gebhart/patrepeval huggingface dataset:
Abstract 654: Targeting K-ras mutant cancer cells with a lupus anti-guanosine antibody (2014)

Abstract Aberrant G-protein signaling due to mutations in genes encoding the Ras family of small GTPases is associated with approximately 30% of human cancers, and K-ras is one of the most commonly mutated Ras proteins. Development of targeted therapies that are preferentially toxic to cancer cells harboring K-ras mutations is therefore an important goal in cancer research. We have identified an unusual cell-penetrating lupus autoantibody, 4H2, as a potential candidate for development as a targeted therapy for tumors with activating K-ras mutations. 4H2 is an anti-guanosine antibody that has previously been shown to penetrate living cells and inhibit cAMP formation. Taken together, the ability of 4H2 to bind guanosine (a component of GDP/GTP) and to inhibit cAMP formation suggests that 4H2 perturbs G-protein signaling. We therefore hypothesized that 4H2 would be selectively toxic to cancer cells with aberrant G-protein signaling due to activating K-ras mutations compared to cells without mutations in K-ras. To test this hypothesis, we evaluated the effects of 4H2 on a panel of isogenic pairs of cells with and without activating K-ras mutations, including Cal12T lung cancer cells (with and without a G12C activating K-ras mutation), NCI-H1975 lung cancer cells (with and without a G12D activating K-ras mutation), and SW48 colon cancer cells (with and without a G12A activating K-ras mutation). Immunofluorescence experiments confirmed that 4H2 penetrates into and localizes to the cytoplasm of cells with and without an activating K-ras mutation. In cell proliferation assays the matched pairs of cells were treated with 4H2 while growing as subconfluent monolayers, and 4H2 was observed to significantly inhibit the proliferation of the cells with activating K-ras mutations but not the cells without K-ras mutations. Next, colony formation assays confirmed that treatment with 4H2 was significantly more toxic to cells with activating K-ras mutations compared to cells without K-ras mutations. Mechanistically, Western blot analyses suggest a differential effect of 4H2 on the MAP kinase and Akt signaling pathways in K-ras mutant and wild type cells, consistent with the hypothesis that 4H2 interferes with G-protein associated intracellular signaling pathways. In summary, this work has demonstrated that 4H2 is an intriguing candidate for further study and development as a potential targeted therapy for tumors with activating mutations in K-ras. Citation Format: Melissa R. Young, Philip W. Noble, Richard H. Weisbart, James E. Hansen. Targeting K-ras mutant cancer cells with a lupus anti-guanosine antibody. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 654. doi:10.1158/1538-7445.AM2014-654
Identification of Mycobacterial Antigens Recognized by T Lymphocytes (1989)

The development of vaccines capable of inducing protective immunity against mycobacterial infection depends in part on the identification of antigenic determinants that activate T cells with antimycobacterial effector function. Various approaches designed to analyze the recognition of mycobacterial antigens by T cells are reviewed. In addition to the established approach of using serologically defined antigens, alternative methods independent of antibody preselection, such as polyacrylamide gel electrophoresis-fractionated immunoblots of mycobacteria, can be used to probe the specificity of the T cell repertoire. Furthermore, the application of recombinant DNA expression combined with that of synthetic peptides whose sequences are predicted to constitute T cell determinants allow the localization of T cell epitopes within a protein. The use of these techniques in defining potentially "pathogenic and protective" T cell epitopes in mycobacteria is discussed.
Adaptive radial basis function nonlinearities, and the problem of generalisation (1989)

The author and D.S. Broomhead developed (1988) the opinion that most current feedforward layered neural networks perform a curve fitting operation in a high-dimensional space. To create the analogy, it was necessary to generalise earlier papers' assumptions, and so a mechanism for choosing radial basis functions was needed. The method involves optimisation. It is concluded that nonlinear optimisation of the first layer parameters is beneficial only when a minimal network is required to solve a given problem, since the same generalisation performance can be achieved simply by using more centres and adapting only the final layer by linear optimisation. The processing time is many orders of magnitude longer when full adaptation was used. Nonlinear optimisation cannot be used to improve the generalisation performance of the network. Choice of the nonlinearity is not crucial. >
Sorbic acid resistance: the inoculum effect (2000)

