent and synergistic with M-CSF. LPS abolished the basal level of PCNA labeling in adult microglia, but in fetal microglia, caused a slight increase in PCNA labeling (1.9) at 96 h and consistently enhanced microglial cell survival and differentiation into highly branched cells. The production of GM-CSF in purified human fetal astrocyte and microglial cultures was examined after stimulation with LPS, TNF-alpha, or IL-1 beta. Unlike M-CSF, neither cell type produced GM-CSF in unstimulated cultures; however, when stimulated with IL-1 beta, astrocytes expressed GM-CSF mRNA and protein, which accumulated in the culture through 72 h. In microglia, LPS was the only effective inducing agent. An immunocytochemical study performed to identify in vivo sources of GM-CSF revealed selective labeling of reactive astrocytes in active lesions of multiple sclerosis and senile plaques of Alzheimer's disease. Our data demonstrate that both fetal and adult human microglia are capable of proliferation in response to CSFs, GM-CSF being the more effective stimulus.
Identification, Characterization, and Cloning of a Phosphonate Monoester Hydrolase from Burkholderia caryophilli PG2982 (1996)

The glyphosate-degrading bacterium, Burkholderia caryophilli PG2982, was observed to utilize glyceryl glyphosate as a sole phosphorus source. The hydrolysis of glyceryl glyphosate to glyphosate by a phosphonate ester hydrolase (PEH) was identified as the first metabolic step in the mineralization pathway. This observation provides the first biological role for a phosphonate ester hydrolase activity. Purified PEH enzyme hydrolyzed several phosphonate esters including p-nitrophenyl phenylphosphonate, beta-naphthyl phenylphosphonate, and 5-bromo-4-chloro-3-indolyl phenylphosphonate. The purified PEH also hydrolyzed some phosphodiesters including p-nitrophenyl 5'-thymidine monophosphate and p-nitrophenyl phosphorylcholine. The most catalytically efficient substrate identified was bis-(p-nitrophenyl) phosphate with a Km of 0.9 mM and a kcat of 6.2 x 10(2) min-1, suggesting that the enzyme may also function in vivo as a phosphodiesterase. The native enzyme was a homotetramer of 58-kDa subunits and exhibited a pI of 4.2. The enzyme activity had a pH activity optimum of 9.0 and was stimulated 14-fold by Mn2+ ions, but a metal cofactor was not essential for activity. N-terminal and tryptic fragment amino acid sequences were obtained from the purified PEH protein and used to clone the B. caryophilli PG2982 gene, designated pehA. The unique substrate specificity of the enzyme and potential use as a novel conditional lethal gene in plants are discussed.
Isolation and identification of microorganisms for the degradation of Dicamba (1989)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and identification of microorganisms for the degradation of DicambaJames P. Krueger, Robert G. Butz, Yousef H. Atallah, and Douglas J. CorkCite this: J. Agric. Food Chem. 1989, 37, 2, 534–538Publication Date (Print):March 1, 1989Publication History Published online1 May 2002Published inissue 1 March 1989https://pubs.acs.org/doi/10.1021/jf00086a057https://doi.org/10.1021/jf00086a057research-articleACS PublicationsRequest reuse permissionsArticle Views412Altmetric-Citations38LEARN 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
Use of Akt Inhibitor and a Drug-resistant Mutant Validates a Critical Role for Protein Kinase B/Akt in the Insulin-dependent Regulation of Glucose and System A Amino Acid Uptake (2008)

Protein kinase B (PKB)/Akt has been strongly implicated in the insulin-dependent stimulation of GLUT4 translocation and glucose transport in skeletal muscle and fat cells. Recently an allosteric inhibitor of PKB (Akti) that selectively targets PKBalpha and -beta was reported, but as yet its precise mechanism of action or ability to suppress key insulin-regulated events such as glucose and amino acid uptake and glycogen synthesis in muscle cells has not been reported. We show here that Akti ablates the insulin-dependent regulation of these processes in L6 myotubes at submicromolar concentrations and that inhibition correlates tightly with loss of PKB activation/phosphorylation. Similar findings were obtained using 3T3-L1 adipocytes. Akti did not inhibit IRS1 tyrosine phosphorylation, phosphatidylinositol 3-kinase signaling, or activation of Erks, ribosomal S6 kinase, or atypical protein kinases C but significantly impaired regulation of downstream PKB targets glycogen synthase kinase-3 and AS160. Akti-mediated inhibition of PKB requires an intact kinase pleckstrin homology domain but does not involve suppression of 3-phosphoinositide binding to this domain. Importantly, we have discovered that Akti inhibition is critically dependent upon a solvent-exposed tryptophan residue (Trp-80) that is present within the pleckstrin homology domain of all three PKB isoforms and whose mutation to an alanine (PKB(W80A)) yields an Akti-resistant kinase. Cellular expression of PKB(W80A) antagonized the Akti-mediated inhibition of glucose and amino acid uptake. Our findings support a critical role for PKB in the hormonal regulation of glucose and system A amino acid uptake and indicate that use of Akti and expression of the drug-resistant kinase will be valuable tools in delineating cellular PKB functions.
High-Sulphur Proteins From a-Keratins I. Heterogeneity of the Proteins From Mouse Hair (1976)

