gebhart/patrepeval huggingface dataset:
"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence (2009)

Latently infected, resting memory CD4+ T cells and macrophages represent a major obstacle to the eradication of HIV-1. For this purpose, "shock and kill" strategies have been proposed (activation of HIV-1 followed by stimuli leading to cell death). Histone deacetylase inhibitors (HDACIs) induce HIV-1 activation from quiescence, yet class/isoform-selective HDACIs are needed to specifically target HIV-1 latency. We tested 32 small molecule HDACIs for their ability to induce HIV-1 activation in the ACH-2 and U1 cell line models. In general, potent activators of HIV-1 replication were found among non-class selective and class I-selective HDACIs. However, class I selectivity did not reduce the toxicity of most of the molecules for uninfected cells, which is a major concern for possible HDACI-based therapies. To overcome this problem, complementary strategies using lower HDACI concentrations have been explored. We added to class I HDACIs the glutathione-synthesis inhibitor buthionine sulfoximine (BSO), in an attempt to create an intracellular environment that would facilitate HIV-1 activation. The basis for this strategy was that HIV-1 replication decreases the intracellular levels of reduced glutathione, creating a pro-oxidant environment which in turn stimulates HIV-1 transcription. We found that BSO increased the ability of class I HDACIs to activate HIV-1. This interaction allowed the use of both types of drugs at concentrations that were non-toxic for uninfected cells, whereas the infected cell cultures succumbed more readily to the drug combination. These effects were associated with BSO-induced recruitment of HDACI-insensitive cells into the responding cell population, as shown in Jurkat cell models for HIV-1 quiescence. The results of the present study may contribute to the future design of class I HDACIs for treating HIV-1. Moreover, the combined effects of class I-selective HDACIs and the glutathione synthesis inhibitor BSO suggest the existence of an Achilles' heel that could be manipulated in order to facilitate the "kill" phase of experimental HIV-1 eradication strategies.
Generation and Characterization of Bispecific Tandem Diabodies for Tumor Therapy (2003)

Bispecific antibodies (BsAb) provide an effective means of retargeting cytotoxic effector cells against tumor cells (1). They have mainly been produced using murine hybrid hybridomas (2) or by chemical crosslinking (3,4). However, the immunogenicity of BsAb derived from rodent monoclonal antibodies (MAbs) is a major drawback for clinical use (5). They are also difficult to produce and purify in large quantities. Recent advances in recombinant antibody technology have provided several alternative methods for constructing and producing BsAb molecules (6) (Fig. 1). For example, single chain Fv (scFv) fragments have been genetically fused with adhesive polypeptides (7) or protein domains (8) to facilitate the formation of heterodimers (Fig. 1A). The genetic engineering of scFv-scFv tandems linked with a third polypeptide linker has also been carried out in several laboratories (9,10) (Fig. 1B). A bispecific diabody was obtained by the non-covalent association of two single chain fusion products consisting of the VH domain from one antibody connected by a short linker to the VL domain of another antibody (11,12) (see Chapter 18 of Arndt and Krauss in this issue) (Fig. 1C). The two antigen binding domains have been shown by crystallographic analysis to be on opposite sides of the diabody such that they are able to crosslink two cells (13). However, the co-secretion of two hybrid scFv fragments can give rise to two types of dimer: active heterodimers and inactive homodimers. A second problem is that the two chains of diabodies are held together by noncovalent associations of the VH and VL domains and can diffuse away from one another. Moreover, to ensure the assembly of a functional diabody, both hybrid scFv fragments must be expressed in the same cell in similar amounts. This latter requirement is difficult to uphold in eukaryotic expression systems such as yeast, which are often preferred because high yields of enriched product can be obtained (14,15). Finally, the small size of bispecific diabodies (50–60 kDa) leads to their rapid clearance from the bloodstream through the kidneys, thus requiring the application of relatively high doses for therapy. In contrast to native antibodies, all of the aforementioned bispecific molecules have only one binding domain for each specificity. However, bivalent binding is an important means of increasing the functional affinity and possibly the selectivity for particular cell types carrying densely clustered antigens.
A pilot study of IL-1 inhibition by anakinra in acute gout (2007)