Zygosaccharomyces is a genus associated with the more extreme spoilage yeasts. Zygosaccharomyces spoilage yeasts are osmotolerant, fructophiles (preferring fructose), highly-fermentative and extremely preservative-resistant. Zygosaccharomyces bailii can grow in the presence of commonly-used food preservatives, benzoic, acetic or sorbic acids, at concentrations far higher than are legally permitted or organolepically acceptable in foods. An inoculum effect has been described for many micro-organisms and antimicrobial agents. The minimum inhibitory concentration (MIC) increases with the size of the inoculum; large inocula at high cell density therefore require considerably higher concentrations of inhibitors to prevent growth than do dilute cell suspensions. A substantial inoculum effect was found using sorbic acid against the spoilage yeast Zygosaccharomyces bailii NCYC 1766. The inoculum effect was not caused by yeasts metabolizing or adsorbing sorbic acid, thereby lowering the effective concentration; was not due to absence of cell-cell signals in dilute cell suspensions; and was not an artefact, generated by insufficient time for small inocula to grow. The inoculum effect appeared to be caused by diversity in the populations of yeast cells, with higher probability of sorbic acid-resistant cells being present in large inocula. It was found that individual cells of Zygosaccharomyces bailii populations, grown as single cells in microtitre plate wells, were very diverse, varying enormously in resistance to sorbic acid. 26S ribosomal DNA sequencing did not detect differences between the small fraction of resistant 'super cells' and the average population. Re-inoculation of the 'super cells' after overnight growth on YEPD showed a normal distribution of resistance to sorbic acid, similar to that of the original population. The resistance phenotype was therefore not heritable and not caused by a genetically distinct subpopulation. It was concluded that resistance of the spoilage yeast Zygosaccharomyces bailii to sorbic acid was due to the presence of small numbers of phenotypically resistant cells in the population.
Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes (2013)

Despite significant progress in the development of adoptive cell-transfer therapies (ACTs) using gene-engineered T cells, little is known about the fate of cells following infusion. To address that, we performed a comparative analysis of gene expression between T-cell receptor-engineered lymphocytes persisting in the circulation 1 month after administration and the product that was infused. We observed that 156 genes related to immune function were differentially expressed, including underexpression of stimulators of lymphocyte function and overexpression of inhibitory genes in postinfusion cells. Of genes overexpressed postinfusion, the product of programmed cell death 1 (PDCD1), coinhibitory receptor PD-1, was expressed at a higher percentage in postinfusion lymphocytes than in the infusion product. This was associated with a higher sensitivity to inhibition of cytokine production by interaction with its ligand PD-L1. Coinhibitory receptor CD160 was also overexpressed in persisting cells, and its expression was associated with decreased reactivity, which surprisingly was found to be ligand-independent. These results contribute to a deeper understanding of the properties of transgenic lymphocytes used to treat human malignancies and may provide a rationale for the development of combination therapies as a method to improve ACT.
An open‐label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5‐fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer : The GC4 study (2006)

The results demonstrated that successful G17DT vaccination was correlated with longer TTP and MS. AGA response was an independent OS prognosticator. A Phase III evaluation of G17DT in gastric cancer is warranted.
Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495 (2003)

The Ca2+ antagonist, amlodipine, enhances endothelial NO generation by inducing changes in the phosphorylation of eNOS. Although the activation of eNOS was related to the activation of the B2 kinin receptor in the porcine coronary artery, a B2 receptor-independent mechanism involving the inhibition of PKC appears to account for the effects observed in the rat aorta as well as in cultured endothelial cells.
B Cells Are Essential for Vaccination-Induced Resistance to VirulentToxoplasma gondii (2000)

T lymphocytes and gamma interferon (IFN-gamma) are known mediators of immune resistance to Toxoplasma gondii infection, but whether B cells also play an important role is not clear. We have investigated this issue using B-cell-deficient (muMT) mice. If vaccinated with attenuated T. gondii tachyzoites, muMT mice are susceptible to a challenge intraperitoneal infection with highly virulent tachyzoites that similarly vaccinated B-cell-sufficient mice resist. Susceptibility is evidenced by increased numbers of parasites at the challenge infection site and by extensive mortality. The susceptibility of B-cell-deficient mice does not appear to be caused by deficient T-cell functions or diminished capacity of vaccinated and challenged B-cell-deficient mice to produce IFN-gamma. Administration of Toxoplasma-immune serum, but not nonimmune serum, to vaccinated B-cell-deficient mice significantly prolongs their survival after challenge with virulent tachyzoites. Vaccinated mice lacking Fc receptors or the fifth component of complement resist a challenge infection, suggesting that neither Fc-receptor-dependent phagocytosis of antibody-coated tachyzoites nor antibody-dependent cellular cytotoxicity nor antibody-and-complement-dependent lysis of tachyzoites is a crucial mechanism of resistance. However, Toxoplasma-immune serum effectively inhibits the infection of host cells by tachyzoites in vitro. Together, the results support the hypothesis that B cells are required for vaccination-induced resistance to virulent tachyzoites in order to produce antibodies and that antibodies may function protectively in vivo by blocking infection of host cells by tachyzoites.
Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis (1993)