The heterogeneity of the reduced and S-carboxymethylated high-sulphur protein fraction from mouse hair has been examined by chromatography and polyacrylamide gel electrophoresis at pH values above and below the isoelectric region. Considerable heterogeneity is observed both in size (molecular weight range 12000-45000) and in charge. Amino acid analysis of a number of column chromatographic fractions shows the high-sulphur proteins to be largely composed of proteins with a carboxymethylcysteine content above 25 residues and a pronounced heterogeneity in arginine content. Their chromatographic behaviour is similar to that observed for the ultra-high-sulphur proteins from wool.
Achieving Antigen-Specific Tolerance in Diabetes: Regulating Specifically (2005)

Autoreactive T cells that escape negative selection in the thymus do not normally cause productive immune responses to self-antigens because of a number of regulatory mechanisms. Studies with anti-CD3 monoclonal antibodies (mAbs) have suggested that immune regulatory mechanisms are induced by drug treatments that are able to stop on-going unwanted immune responses, such as type 1 diabetes, involving induction of regulatory T cells. TGF-beta dependent and independent mechanisms have been described involving CD4(+) as well as CD8(+) T cells. The challenge is now to apply these mechanisms in an antigen-specific manner and so that lasting tolerance to the autoimmune responses can be maintained. We discuss recent data concerning the mechanisms of anti-CD3 mAb treatment and the ways in which our understanding of these mechanisms can be used to develop adoptive immune therapy with regulatory T cells to treat patients with type 1 diabetes or other autoimmune diseases.
Transfer of Some Carboxylic Acids in the Olfactory System Following Intranasal Administration (1999)

The uptake of [14C]benzoic acid, 4-chloro[14C]benzoic acid, [3H]phthalic acid and [14C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [14C]benzoic acid and [14C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [14C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [14C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.
A ligand-dependent hammerhead ribozyme switch for controlling mammalian gene expression (2010)

The possibility to externally control gene expression is of fundamental importance in both basic and applied life sciences. Although there are some techniques available to regulate expression in mammalian cells, they rely on the presence of ligand-sensing transcription factors, making it necessary to generate cell lines or organisms that stably express these regulatory factors. In recent years, mechanisms relying on direct RNA-ligand interactions for controlling gene expression have been both discovered in nature and engineered artificially. Among the latter, RNA switches relying on catalytically active RNA have been described. In principle, ligand-dependent triggering of mRNA self-cleavage should be a universal mechanism in order to control gene expression in a variety of organisms. Nevertheless, no examples of such aptazymes acting as RNA-based switches have been reported so far in mammalian cells. Here we present the theophylline-induced activation of an mRNA-based hammerhead ribozyme, resulting in an off-switch of gene expression. Starting from an artificial aptazyme switch reported to function in bacteria, we identified and optimized important parameters such as artificial start codons and the communicating sequence connecting ribozyme and aptamer, resulting in an RNA switch that allows for controlling transgenic expression in mammalian cells without the need to express a corresponding ligand-sensing transcription factor.
Dehydrogenase and transhydrogenase properties of the soluble NADH dehydrogenase of bovine heart mitochondria. (1977)

The soluble NADH dehydrogenase of low molecular weight, isolated from complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) of the respiratory chain, has been shown to have NADPH dehydrogenase and NADPH leads to NAD transhydrogenase activities. Both activities are greatly increased in the presence of added guanidine-HCl and at pH values less than 6.5. The chromophores of the soluble enzyme (flavin and iron--sulfur centers) are reduced by NADH and NADPH to the same extent. The latter reduction is extremely slow, and is considerably stimulated in the presence of guanidine-HCl. The soluble dehydrogenase has little or no NADH leads to NADP and NADPH leads to NADP transhydrogenase activity. The former reaction is known to be energy-linked in submitochondrial particles; the latter was shown in the present studies also to be energy-linked. In view of the above and earlier results, possible mechanisms for dehydrogenation and transhydrogenation (nonenergy-linked and energy-linked) involving reduced and oxidized NAD and NADP are proposed.
Code injection in C and C++: a survey of vulnerabilities and countermeasures (2004)

Implementation errors relating to memory-safety are the most common vulnerabilities used by attackers to gain control over the execution-flow of an application. By carefully crafting an exploit for these vulnerabilities, attackers can make an application transfer execution-flow to code that they have injected. Such code injection attacks are among the most powerful and common attacks against software applications. This report documents possible vulnerabilities in C and C++ applications that could lead to situations that allow for code injection and describes the techniques generally used by attackers to exploit them. A fairly large number of defense techniques have been described in literature. An important goal of this report is to give a comprehensive survey of all available preventive and defensive countermeasures that either attempt to eliminate specific vulnerabilities entirely or attempt to combat their exploitation. Finally, the report presents a synthesis of this survey that allows the reader to weigh the advantages and disadvantages of using a specific countermeasure as opposed to using another more easily.