Monosodium urate crystals stimulate monocytes and macrophages to release IL-1beta through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.
Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau (2000)

The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.
Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA) (2005)

Gefitinib (IRESSA), an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, has antitumour activity in the advanced non-small-cell lung cancer (NSCLC) setting. However, in chemotherapy-naïve patients with advanced NSCLC, the addition of gefitinib to standard chemotherapy regimens failed to increase survival. These results suggest the need for improved patient selection and combination rationales for targeted therapies. We have identified subpopulations of an adenocarcinoma cell line that are naturally resistant to gefitinib, and have analysed the cDNA expression profiles, genomic status of EGFR gene and the effect of gefitinib on signalling pathways in these cell lines in order to identify key mechanisms for naturally acquired resistance to gefitinib. Gefitinib-resistant subpopulations demonstrated increased Akt phosphorylation (not inhibited by gefitinib), reduced PTEN protein expression and loss of the EGFR gene mutation when compared with parental cell lines. These differences in Akt and PTEN protein expression were not evident from the cDNA array profiles. These data suggests that (1) the EGFR gene mutation may be possibly lost in some cancer cells with other additional mechanisms for activating Akt, (2) reintroduction of PTEN or pharmacological downregulation of the constitutive PI3K-Akt-pathway activity may be an attractive therapeutic strategy in cancers with gefitinib resistance.
Ultra-Responsive Phase Shifters for Depletion Mode Silicon Modulators (2013)

We propose a novel phase shifter design for carrier depletion based silicon modulators, based on an experimentally validated model. We note that the heretofore neglected effect of incomplete ionization will have a significant impact on ultra-responsive phase shifters. We predict a low V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">π</sub> L product of 0.31 V.cm associated with a low propagation loss of 20 dB/cm. This would enable significantly smaller Mach-Zehnder modulators to be constructed that nonetheless would have low drive voltages, with substantial decreases in insertion loss. The proposed fabrication process is of minimal complexity; in particular, no high-resolution lithographic step is required.
PMUT: a web-based tool for the annotation of pathological mutations on proteins (2005)

PMUT allows the fast and accurate prediction (approximately 80% success rate in humans) of the pathological character of single point amino acidic mutations based on the use of neural networks. The program also allows the fast scanning of mutational hot spots, which are obtained by three procedures: (1) alanine scanning, (2) massive mutation and (3) genetically accessible mutations. A graphical interface for Protein Data Bank (PDB) structures, when available, and a database containing hot spot profiles for all non-redundant PDB structures are also accessible from the PMUT server.
A rapid method for localized mutagenesis of yeast genes (1992)

We have developed a simple procedure for the localized mutagenesis of yeast genes. In this technique the region of interest is first amplified under mutagenic polymerase chain reaction (PCR) conditions. Cotransformation of the PCR product with a gapped plasmid containing homology to both ends of the PCR product allows in vivo recombination to repair the gap with the mutagenized DNA. This procedure is efficient, allows targeting of specific regions for mutagenesis, and requires no subcloning steps in Escherichia coli.
Gene regulation and epigenetics in Friedreich's ataxia (2013)

This is an exciting time in the study of Friedreich's ataxia. Over the last 10 years much progress has been made in uncovering the mechanisms, whereby the Frataxin gene is silenced by (GAA)n repeat expansions and several of the findings are now ripe for testing in the clinic. The discovery that the Frataxin gene is heterochromatinised and that this can be antagonised in vivo has led to the tantalizing possibility that the disease might be amenable to a more radical therapeutic approach involving epigenetic modifiers. Here, we set out to review progress in the understanding of the fundamental mechanisms whereby genes are regulated at this level and how these findings have been applied to achieve a deeper understanding of the dysregulation that occurs as the primary genetic lesion in Friedreich's ataxia.
Selective Targeting of Gene Transfer to Vascular Endothelial Cells by Use of Peptides Isolated by Phage Display (2000)

