gebhart/patrepeval huggingface dataset:
S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability (2014)

Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.
A volume-activated cell sorter. (1977)

A sorter that is activated by the resistance pulses of a Coulter orifice (volume detector) has been developed. The problem arising from the distortion of the volume signals produced by the electric droplet forming and charging voltages are avoided by special shielding and grounding of the volume detector. Experiments with beads and leukocytes are described. The maximal processing rate at this time is 2000 cells/sec, the purity of sorted fractions is better than 97%, and the viability of sorted cells is better than 80%.
Harnessing a High Cargo-Capacity Transposon for Genetic Applications in Vertebrates (2006)

Viruses and transposons are efficient tools for permanently delivering foreign DNA into vertebrate genomes but exhibit diminished activity when cargo exceeds 8 kilobases (kb). This size restriction limits their molecular genetic and biotechnological utility, such as numerous therapeutically relevant genes that exceed 8 kb in size. Furthermore, a greater payload capacity vector would accommodate more sophisticated cis cargo designs to modulate the expression and mutagenic risk of these molecular therapeutics. We show that the Tol2 transposon can efficiently integrate DNA sequences larger than 10 kb into human cells. We characterize minimal sequences necessary for transposition (miniTol2) in vivo in zebrafish and in vitro in human cells. Both the 8.5-kb Tol2 transposon and 5.8-kb miniTol2 engineered elements readily function to revert the deficiency of fumarylacetoacetate hydrolase in an animal model of hereditary tyrosinemia type 1. Together, Tol2 provides a novel nonviral vector for the delivery of large genetic payloads for gene therapy and other transgenic applications.
Hepatic safety of galcanezumab in patients with migraine: Results of three Phase 2 double-blind placebo-controlled trials (P2.164) (2017)

To determine the hepatic safety of galcanezumab injection compared with placebo.
Phase I trial of an oral immunomodulator and interferon inducer in cancer patients. (1993)

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a compound of low molecular weight that, when administered p.o., induces interferon-alpha in several animal species and inhibits tumor growth in mice. To determine maximum tolerated dose, toxicity, and biological response in humans, a phase I clinical trial was conducted with 14 eligible cancer patients who received 100-500 mg imiquimod p.o. either once or twice weekly. Imiquimod induced interferon-alpha in serum in 10 of 19 doses of 200-300 mg. Interferon serum levels peaked 8-24 h after treatment and reached a maximum of 23,000 IU/ml in one patient. Significant mean increases (P < 0.01) in serum beta 2-microglobulin (1.5-fold), serum neopterin (3.5-fold), and 2-5A synthetase activity in peripheral blood mononuclear cells (7.9-fold) indicated that 200-300 mg imiquimod had biological and immunological activity in all evaluable patients. Increases in serum interferon, beta 2-microglobulin, and neopterin correlated significantly with dose (P < 0.001). No patient developed measurable antibody to interferon-alpha. Dose-limiting side effects included fatigue, malaise, fever, headache, and lymphocytopenia; no hepatic or renal toxicity or other hematological changes exceeded the normal range. Patients tolerated weekly doses of up to 500 mg, with the longest treatment lasting 4 weeks at 200 mg weekly. Twice-weekly doses up to to 300 mg were tolerated, with the longest twice-weekly treatments being 200 mg for 9 weeks and 100 mg for 25 weeks. No clinical responses were observed. Imiquimod, as an oral inducer of interferon, may have therapeutic usefulness in human cancers, viral infections, and other diseases. However, before initiation of phase II trials, additional work will be required to establish a tolerated dose and schedule for continued administration.
IDENTIFYING JUSTIFICATIONS IN WRITTEN DIALOGS BY CLASSIFYING TEXT AS ARGUMENTATIVE (2011)

In written dialog, discourse participants need to justify claims they make, to convince the reader the claim is true and/or relevant to the discourse. This paper presents a new task (with an associated corpus), namely detecting such justifications. We investigate the nature of such justifications, and observe that the justifications themselves often contain discourse structure. We therefore develop a method to detect the existence of certain types of discourse relations, which helps us classify whether a segment is a justification or not. Our task is novel, and our work is novel in that it uses a large set of connectives (which we call indicators), and in that it uses a large set of discourse relations, without choosing among them.
Multiple genes for G protein‐coupled receptors and their expression in lingual epithelia (1993)

