gebhart/patrepeval huggingface dataset:
Vaccination strategy to target lysyl oxidase-like 4 in dendritic cell based immunotherapy for head and neck cancer (2008)

Overexpression of lysyl oxidase (LOX) is associated with the invasive potential of metastatic breast and head and neck cancer (HNC) cells and reduced metastasis-free and overall survival. Recently, we have demonstrated up-regulation of a new member of the LOX family, lysyl oxidase-like 4 (LOXL4), in invasive HNC revealed a significant correlation between LOXL4 expression and local lymph node metastases and higher tumour stages. The objective of this study was to examine whether cellular LOXL4 may provide an effective target for cell-meditated immunotherapy in invasive tumours associated with LOXL4 overexpression. As a feasibility study we expressed LOXL4 mRNA in immature dendritic cells derived from human peripheral blood mononuclear cells (PBMC). LOXL4 protein expression was ascertained using Western blotting and immunocytochemistry with polyclonal rabbit anti-LOXL4 antibody. The successfully transfected immature dendritic cells (DCs) were induced to mature with GM-CSF, IL-4, IL-1beta, TNF-alpha, IL-6, and PGE2, and then used to stimulate T cell enriched non-adherent fraction of PBMC. LOXL4 specific T cell stimulation induced cytotoxic T lymphocyte (CTL) response was monitored using IFN-gamma secretion from the non-adherent PBMC fraction exposed to mature, LOXL4 transfected DCs acting as the antigen presenting target cells. LOXL4-DC stimulated T cells produced higher IFN-gamma secretion compared to unstimulated T cells and T cells stimulated with untransfected DCs, in the presence of the pan-DR-epitope (PADRE). These initial results demonstrated the potential for LOXL4-transfected DCs to serve as efficient tumour vaccine and support their suitability as a vaccination strategy applicable to cancer patients with tumour specific up-regulation of LOXL4.
Human neural stem cells genetically modified for brain repair in neurological disorders (2004)

Existence of multipotent neural stem cells (NSC) has been known in developing or adult mammalian CNS, including humans. NSC have the capacity to grow indefinitely and have multipotent potential to differentiate into three major cell types of CNS, neurons, astrocytes and oligodendrocytes. Stable clonal lines of human NSC have recently been generated from the human fetal telencephalon using a retroviral vector encoding v-myc. One of the NSC lines, HB1.F3, carries normal human karyotype of 46XX and has the ability to self-renew, differentiate into cells of neuronal and glial lineages, and integrate into the damaged CNS loci upon transplantation into the brain of animal models of Parkinson disease, HD, stroke and mucopolysaccharidosis. F3 human NSC were genetically engineered to produce L-dihydroxyphenylalanine (L-DOPA) by double transfection with cDNA for tyrosine hydroxylase and guanosine triphosphate cylohydrolase-1, and transplantation of these cells in the brain of Parkinson disease model rats led to L-DOPA production and functional recovery. Proactively transplanted F3 human NSC in rat striatum, supported the survival of host striatal neurons against neuronal injury caused by 3-nitropro-pionic acid in rat model of HD. Intravenously introduced through the tail vein, F3 human NSC were found to migrate into ischemic lesion sites, differentiate into neurons and glial cells, and improve functional deficits in rat stroke models. These results indicate that human NSC should be an ideal vehicle for cell replacement and gene transfer therapy for patients with neurological diseases. In addition to immortalized human NSC, immortalized human bone marrow mesenchymal stem cell lines have been generated from human embryonic bone marrow issues with retroviral vectors encording v-myc or teromerase gene. These immortalized cell lines of human bone marrow mesenchymal stem cells differentiated into neurons/glial cells, bone, cartilage and adipose tissue when they were grown in selective inducing media. There is further need for investigation into the neurogenic potential of the human bone marrow stem cell lines and their utility in animal models of neurological diseases.
Topiramate: Preclinical Evaluation of a Structurally Novel Anticonvulsant (1994)

Topiramate [TPM, 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] (RWJ-17021-000, formerly McN-4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident < or = 0.5 h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)-induced clonic seizures at high doses in mice (ED50 = 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF-525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.
Abstract A225: The mTOR kinase inhibitor AZD8055 modulates 18F-FDG uptake in vivo in the human glioma xenograft model U87-MG (2009)