Our study demonstrates the feasibility of using small, novel peptides isolated via phage display to target gene delivery specifically and efficiently to HUVECs and highlights their use for retargeting both viral and nonviral gene transfer to vascular endothelial cells for future clinical applications.
Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-d-glucose (2007)

Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-d-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF(+)) or absence (HIF(-)) of hypoxia, (b) cells treated with small interfering RNA specific for HIF-1alpha and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF(+) counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.
Pharmacokinetics of cyclophosphamide in man (1971)

1. The pharmacokinetics of cyclophosphamide were investigated in cancer patients. The data can be characterized by a two-compartment open model. The half life of the elimination phase of the drug ranged between 3 and 11 hours.2. Extensive tubular reabsorption of the drug resulted in the excretion of only a small percentage of the administered dose. The mean renal clearance was 10.7 ml/minute.3. The calculated fraction of the dose of drug which was metabolized averaged 88%.
Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans (2010)

Elevated cardiac-specific miR-208a in plasma may be a novel biomarker for early detection of myocardial injury in humans.
Antigen-armed antibodies targeting B lymphoma cells effectively activate antigen-specific CD4+ T cells (2015)

The treatment of non-Hodgkin lymphomas has benefited enormously from the introduction of monoclonal antibody-based therapies. However, the efficacy of these treatments varies with lymphoma subtypes and typically decreases with subsequent relapses. Here, we report on antigen-armed antibodies (AgAbs) as a potential treatment of B-cell lymphoma. AgAbs include antigens from ubiquitous pathogens, such as Epstein-Barr virus (EBV), that persist in their host and elicit strong lifelong T-cell responses. They act as vectors by introducing antigen directly into tumor cells to induce an antigen-specific CD4(+) T-cell response against these cells. We have fused antibodies targeting human B-cell surface receptors (CD19-22) to immunodominant T-cell antigens from EBV proteins, including EBNA1, EBNA3B, and EBNA3C. Exposure of EBV-transformed B cells and of Burkitt lymphoma cells to AgAbs led to antigen presentation, T-cell recognition, and target cell killing. The efficiency of AgAb action paralleled the abundance of the targeted molecules on lymphoma cells as well as their HLA class II expression levels. AgAbs can also induce activation and proliferation of EBV-specific memory CD4(+) T cells ex vivo. These studies show the potential of AgAbs as an effective therapeutic strategy against B-cell lymphomas.
Catalyzed Catalysis Using Carbophilic Lewis Acidic Gold and Lewis Basic Palladium: Synthesis of Substituted Butenolides and Isocoumarins (2009)

A new strategy for gold and palladium dual-catalytic reactivity and turnover, called catalyzed catalysis, enhanced the synthetic usefulness of vinylgold intermediates by providing dual-catalytic carbon-carbon cross-coupling as an alternative to protodemetalation. This protocol enabled the synthesis of substituted butenolides and isocoumarins from allyl esters. Kinetic and spectroscopic experiments support a mechanism in which the Lewis acidic gold complex catalyzes both an initial rearrangement step and a subsequent Lewis basic palladium oxidative-addition step.
Electrochemical Measurement of the Solvent Accessibility of Nucleobases Using Electron Transfer between DNA and Metal Complexes (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTElectrochemical Measurement of the Solvent Accessibility of Nucleobases Using Electron Transfer between DNA and Metal ComplexesDean H. Johnston, Katherine C. Glasgow, and H. Holden ThorpCite this: J. Am. Chem. Soc. 1995, 117, 35, 8933–8938Publication Date (Print):September 1, 1995Publication History Published online1 May 2002Published inissue 1 September 1995https://pubs.acs.org/doi/10.1021/ja00140a006https://doi.org/10.1021/ja00140a006research-articleACS PublicationsRequest reuse permissionsArticle Views1131Altmetric-Citations333LEARN 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
A general strategy for producing conditional alleles of Src-like tyrosine kinases. (1995)