Using the polymerase chain reaction (PCR), we identified a gene family including more than 60 members which encoded similar G protein-coupled seven-transmembrane receptors. Sequence analyses of six representatives out of the 60 PCR clones showed that they had significant structural similarity to olfactory and optic receptors. Their expression is restricted in the surface of lingual epithelia.
Effects of Three Insect Growth Regulators, Feeding Substrates, and Colony Origin on Survival and Presoldier Production of the Formosan Subterranean Termite (Isoptera: Rhinotermitidae) (1985)

Journal Article Effects of Three Insect Growth Regulators, Feeding Substrates, and Colony Origin on Survival and Presoldier Production of the Formosan Subterranean Termite (Isoptera: Rhinotermitidae) Get access Nan-Yao Su, Nan-Yao Su 1 Department of Entomology, University of Hawaii, Honolulu, Hawaii 96822 1Current address: Ft. Lauderdale Res. and Educ. Ctr., Univ. of Florida, IFAS, 3205 College Ave., Ft. Lauderdale, FL 33314. Search for other works by this author on: Oxford Academic PubMed Google Scholar Minoru Tamashiro, Minoru Tamashiro Department of Entomology, University of Hawaii, Honolulu, Hawaii 96822 Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael I. Haverty Michael I. Haverty Department of Entomology, University of Hawaii, Honolulu, Hawaii 96822 Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Economic Entomology, Volume 78, Issue 6, 1 December 1985, Pages 1259–1263, https://doi.org/10.1093/jee/78.6.1259 Published: 01 December 1985 Article history Received: 01 February 1985 Accepted: 20 August 1985 Published: 01 December 1985
Human gamma interferon increases the binding of T lymphocytes to endothelial cells. (1985)

Binding of lymphocytes to human umbilical vein endothelial cells (EC) was quantitated by measuring adhesion of 51Cr labelled lymphocytes to endothelial cell monolayers and rosette formation between lymphocytes and EC in suspension. Mitogen stimulated human peripheral blood mononuclear cell culture supernatants and mixed lymphocyte reaction supernatants enhanced the binding of T lymphocytes to EC monolayers or suspensions preincubated with such supernatants. The active component of these supernatants appeared to be gamma interferon (IFN-gamma) since culture supernatants lost activity after heating at 56 degrees C for 60 min, exposure to pH 2.0 or treatment with anti-IFN-gamma. In addition, purified IFN-gamma increased the binding of T lymphocytes to EC (T-EC). This occurred in a concentration dependent manner when IFN-gamma was preincubated with EC but not with lymphocytes. While the optimum concentration of IFN-gamma was 250 u/ml, a significant enhancement was seen with as little as 10 u/ml. These findings suggest that IFN-gamma may play a part in the emigration of lymphocytes to perivascular chronic inflammatory sites by augmenting the adhesion of lymphocytes to the endothelium of small blood vessels.
In utero antiepileptic drug exposure (2006)

More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.
The use of multiple textual forms in distance learning (2000)

This article reports on a study of how students perceive, access and evaluate the different textual forms which comprise a distance education course. The setting for the study was an introductory distance programme in Spanish, using print, aural and visual media. Thirty one students completed a self-report questionnaire which investigated the following aspects of the use of multiple textual forms: primary vs. secondary sources, preferences for initial input, intertextual links, time allocation, source evaluation. Findings revealed a consistent pattern in terms of conceptions of primary vs. secondary sources: in particular, the study guide was consistently judged to be central to the course, more so than other print, visual or aural sources. Students' reported behaviour when embarking on a new unit revealed a distinct preference for either verbal or visual input, each providing a qualitatively different orientation to the unit. Intertextual links characterised the way students worked with the multiple texts: it was possible to identify two 'anchor' texts, which acted as the base texts and were supplemented by other sources. Responses of students highlighted the importance of multiple texts for learning, largely because of their complementary nature, the 'relief' they provide and opportunities for students to establish their own learning paths. The article concludes with a view of the learner not as a course consumer but as a course developer, creating texts and intertexts through engagement with multiple sources.
Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript. (1993)

