gebhart/patrepeval huggingface dataset:
Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid (2006)

Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.
3'-Azido-3',5'-dideoxythymidine-5'-methylphosphonic acid diphosphate: synthesis and HIV-1 reverse transcriptase inhibition. (1992)

3'-Azido-3'-deoxythymidine-5'-phosphonate was synthesized by a five-step reaction sequence. The 5'-phosphonate was inactive against HIV-1 in MT4 cells. The absence of activity against HIV-1 was at least partially explained by demonstrating that the Km value for the 5'-deoxy-5'-methylphosphonic acid diphosphate analog with HIV-1 reverse transcriptase (RT) was 320-fold greater than the Km value for 3'-azido-3'- deoxythymidine-5'-triphosphate (AZTTP), and the kcat value for the 5'-deoxy-5'-methylphosphonic acid diphosphate analog was one-seventh the value for AZTTP. These differences in kinetic constants were due to a change in the rate-determining step from dissociation of the RT chain-terminated template-primer complex to the catalytic step. Thus, substitution of a methylene group for the 5'-oxygen atom of AZTTP resulted in an 1800-fold reduction in the rate constant for RT-catalyzed phosphodiester bond formation.
Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy (2015)

Rearrangements in anaplastic lymphoma kinase (ALK) gene and echinoderm microtubule-associated protein-like 4 (EML4) gene were first described in a small portion of patients with non-small cell lung cancer (NSCLC) in 2007. Fluorescence in situ hybridization is used as the diagnostic test for detecting an EML4-ALK rearrangement. Crizotinib, an ALK inhibitor, is effective in treating advanced ALK-positive NSCLC, and the US Food and Drug Administration approved it for treating ALK-positive NSCLC in 2011. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were designed to overcome these resistance mechanisms. Two of them, ceritinib and alectinib, were approved in 2014 for advanced ALK-positive NSCLC in the US and Japan, respectively. Heat shock protein 90 (Hsp90) inhibitors also showed activity against ALK-positive NSCLC. Here we review the recent development of crizotinib, ceritinib, alectinib and other second-generation ALK inhibitors as well as Hsp90 inhibitors. We also discuss management strategies for advanced ALK-positive NSCLC.
Application of spectral decomposition in hydrocarbon detection (2011)

Spectral decomposition is a robust tool for seismic data interpretation, through its use of common frequency amplitude cubes and tuning cubes. These cubes may be used for imaging and mapping the thickness of sand beds, identifying minor faults and analyzing fluid properties in reservoirs. In this paper, we show an example of spectral decomposition using common frequency cubes and tuning cubes applied to interpretation of low‐frequency, high‐amplitude hydrocarbon detection in the Mananon Basin. We demonstrate that this method is an efficient approach to delineating the extent of reservoirs and the distribution of hydrocarbon within them.
Evaluation of Basic Amphipathic Peptides for Cellular Delivery of Antisense Peptide Nucleic Acids (2006)

Cellular permeation peptides have been used successfully for the delivery of a variety of cargoes across cellular membranes, including large hydrophilic biomolecules such as proteins, oligonucleotides, or plasmid DNA. For the present work, a series of short amphipathic peptides was designed to elucidate the structural requirements for efficient and nontoxic delivery of peptide nucleic acids (PNAs). On the basis of an idealized alpha-helical structure, the helical parameters were modulated systematically to yield peptides within a certain range of hydrophobicity and amphipathicity. The corresponding PNA conjugates were synthesized and characterized in terms of secondary structure, enzymatic stability, and antisense activity. The study revealed correlations between the physicochemical and biophysical properties of the conjugates and their biological activity and led to the development of potent peptide vectors for the cellular delivery of antisense PNAs. Two representative compounds were radiolabeled and evaluated for their biodistribution in healthy mice.
Four Deoxynucleoside Kinase Activities from Drosophila melanogaster Are Contained within a Single Monomeric Enzyme, a New Multifunctional Deoxynucleoside Kinase (1998)