Several studies have suggested that chondrocytes must have the capacity to internalize and degrade extracellular hyaluronan. In the present study we show direct evidence that hyaluronan is, in fact, endocytosed by chondrocytes and that the endocytosis is mediated via cell surface CD44/hyaluronan receptors. Cultures of bovine articular chondrocytes as well as rat chondrosarcoma chondrocytes were incubated with either fluorescein- or 3H-labeled hyaluronan. Intense binding and accumulation of labeled hyaluronan was visualized by fluorescence microscopy or bright-field/dark-field microscopy following autoradiography. Cell surface hyaluronan was removed with either trypsin or Streptomyces hyaluronidase in order to distinguish and quantify intracellular endocytosed hyaluronan. Labeled hyaluronan was visualized within small discrete intracellular vesicles distributed throughout the cytoplasm. Binding and endocytosis of fluorescein- or 3H-labeled hyaluronan was totally blocked by the addition of excess unlabeled hyaluronan or hyaluronan hexasaccharides, competitive inhibitors of hyaluronan/hyaluronan receptor interactions. Binding and endocytosis was also blocked by the addition of anti-CD44 monoclonal antibodies. Characterization of endocytosed 3H-labeled hyaluronan demonstrated that a significant portion of the hyaluronan was degraded by both the bovine articular and rat chondrosarcoma chondrocytes. Interestingly, a higher proportion of bound hyaluronan was internalized by the bovine chondrocytes. Therefore, hyaluronan receptor-mediated endocytosis and degradation of hyaluronan may provide a critical link to the maintenance and homeostasis of cartilage tissue.
A perceptually motivated online benchmark for image matting (2009)

The availability of quantitative online benchmarks for low-level vision tasks such as stereo and optical flow has led to significant progress in the respective fields. This paper introduces such a benchmark for image matting. There are three key factors for a successful benchmarking system: (a) a challenging, high-quality ground truth test set; (b) an online evaluation repository that is dynamically updated with new results; (c) perceptually motivated error functions. Our new benchmark strives to meet all three criteria. We evaluated several matting methods with our benchmark and show that their performance varies depending on the error function. Also, our challenging test set reveals problems of existing algorithms, not reflected in previously reported results. We hope that our effort will lead to considerable progress in the field of image matting, and welcome the reader to visit our benchmark at www.aIphamatting.com.
Coexpression of chemokine receptors CCR5, CXCR3, and CCR4 and ligands for P‐ and E‐selectin on T lymphocytes of patients with juvenile idiopathic arthritis (2011)

CCR4-, CCR5-, CXCR3-, and selectin ligand-expressing CD4+ T cells preferentially accumulate in the joints of children with JIA. The marked enrichment of CCR5+ T cells coexpressing P-selectin and/or E-selectin ligand in CD4+ SF T cells suggests that the few such cells in blood selectively migrate to inflamed joints via endothelial P- and E-selectin- and CCR5-activating chemokines. The predominance of CCR4-expressing CD4+ T cells coexpressing E-selectin ligand suggests that such cells migrate not only to areas of cutaneous inflammation, as previously reported, but also to the joints in JIA. Combined targeting of CCR5- and E-selectin-dependent mechanisms may be a relevant treatment strategy.
Cement Sheath Stress Failure (1992)

Summary Observation of the sudden appearance of annular pressure in wells exposed to high temperature changes or excessive internal casing pressure prompted a laboratory investigation to simulate conditions under which cement sheath failure could occur and thereby define the causes, characteristics, and limits of the problem. Cement sheath failure is manifested by interzonal problem. Cement sheath failure is manifested by interzonal annular-fluid movement and abnormally high annular pressure at some point behind the casing up to and at the surface. Cement sheath point behind the casing up to and at the surface. Cement sheath failure can be observed in any producing area where excessive flowing temperatures exist at the surface or where excessive internal casing test pressures are used. The detrimental effects of cement sheath failure are numerous and may include lost revenue from lost production, potentially hazardous rig operations (especially when annular isolation loss creates shallow-water sands supercharged with gas), and potentially hazardous producing operations. Exposure of steel casing to excessive temperature increases or internal test pressures causes diametrical and circumferential casing expansion. This circumferential force creates a shearing force at the cement/casing interface, causing failure at the cement/casing interface or radial fracturing of the cement sheath from the inner casing surface to the outer casing (or borehole) surface.
Matching utterances to rich knowledge structures to acquire a model of the speaker's goal (2005)

