gebhart/patrepeval huggingface dataset:
Activation of the sphingomyelin cycle by brefeldin A: effects of brefeldin A on differentiation and implications for a role for ceramide in regulation of protein trafficking. (1996)

The sphingomyelin (SM) cycle is an emerging pathway of signal transduction that plays a role in the control of cell growth, cell differentiation, and apoptosis. During earlier investigation of SM pools hydrolyzed in the SM cycle, we examined the effects of the fungal macrolide brefeldin A (BFA) on cellular levels of SM in HL-60 leukemia cells. We found that BFA induced up to 20-25% hydrolysis of SM. Here we show that this BFA-sensitive SM pool corresponds to the pool of SM hydrolyzed by a previously discovered activator of the SM cycle, 1,25-dihydroxyvitamin D3. BFA was also able to induce the biological end points of SM cycle activation: growth inhibition and differentiation. Reciprocally, ceramide inhibited the secretion of 35S-labeled proteins from HL-60 cells and induced a subset of effects of BFA on organelle morphology. Since a ceramide-activated protein phosphatase has been previously suggested as a direct in vitro target of ceramide action, the effects of modulators of protein kinases and phosphatases were examined. Okadaic acid enhanced protein secretion and was able to oppose the effects of both ceramide and BFA on organelle morphology. Dioctanoylglycerol and phorbol myristate acetate, known activators of protein kinase C, were also found to oppose the inhibitory actions of ceramide on secretion. These studies identify BFA as an activator of the SM cycle, with ceramide as a potential mediator of some of the effects of BFA. Additionally, taken with the effects of the PKC activators, these studies suggest that constitutive protein secretion is not a default pathway but is subject to regulation by processes of signal transduction.
Phase I study of recombinant human interleukin-3 in patients with bone marrow failure. (1991)

Interleukin-3 (IL-3) is a T-cell-derived colony-stimulating factor (CSF) whose primary targets include relatively early, multipotential, hematopoietic progenitor cells. In this trial, we treated 24 patients with recombinant human IL-3 given by a daily 4-hour intravenous infusion for 28 days. The dose levels were 30, 60, 125, 250, 500, 750, and 1,000 micrograms/m2/d. At least three patients were entered at every dose level. Each participant suffered from bone marrow failure, with the underlying diagnosis being myelodysplastic syndrome (13 patients), aplastic anemia (eight patients), or aplasia after prolonged high-dose chemotherapy (three patients) for multiple myeloma, breast cancer, or acute myelogenous leukemia. Most patients tolerated therapy well, with the most frequent side effects being low-grade fever and headaches. Hematopoietic changes included modest increases in neutrophil counts (eight patients), eosinophil counts (six patients), platelet counts (three patients), and reticulocyte counts (two patients). An increase in blasts occurred in one patient who had refractory anemia with excess blasts in transformation and was reversible once IL-3 was discontinued. In addition, one patient with chronic myelomonocytic leukemia showed an increase in monocytes (and granulocytes). Progression to acute leukemia did not occur. Pharmacokinetic analyses showed a rapid clearance with a mean half-life of 18.8 minutes at the 60 micrograms/m2/d dose, and 52.9 minutes at the 250 micrograms/m2/d dose. Serum concentrations of 10 to 20 ng/mL of IL-3 were achievable at the 250 micrograms/m2/d dose. Our observations indicate that recombinant human IL-3 can be given safely at doses of 1,000 micrograms/m2/d or less. In addition, on the basis of preclinical data and the biologic activity observed in this study, further trials of this molecule, alone and in combination with other growth factors, are warranted in patients with pancytopenia.
Plasma Levels and Bioavailability of Cyclobenzaprine in Human Subjects (1977)

Cyclobenzaprine was extensively metabolized in man, less than 1% of the dose being excreted unchanged in the urine. Comparison of areas under plasma level curves (AUC) after oral and intravenous doses suggests that the drug may be partly metabolized in the lumen or during its first passage through the gut wall and/or liver. Average plasma levels of the drug increased with increasing dosage, but the AUC increased less rapidly with increasing dose, possibly because of dose-dependent absorption.
Astrocytic Gap Junctions Remain Open during Ischemic Conditions (1998)