The CREM (cyclic AMP-responsive element modulator) gene encodes multiple regulators of the cyclic AMP transcriptional response. CREM expression has been linked with several key physiological aspects of neuroendocrine pathways. We investigated the conservation of CREM during evolution. Here, we show conservation of CREM sequences in the pig, humans, the chicken, the lemur, and Xenopus. We have also determined the chromosomal localization of the CREM and CREB genes both in the mouse and in humans. We cloned the full human CREM complementary DNA sequence and demonstrate that it has a high degree of sequence identity with the mouse gene. Finally, we show the conservation of CREM cyclic AMP transcriptional inducibility in humans and establish that the induced transcripts correspond to the mouse ICER products.
Longitudinal radiologic evaluation of osteoarthritis of the knee. (1992)

Radiologic assessment appears to be an objective standard for longterm evaluation of osteoarthritis (OA) and it is inexpensive, quick, simple and noninvasive. We conducted a one year followup study of patients with OA of the knee to evaluate the reproducibility and validity of this evaluation. The intra and interobserver reproducibility of the radiologic variables were evaluated on 275 and 539 patients, respectively, and found to be satisfactory (intraclass coefficient of correlation above 0.70 for the evaluation of the space narrowing of the joint). During the one year followup study, there was a slight but statistically significant deterioration of the joint space narrowing, evaluated on a 6 grade scale on 360 patients (p less than 0.001). The changes in the joint space narrowing were more closely correlated with treatments received by the patients for OA (nonsteroidal antiinflammatory drug (NSAID) intake, synovial fluid aspiration) than with changes in the recorded clinical variables (pain on a visual analog scale, Lequesne algofunctional index). Moreover, some factors such as obesity, generalized OA and flares of OA appeared to be correlated with the deterioration of joint space narrowing. Further studies are necessary to confirm and/or explain the relationship between the deterioration of the joint space narrowing and such factors (i.e., NSAID intake, obesity, flares of OA, generalized OA), which were detected in this study.
Genome-wide transcriptional analysis of carboplatin response in chemosensitive and chemoresistant ovarian cancer cells (2005)

Abstract We have recently described an ex vivo chemoresponse assay for determining chemosensitivity in primary cultures of human tumors. In this study, we have extended these experiments in an effort to correlate chemoresponse data with gene expression patterns at the level of transcription. Primary cultures of cells derived from ovarian carcinomas of individual patients (n = 6) were characterized using the ChemoFx assay and classified as either carboplatin sensitive (n = 3) or resistant (n = 3). Three representative cultures of cells from each individual tumor were then subjected to Affymetrix gene chip analysis (n = 18) using U95A human gene chip arrays. Data were analyzed using the dCHIP software package. We identified a significant number of genes whose expression patterns were altered between carboplatin chemosensitive and chemoresistant cells, in normal culture conditions and in the presence of carboplatin for either 2 or 72 hours. Among these differentially expressed genes, we found a significant proportion to be associated with apoptosis, cell-cell communication, cell adhesion, DNA repair, and cell proliferation. In general, the molecular phenotype displayed by chemoresistant cells was reflective of an extended life span in culture in the presence of carboplatin and the genes that define this phenotype are potential biomarkers for the prognostic management of ovarian cancer patients.
Local therapies for inflammatory eye disease in translation: past, present and future (2013)

Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.
Factors that influence VSV‐G pseudotyping and transduction efficiency of lentiviral vectors—in vitro and in vivo implications (2007)