An ultimate goal of AI is to build end-to-end systems that interpret natural language, reason over the resulting logical forms, and perform actions based on that reasoning. This requires systems from separate fields be brought together, but often this exposes representational gaps between them. The logical forms from a language interpreter may mirror the surface forms of utterances too closely to be usable as-is, given a reasoner's requirements for knowledge representations. What is needed is a system that can match logical forms to background knowledge flexibly to acquire a rich semantic model of the speaker's goal. In this paper, we present such a "matcher" that uses semantic transformations to overcome structural differences between the two representations. We evaluate this matcher in a MUC-like template-filling task and compare its performance to that of two similar systems.
The Vibrio cholerae chitin utilization program (2004)

Chitin, an insoluble polymer of GlcNAc, is an abundant source of carbon, nitrogen, and energy for marine microorganisms. Microarray expression profiling and mutational studies of Vibrio cholerae growing on a natural chitin surface, or with the soluble chitin oligosaccharides (GlcNAc)(2-6), GlcNAc, or the glucosamine dimer (GlcN)2 identified three sets of differentially regulated genes. We show that (i) ChiS, a sensor histidine kinase, regulates expression of the (GlcNAc)(2-6) gene set, including a (GlcNAc)2 catabolic operon, two extracellular chitinases, a chitoporin, and a PilA-containing type IV pilus, designated ChiRP (chitin-regulated pilus) that confers a significant growth advantage to V. cholerae on a chitin surface; (ii) GlcNAc causes the coordinate expression of genes involved with chitin chemotaxis and adherence and with the transport and assimilation of GlcNAc; (iii) (GlcN)2 induces genes required for the transport and catabolism of nonacetylated chitin residues; and (iv) the constitutively expressed MSHA pilus facilitates adhesion to the chitin surface independent of surface chemistry. Collectively, these results provide a global portrait of a complex, multistage V. cholerae program for the efficient utilization of chitin.
Intratumoral COX-2 Gene Expression Is a Predictive Factor for Colorectal Cancer Response to Fluoropyrimidine-Based Chemotherapy (2005)

Intratumoral COX-2 gene expression is associated with likelihood of response to chemotherapy with S-1 and is a prognostic factor for survival of patients after the start of S-1 chemotherapy.
Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. (1996)

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is a promising water-soluble analogue of camptothecin [S. Sawada et al., Chem. & Pharm. Bull. (Tokyo), 39: 1446-1454, 1991]. We have reported previously the presence of an important polar metabolite, in addition to 7-ethyl-10-hydroxycamptothecin (SN-38) beta-glucuronide, in samples of plasma taken from patients undergoing treatment with CPT-11 (L.P. Rivory and J. Robert, Cancer Chemother. Pharmacol. 36: 176-179, 1995; L. P. Rivory and J. Robert, J. Cromatogr., 661: 133-141, 1994). Plasma samples (0.5 ml) containing comparatively large amounts of this metabolite were extracted by solid-phase columns and subjected to high-performance liquid chromatography and mass spectrometry in parallel to fluorometric detection. The metabolite yielded [M + 1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11. Purified fractions were subjected to proton nuclear magnetic resonance, and the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycampothecin (APC), was further validated following synthesis. Like CPT-11, APC was found to be only a weak inhibitor of the cell growth of KB cells in culture (IC50, 2.1 versus 5.5 micrograms/ml for CPT-11 and 0.01 microgram/ml for SN-38, the active metabolite of CPT-11) and was a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). In contrast to CPT-11, APC was not hydrolyzed to SN-38 by human liver microsomes or purified human liver carboxylesterase. Furthermore, APC did not inhibit the hydrolysis of CPT-11 in these preparations. Interestingly, APC was only a weak inhibitor of acetylcholinesterase in comparison to CPT-11 and neostigmine. It appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo.
Regulation of GluR2 promoter activity by neurotrophic factors via a neuron‐restrictive silencer element (2000)

The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254-nucleotide fragment of the 5'-promoter region of the mouse GluR2 gene in neural-derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial-cell line derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron-restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.