Gap junctions are highly conductive channels that allow the direct transfer of intracellular messengers such as Ca2+ and inositol triphosphate (IP3) between interconnected cells. In brain, astrocytes are coupled extensively by gap junctions. We found here that gap junctions among astrocytes in acutely prepared brain slices as well as in culture remained open during ischemic conditions. Uncoupling first occurred after the terminal loss of plasma membrane integrity. Gap junctions therefore may link ischemic astrocytes in an evolving infarct with the surroundings. The free exchange of intracellular messengers between dying and potentially viable astrocytes might contribute to secondary expansion of ischemic lesions.
The Amiloride-sensitive Epithelial Sodium Channel α-Subunit Is Transcriptionally Down-regulated in Rat Parotid Cells by the Extracellular Signal-regulated Protein Kinase Pathway (1998)

Previous studies have shown that an inducible Raf-1 kinase protein, DeltaRaf-1:ER, activates the mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK)-signaling pathway, which is required for the transformation of the rat salivary epithelial cell line, Pa-4. Differential display polymerase chain reaction was employed to search for mRNAs repressed by DeltaRaf-1:ER activation. Through this approach, the gene encoding the alpha-subunit of the amiloride-sensitive epithelial sodium channel (alpha-ENaC) was identified as a target of activated Raf-1 kinases. alpha-ENaC down-regulation could also be seen in cells treated with 12-O-tetradecanoyl-1-phorbol-13-acetate (TPA), indicating that the repression of steady-state alpha-ENaC mRNA level was dependent upon the activity of protein kinase C, the target of TPA, as well. Pretreatment of cells with a specific inhibitor of the ERK kinase pathway, PD 98059, markedly abolished the down-regulation of alpha-ENaC expression, consistent with the hypothesis that the ERK kinase-signaling pathway is involved in TPA-mediated repression. Moreover, through the use of transient transfection assays with alpha-ENaC-reporter and activated Raf expression construct(s), we provide the first evidence that activation of the ERK pathway down-regulates alpha-ENaC expression at the transcriptional level. Elucidating the molecular programming that modulates the expression of the alpha-subunit may provide new insights into the modulation of sodium reabsorption across epithelia.
Building searchable collections of enterprise speech data (2001)

We have applied speech recognition and text-mining technologies to a set of recorded outbound marketing calls and analyzed the results. Since speaker-independent speech recognition technology results in a significantly lower recognition rate than that found when the recognizer is trained for a particular speaker, we applied a number of post-processing algorithms to the output of the recognizer to render it suitable for the Textract text mining system.
Correlation betweenin vitroandin vivoconcentration–effect relationships of naproxen in rats and healthy volunteers (2006)

Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. The current investigation characterises the inhibition of prostaglandin E2 (PGE(2)) and thromboxane B2 (TXB(2)) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE(2) in the absence or presence of increasing concentrations of naproxen (10(-8)-10(-1) M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB(2) was measured in serum following blood clotting. In further experiments, inhibition of PGE(2) and TXB(2) levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg(-1)). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). Inhibition of PGE(2) and TXB(2) was characterised by a sigmoid E(max) model. The exposure-response relationships in vitro and in vivo were of the same order of magnitude in both species. IC(80) estimates obtained in vitro were similar for PGE(2) inhibition (130.8 +/- 11 and 131.9 +/- 19 10(-6) M, mean +/- s.d. for humans and rats, respectively), but slightly different for TXB(2) inhibition (103.9+/-15 and 151.4 +/- 40 10(-6) M, mean +/- s.d. for humans and rats, respectively, P < 0.05). These differences, however, may not be biologically relevant. The results confirm the value of exposure-effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration-effect relationships in early drug development, as indicated by the estimates of IC(80) for PGE(2) and TXB(2) inhibition.
Bluetooth-based wireless connectivity in an automotive environment (2002)

In contrast to a home or office environment the automotive environment represents a relatively underdeveloped application field regarding the provision of new services (e.g. car-specific services) and/or access to existing services (e.g. Internet services). One of the key elements for accomplishing such a task is an appropriate, wireless delivery media. A combination of several dedicated access technologies (e.g. stationary/mobile operation) is not precluded. The integration of existing and new communication technologies requires an appropriate in-car infrastructure for the support of communication, information and entertainment services, which takes into account the specific characteristics and constraints of the considered automotive environment. It can be foreseen that Bluetooth, an emerging technology for short range wireless connectivity, will be an integral part of future car-based networks. The paper describes concepts for integration of the Bluetooth technology, the achievable transmission performance and a potential user application framework.
BAC contig development by fingerprint analysis in soybean (1997)