Pseudotyping viral vectors with vesicular stomatitis virus glycoprotein (VSV-G) enables the transduction of an extensive range of cell types from different species. We have discovered two important parameters of the VSV-G-pseudotyping phenomenon that relate directly to the transduction potential of lentiviral vectors: (1) the glycosylation status of VSV-G, and (2) the quantity of glycoprotein associated with virions. We measured production-cell and virion-associated quantities of two isoform variants of VSV-G, which differ in their glycosylation status, VSV-G1 and VSV-G2, and assessed the impact of this difference on the efficiency of mammalian cell transduction by lentiviral vectors. The glycosylation of VSV-G at N336 allowed greater maximal expression of VSV-G in HEK293T cells, thus facilitating vector pseudotyping. The transduction of primate cell lines was substantially affected (up to 50-fold) by the degree of VSV-G1 or VSV-G2 incorporation, whereas other cell lines, such as D17 (canine), were less sensitive to virion-associated VSV-G1/2 quantities. These data indicate that the minimum required concentration of virion-associated VSV-G differs substantially between cell species/types. The implications of these data with regard to VSV-G-pseudotyped vector production, titration, and use in host-cell restriction studies, are discussed.
Lessons Learned from Marketed and Investigational Prodrugs (2004)

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTLessons Learned from Marketed and Investigational ProdrugsPeter Ettmayer, Gordon L. Amidon, Bernd Clement, and Bernard TestaView Author Information Novartis Institute for BioMedical Research, Brunnerstrasse 59, A-1235 Vienna, Austria, College of Pharmacy, The University of Michigan, Ann Arbor, Michigan 48109-1065, Pharmaceutical Institute, University of Kiel, D-24118 Kiel, Germany, and Department of Pharmacy, University Hospital Centre (CHUV), CH-1011 Lausanne, Switzerland Cite this: J. Med. Chem. 2004, 47, 10, 2393–2404Publication Date (Web):April 13, 2004Publication History Received7 August 2003Published online13 April 2004Published inissue 1 May 2004https://doi.org/10.1021/jm0303812Copyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views6980Altmetric-Citations282LEARN 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 Read OnlinePDF (231 KB) Get e-AlertsSUBJECTS:Cells,Metabolism,Peptides and proteins,Pharmaceuticals,Targeting Get e-Alerts
On the stability of nucleic acid structures in solution: enthalpy - entropy compensations, internal rotations and reversibility (1993)

The thermodynamics of self-association (stacking) of free bases and nucleotides, intramolecular stacking in dinucleotides, nearest-neighbour base pair stacking interactions in duplex DNA and RNA, and the formation of hairpin loops illustrate enthalpy/entropy compensations. Large stacking exothermicities are associated with large negative entropy changes that ensure that delta G is small, permitting readily reversible associations in solution. We rationalise enthalpy/entropy compensations with reference to residual motions and torsional vibrations which make a larger entropic contribution to binding when - delta H approximately kT (thermal energy at room temperature), than when - delta H >> kT. We present a factorisation of experimental free energies for helix formation in terms of approximate contributions from the restriction of rotations, hydrophobic interactions, electrostatic interactions due to base stacking, and contributions from hydrogen bonding, and estimate the adverse free energy cost per rotor (mainly entropy) of ordering the phosphate backbone as between 1.9 and 5.4 kJ mol-1 [averaged over 12 rotors per base pair for A-U on A-U stacking (lower limit), and G-C on C-G stacking (upper limit)]. The largest cost is associated with the most exothermic stacking interactions, while the range of values is consistent with earlier conclusions from data on the fusion of hydrocarbon chains (lower value), and with entropy changes in covalent isomerisations of small molecules involving severe restrictions (upper value).
Candida albicans Stimulates Endothelial Cell Eicosanoid Production (1991)

The response of human umbilical vein endothelial cells to invasion by Candida species was examined in vitro. Live Candida albicans caused significant endothelial release of eicosanoids, mainly prostaglandins. Since prostaglandin I2 (PGI2) is an important prostaglandin produced by endothelial cells, factors influencing its release were studied. The ability of different strains and species of Candida to induce endothelial PGI2 release was closely related to their capacity to injure the endothelium (r = .99). C. albicans was the only species tested that either stimulated PGI2 release or damaged the endothelial cells; only this organism possessed detectable phospholipase activity. Candida glabrata and Candida tropicalis had no phospholipase activity and neither increased PGI2 release nor caused significant endothelial damage. Close proximity with germinated C. albicans was required for endothelial injury and PGI2 release. The ability of C. albicans to stimulate endothelial cells may have important implications in regulating neutrophil activities against organisms that interact with endothelial cells.