The Src-like tyrosine kinases require membrane localization for transformation and probably for their normal role in signal transduction. We utilized this characteristic to prepare Src-like tyrosine kinases that can be readily activated with the rationally designed chemical inducer of dimerization FK1012. Dimerization of cytoplasmic Src-like tyrosine kinases was not sufficient for signaling, but their recruitment to the plasma membrane led to the rapid activation of transcription factors identical to those regulated by crosslinking the antigen receptor. Moreover, recruitment of activated Src-like kinases to the membrane replaced signaling by the T-lymphocyte antigen receptor complex, leading to the activation of both the Ras/protein kinase C and Ca2+/calcineurin pathways normally activated by antigen receptor signaling. Since these chemical inducers of dimerization are cell permeable, this approach permits the production of conditional alleles of any of the Src-like tyrosine kinases, thereby allowing a delineation of their developmental roles.
The use of real‐time quantitative polymerase chain reaction and comparative genomic hybridization to identify amplification of the REL gene in follicular lymphoma (2000)

Using comparative genomic hybridization (CGH), aberrations in DNA copy number were studied before and after transformation of follicular lymphoma to diffuse large B‐cell lymphoma in six patients (15 lymph node biopsies in total). The most common and also the most discrete and intense amplification occurring in four out of 15 biopsies from three different patients was of 2p13–16. Using real‐time quantitative polymerase chain reaction (RQ‐PCR), REL amplification was found to be implicated at this locus. This technique also identified amplified REL in a further two biopsies, presumably below the detection level of CGH. REL amplification was quantified by comparing it, in most cases, with three endogenous reference genes, albumin , β 2 ‐microglobulin and CD8α , that lie close to REL on 2p. There was no correlation apparent between 2p13–16 amplification or REL amplification and transformation. This study shows the usefulness of coupling CGH, for detecting recurring abnormalities, with the real‐time PCR technique for rapid gene dosage quantification and confirms that the REL gene is a potential candidate in the pathogenesis of a particular subset of follicular lymphomas.
Comparison of the Effects of Phenethyl Isothiocyanate and Sulforaphane on Gene Expression in Breast Cancer and Normal Mammary Epithelial Cells (2009)

Phenethyl isothiocyanate (PEITC) and sulforaphane (SF) exhibit tumor preventive activity in lung, prostate, breast and colon cancers. Our objective was to examine the effect of these two isothiocyanates on estrogen receptor-related genes, and genes related to apoptosis and cell cycle in the estrogen-dependent breast cancer cell line MCF7 and in normal human epithelial breast (HME) cells. We treated cells with 0.3 microM or 3.0 microM concentrations of PEITC or SF. In HME cells, gene expression was significantly altered for 23 genes by PEITC at a concentration of 0.3 microM and 4 genes at 3.0 microM. SF altered the expression of 16 genes at a concentration of 0.3 microM and 2 genes at 3.0 microM. In HME cells, genes altered by both PEITC and SF exhibited changes in gene expression that were similar in extent as well as direction of change. In MCF-7 cells, PEITC did not produce any significant changes in the gene expression at both treatment levels. SF produced significant changes in 7 genes, but only at the higher treatment level of 3.0 microM. Normal mammary cells exhibited more changes in the expression of estrogen receptor related genes than did breast cancer cells, and significantly these changes occurred predominantly at the low concentration of 0.3 microM, a concentration achievable by dietary input of isothiocyanates. Novel findings were the upregulation of the pro-apoptotic gene BAD and estrogen receptor beta gene in normal human mammary cells. These gene alterations observed, along with upregulation of tumor suppressors p21 and p27, may provide a protective effect to mammary cells against breast cancer.