In mammalian cells, there are three pyrimidine nucleoside salvage enzymes with the capacity to phosphorylate all four deoxynucleosides, the two thymidine kinase isoenzymes, TK1 and TK2, and the deoxycytidine kinase, dCK. TK1 is cell cycle-regulated; TK2 is expressed constitutively and can phosphorylate deoxycytidine to the same extent as thymidine. dCK phosphorylates deoxycytidine, deoxyadenosine, and deoxyguanosine, but not thymidine. In addition, the three kinases can phosphorylate a number of medically important analogs. In cultured Drosophila melanogaster embryonic cells, only one pyrimidine deoxynucleoside kinase was present. This kinase was purified and showed a broad substrate specificity, since it was able to phosphorylate all four deoxynucleosides with high efficiency, as compared with the kinases in mammalian cells. Additionally, a number of nucleoside analogs such as arabinofuranosyl pyrimidines, deoxyuridine, and 5'-fluorodeoxyuridine, were phosphorylated. There was negligible 3'-azidothymidine and no dTMP phosphorylation. The enzyme was active as a monomer of about 30 kDa. We suggest the name D. melanogaster deoxynucleoside kinase for this multifunctional kinase. The substrate specificity, size, and other characteristics show that this enzyme is more related to human TK2 than to the other mammalian deoxyribonucleoside kinases, but is unique with respect to the capacity to phosphorylate all four deoxynucleosides.
A Chimera between Platelet-Derived Growth Factor β-Receptor and Fibroblast Growth Factor Receptor-1 Stimulates Pancreatic β-Cell. DNA Synthesis in the Presence of PDGF-BB (1992)

This study was undertaken to characterize the expression of a chimeric growth factor receptor composed of the extracellular and transmembrane domains of the platelet-derived growth factor (PDGF) beta-receptor (PDGFR-beta) fused to the intracellular domain of the fibroblast growth factor receptor-1 (FGFR-1) and to assess its effect on the growth potential of pancreatic islet cells. For this purpose rat pancreatic islets or monolayers of pancreatic islet cells were transfected with recombinant DNA constructs coding for the PDGF B-chain, the PDGFR-beta, the FGFR-1 and the chimera between PDGFR-beta and FGFR-1. DNA synthesis, monitored as the percentage of labelled nuclei and [3H]thymidine incorporation, was stimulated in pancreatic islet cells cotransfected with the constructs coding for the PDGF B-chain and the PDGFR-beta or the chimeric PDGFR-beta/FGFR-1 as compared with that determined after transfection with control plasmid. PDGF-BB stimulated DNA synthesis when islet cells had been transfected with PDGFR-beta or PDGFR-beta/FGFR-1. Cotransfection of the PDGFR-beta and the chimeric PDGFR-beta/FGFR-1 constructs attenuated the stimulation of DNA synthesis in response to PDGF-BB. Receptor binding studies showed binding with a Kd of 0.7 nM to the chimeric receptor. The present findings show that when the chimeric PDGFR-beta/FGFR-1 construct is expressed in beta-cells it is efficient in increasing DNA synthesis when stimulated with ligand.
Enhancing waveform interpolative coding with weighted REW parametric quantization (2002)

This paper presents an efficient quantization technique for the rapidly-evolving waveforms in waveform interpolative (WI) coders. The scheme, based on a parametrization of the rapidly-evolving waveform (REW) magnitude, and analysis-by-synthesis (AbS) vector quantization (VQ) of the REW parameters, allows both higher temporal and spectral resolution of the REW. A perceptually weighted distortion measure takes advantage of spectral and temporal masking and leads to improved reconstructed speech quality, most notably in mixed voiced and unvoiced speech segments. The technique is an important component of the enhanced waveform interpolative (EWI) speech coder at 2.8 kbps that achieves a subjective quality slightly better than that of G.723.1 at 6.3 kbps.
Trial watch (2012)

Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8(+) cytotoxic T lymphocytes, Th1 and Th17 CD4(+) T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4(+)CD25(+)FOXP3(+) regulatory T cells, Th2 CD4(+) T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that-at least in some clinical settings-the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.
Nucleotide sequence and high‐level expression of the major Escherichia coli phosphofructokinase (1985)