We constructed a soybean bacterial artificial chromosome (BAC) library suitable for map-based cloning and physical mapping in soybean. This library consists of approximately 40 000 clones (4-5 genome equivalents) stored individually in 384-well microtiter dishes. A random sampling of 224 clones yielded an average insert size of 150 kb, giving a 98% probability of recovering any specific sequence. We screened the library for seven single or very low copy genie or genomic sequences using the polymerase chain reaction (PCR) and found between one and seven BACs for each of the seven sequences. When testing the library with a portion of the soybean psbA chloroplast gene, we found less than 1% chloroplast DNA representation. We also screened the library for eight different classes of disease resistance gene analogs (RGAs) and identified BACs containing all RGAs except class 8. We arranged nine of the class 1 RGA BACs and six of the class 3 RGA BACs into individual contigs based on fingerprint patterns observed after Southern probing of restriction digests of the member BACs with a class-specific sequence. This resulted in the partial localization of the different multigene family sequences without precise definition of their exact positions. Using PCR-based end rescue techniques and RFLP mapping of BAC ends, we mapped individual BACs of each contig onto linkage group J of the soybean public map. The class 1 contig mapped to the region on linkage group J that contains several disease resistance genes. The class 1 contig extended approximately 400 kb. The arrangement of the BACs within this contig has been confirmed using PCR. One end of the class 1 contig core BAC mapped to two positions on linkage group J and cosegregated with two class 1 RGA loci, suggesting that this segment is within an area of regional duplication.
A Lamp for Cancer Phototherapy (1983)

The lamp described comprises a 1000 W incandescent filament source, long- and short-wave pass filters, and a non-imaging reflector system. The output of 24 W in the 620-720 nm band is delivered through a 53 mm diameter aperture with a maximum divergence half-angle of 60°. Refracting components may be fitted to modify the output angular or intensity distribution. This lamp has been used to irradiate several different types of malignant tumour in human patients, following intravenous injection of the photoactive drug haematoporphyrin derivative, causing selective necrosis of the malignant tissue. The clinical results are regarded as encouraging.
Pressure-mediated oligonucleotide transfection of rat and human cardiovascular tissues (1999)

The application of gene therapy to human disease is currently restricted by the relatively low efficiency and potential hazards of methods of oligonucleotide or gene delivery. Antisense or transcription factor decoy oligonucleotides have been shown to be effective at altering gene expression in cell culture expreriments, but their in vivo application is limited by the efficiency of cellular delivery, the intracellular stability of the compounds, and their duration of activity. We report herein the development of a highly efficient method for naked oligodeoxynucleotide (ODN) transfection into cardiovascular tissues by using controlled, nondistending pressure without the use of viral vectors, lipid formulations, or exposure to other adjunctive, potentially hazardous substances. In this study, we have documented the ability of ex vivo, pressure-mediated transfection to achieve nuclear localization of fluorescent (FITC)-labeled ODN in approximately 90% and 50% of cells in intact human saphenous vein and rat myocardium, respectively. We have further documented that pressure-mediated delivery of antisense ODN can functionally inhibit target gene expression in both of these tissues in a sequence-specific manner at the mRNA and protein levels. This oligonucleotide transfection system may represent a safe means of achieving the intraoperative genetic engineering of failure-resistant human bypass grafts and may provide an avenue for the genetic manipultation of cardiac allograft rejection, allograft vasculopathy, or other transplant diseases.
Immunogenicity and Protective Efficacy in Mice of Influenza B Virus Vaccines Grown in Mammalian Cells or Embryonated Chicken Eggs (1998)

The immunogenicity and protective efficacy of formalin-inactivated influenza B/Memphis/1/93 virus vaccines propagated exclusively in Vero cells, MDCK cells, or embryonated chicken eggs (hereafter referred to as eggs) were investigated. Mammalian cell-grown viruses differ from the egg-grown variant at amino acid position 198 (Pro/Thr) in the hemagglutinin gene. The level of neuraminidase activity was highest in egg-grown virus, while MDCK and Vero cell-derived viruses possessed 70 and 90% less activity, respectively. After boosting, each of the vaccines induced high levels of hemagglutinin-inhibiting, neuraminidase-inhibiting, and neutralizing antibodies that provided complete protection from MDCK-grown virus challenge. Mammalian cell-derived virus vaccines induced serum antibodies that were more cross-reactive, while those induced by egg-grown virus vaccines were more specific to the homologous antigen. Enzyme-linked immunospot analysis indicated that cell-grown virus vaccines induced high frequencies of immunoglobulin G (IgG)-producing cells directed against both cell- and egg-grown virus antigens, whereas egg-grown virus vaccine induced higher frequencies of IgG- and IgM-producing cells reacting with homologous antigen and low levels of IgG-producing cells reactive with cell-grown viruses. These studies indicate that influenza B virus variants selected in different host systems can elicit different immune responses, but these alterations had no detectable influence on the protective efficacy of the vaccines with the immunization protocol used in this study.
R.F. Impedance of the Electrical Network of Cars (1976)

Measurements of the r.f. impedance of the electrical network of cars - observed from several input. points - have been made. Using parameters that were averaged over the measurements, a normalized network - which is equivalent to the electrical system operating either as a disturbing source or as a disturbed load - has been determined. Though the measurements were performed in the frequency range 0.5 - 108.MHz with satisfactory results, the proposed normalized network should be used up to 30 MHz only: a more extensive investigation for frequencies above 30 MHz is necessary.
Technology's changing role in intellectual property rights (2002)

Technological barriers are declining as a means to protect intellectual property, and this change is emerging as the greatest threat to intellectual property rights (IPRs). In particular, the Internet and digital storage methods are radically lowering the technological barriers and consequently forcing changes in the way providers distribute content, especially entertainment. Such a major change will require an equally radical shift in thinking about how to pay content producers and how to restructure the entire production and distribution network's economics. The technological and legal barriers are only one part of a multipart solution, one in which all parts have a role in thwarting inappropriate use of intellectual property by encouraging and rewarding legitimate uses.
Development of a gastrointestinal tract microscale cell culture analog to predict drug transport. (2008)

Microscale cell culture analogs (microCCAs) are used to study the metabolism and toxicity of a chemical or drug. These in vitro devices are physical replicas of physiologically based pharmacokinetic models that combine microfabrication and cell culture. The goal of this project is to add an independent GI tract microCCA to a multi-chamber chip microCCA representing the primary circulation. The GI tract microCCA consists of two chambers separated by a microporous membrane on which intestinal epithelial cells are cultured. Compounds of interest are pumped through the top chamber, allowing drug to be absorbed through the epithelial layer and circulated into the chip microCCA. The chip and GI tract microCCAs have been used to recreate the toxic effects of acetaminophen. Preliminary results have shown that the GI tract microCCA acts as a barrier to drugs entering the chip, mimicking in vivo function in this regard.
The Tat Protein of HIV-1 Induces Tumor Necrosis Factor-α Production (1997)

Human immunodeficiency virus (HIV) infection may cause a dementing illness. HIV-mediated dementia is clinically and pathologically correlated with the infiltration of activated macrophages and elevated levels of tumor necrosis factor (TNF)-alpha, both of which occur in an environment of small numbers of infected cells. We examined the possibility that HIV protein Tat, which is released extracellularly from infected cells, may induce the production of TNF-alpha. Tat induced TNF-alpha mRNA and protein production dose-dependently, primarily in macrophages but also in astrocytic cells. The TNF-alpha induction was NF-kappaB-dependent and could be eliminated by inhibiting protein kinase A or protein tyrosine kinase activity. In addition, Tat-induced TNF-alpha release was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial cell activation and suggest new therapeutic approaches for HIV dementia.
Tyrosine kinase inhibitors. 1. Structure-activity relationships for inhibition of epidermal growth factor receptor tyrosine kinase activity by 2,3-dihydro-2-thioxo-1H-indole-3-alkanoic acids and 2,2'-dithiobis(1H-indole-3-alkanoic acids) (1993)

A series of 2,3-dihydro-2-thioxo-1H-indole-3-alkanoic acids, and their methyl esters were prepared, the majority by oxidation of 1H-indole-3-alkanoic acids (DMSO/HCl), followed by thiation of the corresponding 2,3-dihydro-2-oxo-1H-indole-3-alkanoic acid esters. The monomeric thiones undergo facile and reversible oxidation to the corresponding 2,2'-dithiobis(1H-indole-3-alkanoic acids). The compounds were evaluated for their abilities to inhibit the tyrosine kinase activity of the epidermal growth factor receptor using a native complex contained in plasma membrane vesicles shed from cultured A431 cells, and to inhibit the growth of Swiss 3T3 mouse fibroblast in culture. Enzyme inhibitory activity is dependent on the length of the side chain, with propanoic acid derivatives showing the highest activity. The acids are generally significantly more potent than the corresponding esters, and the disulfides more active than the corresponding monomers. An ability to undergo the thione-thiol tautomerism necessary for dimerization is essential, with 3,3-disubstituted compounds being inactive. Overall, the data suggest that the disulfide is the more active form, with much of the activity of the monomeric thiones being due to varying degrees of conversion to the disulfide during the assay. In the growth inhibition assay, the methyl esters are more potent than their corresponding carboxylic acids, and the dimers are generally more potent than the monomers. The data show these compounds to be a novel and potent class of inhibitors of epidermal growth factor receptor tyrosine kinase activity.