The gene for the major phosphofructokinase enzyme in Escherichia coli, pfkA, has been sequenced. Comparison of the amino acid sequence with other phosphofructokinases showed that this enzyme is related to the Bacillus stearothermophilus and rabbit muscle enzymes, but is different from the second, minor phosphofructokinase found in E. coli. The region which has been sequenced comprises the complete pfkA--tpi interval on the E. coli genetic map. Two other genes have been identified from the nucleotide sequence: a gene for a periplasmic sulphate-binding protein, sbp, and for a membrane-bound enzyme, CDP-diglyceride hydrolase, cdh. This establishes the complete gene arrangement in this region as pfkA-sbp-cdh-tpi. The pfkA gene has been subcloned into a high-copy-number plasmid under the control of a strong, chimaeric promoter which arose as an artefact in the construction of the plasmid gene bank from which the original pfkA recombinant was isolated. A specialised recombinant has been constructed which carries a 1.4 X 10(3)-nucleotide insert containing just the pfkA gene flanked by two HindIII recognition sites providing a simple system for the recloning of this gene into different vectors. This recombinant expresses the enzyme at high levels (40-50% of total cell protein is active, soluble phosphofructokinase). This expression system is now being used to study the enzyme using 'reverse genetics'.
Atypical Antipsychotics and Metabolic Dysregulation (2004)

Atypical antipsychotics are a major advance in the management of schizophrenia. The reevaluation of widely held risk/benefit assessments of the various atypical antipsychotics provides an opportunity to improve treatment patterns. The best available clinical trial evidence indicates that efficacy among the atypical antipsychotics (at equivalent doses) is very similar, but safety and tolerability profiles differ significantly. Atypical antipsychotics differ markedly in their potential to cause metabolic disturbances, including obesity, diabetes, dyslipidemia, and the metabolic syndrome; clozapine and olanzapine carry the greatest risks, atypical antipsychotics like risperidone and quetiapine have lower risks, and newer agents like ziprasidone and aripiprazole are associated with minimal metabolic risks. Results from the Atypical Antipsychotic Therapy and Metabolic Issues (AtAMI) survey define important opportunities for improving medical and psychiatric outcomes during atypical antipsychotic therapy. (See accompanying article by Newcomer et al) Additional educational and research efforts are required to increase understanding of common conditions such as the metabolic syndrome, increase awareness of uncommon but serious events like diabetic ketoacidosis, and pancreatitis, and identify appropriate strategies for monitoring the risks/benefits of atypical antipsychotic therapy. As clinicians refine practice patterns regarding the atypical antipsychotics, they may require additional knowledge and resources to fully incorporate risk/benefit considerations and optimize long-term psychiatric and medical outcomes.
Translesional Synthesis on DNA Templates Containing a Single Abasic Site (1997)

Site-specifically modified oligodeoxynucleotides containing a single natural abasic site or a chemically synthesized (tetrahydrofuran or deoxyribitol) model abasic site were used as templates for primer extension reactions catalyzed by the Klenow fragment of Escherichia coli DNA polymerase I or by calf thymus DNA polymerase alpha. Analysis of the fully extended products of these reactions indicated that both polymerases preferentially incorporate dAMP opposite the natural abasic site and tetrahydrofuran, while DNA templates containing the ring-opened deoxyribitol moiety block translesional synthesis, promoting sequence context-dependent deletions. The frequency of nucleotide insertion opposite the three types of abasic sites follows the order dAMP > dGMP > dCMP > dTMP. The frequency of chain extension was highest when dAMP was positioned opposite a natural abasic site. The frequency of translesional synthesis past abasic sites follows the order tetrahydrofuran > deoxyribose > deoxyribitol. The Klenow fragment promotes blunt end addition of dAMP; this reaction was much less efficient than insertion of dAMP opposite an abasic site. We conclude that the miscoding potential of a natural abasic site in vitro closely resembles that of its tetrahydrofuran analog. Ring-opened abasic sites favor deletions. Studies with polymerase alpha in vitro predict preferential incorporation of dAMP at abasic sites in mammalian cells.
Involvement of the bcl -2 Gene in Human Follicular Lymphoma (1985)

Recombinant DNA probes were cloned for the areas flanking the breakpoint on chromosome 18 in cells from a patient with acute lymphocytic leukemia of the B-cell type; cells of this line carry the t(14;18) chromosomal translocation. Two of the probes detected DNA rearrangements in approximately 60 percent of the cases of follicular lymphoma screened. In follicular lymphoma, most of the breakpoints in band q21 of chromosome 18 were clustered within a short stretch of DNA, approximately 2.1 kilobases in length. Chromosome 18-specific DNA probes for the areas flanking the breakpoints also detected RNA transcripts 6 kilobases in length in various cell types. The gene coding for these transcript (the bcl-2 gene) seems to be interrupted in most cases of follicular lymphomas carrying the t(14;18) chromosomal translocation.
Development of a Rating Scale for Primary Depressive Illness (1967)

This is an account of further work on a rating scale for depressive states, including a detailed discussion on the general problems of comparing successive samples from a ‘population’, the meaning of factor scores, and the other results obtained. The intercorrelation matrix of the items of the scale has been factor‐analysed by the method of principal components, which were then given a Varimax rotation. Weights are given for calculating factor scores, both for rotated as well as unrotated factors. The data for 152 men and 120 women having been kept separate, it is possible to compare the two sets of results. The method of using the rating scale is described in detail in relation to the individual items.
Isolation charge pump fabricated in silicon on sapphire CMOS technology (2005)

The design, fabrication and testing of a four-stage charge-pump fabricated in a 0.5 µm silicon-on-sapphire CMOS technology is reported. The charge pump can generate a 2.68 V output with a 3.3 V input power supply, consuming 2.5 mA. The performance of the architecture is optimised by judiciously employing MOS transistors with different threshold (0, 0.3 and 0.7 V) in the different parts of the circuit. The charge pump input and output power supplies are galvanically isolated to over 800 V by means of the dielectric properties of the coupling capacitors and the insulating sapphire substrate.
A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer (2008)

The addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy results in increased toxicity and decreased PFS. These combinations are not recommended for the treatment of mCRC in clinical practice.
Hydraulic Transients (Waterhammer) in Australia (2000)

A review of the range of water hammer problems met in industry is undertaken. Critical comments and recommendations are made with regard to the need for increased consideration of dynamic problems as new pipe materials are used and more stringent requirements of system operation are called for.
Consequences of IMP Dehydrogenase Inhibition, and its Relationship to Cancer and Apoptosis (1999)

Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, selenazofurin, and benzamide riboside share similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.
Lactoferrin-lipopolysaccharide interactions. Effect on lactoferrin binding to monocyte/macrophage-differentiated HL-60 cells (1991)

Lactoferrin (LF) has been implicated in a number of functions including the negative regulation of myelopoiesis in vitro and in vivo, an effect mediated by suppression of cytokine release from monocytes/macrophages. This suppression is abrogated by bacterial LPS. In the present study, HL-60 cells were induced to differentiate to monocytes/macrophages by 12-O-tetradecanoyl phorbol-13-acetate, and LF-binding assays were performed. After differentiation, HL-60 cells showed a twofold increase of LF-binding sites with no difference in the specificity or affinity of LF between pre- and post-differentiated cells. CD11a, CD11b, and CD11c Ag, which have been associated with specific binding sites for LPS on monocytes/macrophages, were also increased three- to fourfold after differentiation. With the use of this system, the effect of LPS on LF binding was studied. At 37 degrees C, LPS enhanced LF binding on HL-60 cells, especially after differentiation. Conversely, at 4 degrees C, LPS inhibited LF binding. There was little effect of temperature on LF binding in the absence of LPS. In the presence of polymyxin B sulfate, the enhanced LF binding by LPS was abrogated. Also, pretreatment with mAbCD11 and/or mAb5D3, which are associated with or directed against candidate LPS receptors, reduced LF binding. Cross-linking studies using an iodinated, photoactivatable LPS derivative ([125I]ASD-LPS) demonstrated directly the specific binding of LPS to LF. These data indicate a dichotomous nature of LF binding on monocyte/macrophage-differentiated HL-60 cells--one being mediated by specific LF receptors whereas the other is apparently mainly via LPS receptors after formation of an LF-LPS complex. These interactions, for which a model is proposed, help to explain the mechanism behind LPS abrogation of the myelopoietic suppressive effects of LF, and a situation that probably occurs during bacterial infection.