Abstract Introduction: mTOR is a a sensor of mitogen, energy and nutrient levels and a central controller of cell growth. mTOR is present in two multi-protein complexes: mTORC1, rapamycin sensitive and containing raptor, and mTORC2, rapamycin-insensitive. AZD8055 is a small molecule ATP competitive inhibitor of mTOR kinase, thus inhibiting both mTORC1 and mTORC2. This results in a greater reduction of mTORC1 substrates pS6 on Ser235/236 and p4EBP1 on T37/46 compared to rapamycin. AZD8055 also reduces the mTORC2 substrate pAKT on Ser473. The PI3K-AKT-mTOR pathway is involved in glucose uptake/metabolism. 18F-Flurodeoxyglucose (18F-FDG) is a biomarker for glucose metabolism detectable by positron emission tomography (PET). It is used in clinical oncology for tumor diagnosis and is currently under evaluation for therapy monitoring. The aim of this study was to assess the impact of a single and 4 daily dosing of AZD8055 on 18F-FDG uptake in U87-MG human glioma xenografts implanted subcutaneously in nude mice. Methods: AZD8055 was administered orally at a dose of 20 mg/kg qd for 1 or 4 days. Animals received either vehicle or AZD8055 1 hour prior to imaging. Mice were anaesthetised and then injected with approximately 15 MBq 18F-FDG i.v. via the tail vein. Forty-five minutes later, mice underwent PET scanning (20 minute scan, 3D histogramming and OSEM2D reconstruction) followed by biodistribution analysis. Image analysis was carried out using Inveon Research Workplace (IRW) software. Biodistribution data were derived from gamma counting. Results: Plasma drug concentrations were not modified significantly by anesthesia and the imaging procedure. In the vehicle and AZD8055-treated groups, tumor volumes were comparable after single dose, but differed significantly following 4 days of treatment due to drug effect. Image analysis of 18F-FDG uptake after single and multiple doses showed that there was a significant difference (p&amp;lt;0.05) in meanSUV, maxSUV and the percentage of injected dose per gram of tissue (%ID/g) between vehicle and drug treated tumors. Biodistribution analysis showed that the average 18F-FDG %ID/g in vehicle-treated tumors was significantly higher than in AZD8055-treated tumors (p&amp;lt;0.05). The changes in glucose uptake after 1 and 4 administrations were consistent with the pharmacodynamic effects of AZD8055 on pS6 and pAKT biomarkers in U87-MG tumors collected at the same time-points. Conclusions: AZD8055 reduces significantly 18F-FDG uptake in U87-MG human glioma xenografts, as early as 1 hour after a single dose. This data suggests that 18F-FDG uptake could be used as an early sign of metabolic response to AZD8055. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A225.
Role of platelet membrane glycoprotein IIb-IIIa in agonist-induced tyrosine phosphorylation of platelet proteins. (1990)

Treatment of platelets with thrombin was shown previously to induce rapid changes in tyrosine phosphorylation of several platelet proteins. In this report, we demonstrate that a variety of agonists which induce platelet aggregation also stimulate tyrosine phosphorylation of three proteins with apparent molecular masses of 84, 95, and 97 kD. Since platelet aggregation requires the agonist-induced activation of an integrin receptor (GP IIb-IIIa) as well as the binding of fibrinogen to this receptor, we examined the relationship between tyrosine phosphorylation and the function of GP IIb-IIIa. When platelets were examined under conditions that either precluded the activation of GP IIb-IIIa (prior disruption of the complex by EGTA at 37 degrees C) or the binding of fibrinogen (addition of RGDS or an inhibitory mAb), tyrosine phosphorylation of the 84-, 95-, and 97-kD proteins was not observed. However, although both GP IIb-IIIa activation and fibrinogen binding were necessary for tyrosine phosphorylation, they were not sufficient since phosphorylation was observed only under conditions in which the activated platelets were stirred and allowed to aggregate. In contrast, tyrosine phosphorylation was not dependent on another major platelet response, dense granule secretion. Furthermore, granule secretion did not require tyrosine phosphorylation of this set of proteins. These experiments demonstrate that agonist-induced tyrosine phosphorylation is linked to the process of GP IIb-IIIa-mediated platelet aggregation. Thus, tyrosine phosphorylation may be required for events associated with platelet aggregation or for events that follow aggregation.
Gas-Phase Reactions of Nickel Oxide Clusters with Nitric Oxide. 1. Formation of Nitrogen Dioxide on Nickel Oxide Cluster Anions (1998)

A fast-flow reactor quadrupole mass spectrometer coupled with a laser vaporization source is used to study the gas-phase reactions of nickel oxide cluster anions (NixOy)- with nitric oxide (NO). The results show that nitrogen dioxide (NO2) is formed on the nickel oxide clusters and that this formation leads to the loss of one or more species from the clusters in order to dissipate the heat of formation. The species lost from the clusters are nickel (Ni) and nickel oxide (NiO). Also, there is evidence that the association species of nitric oxide with nickel oxide anions rapidly form NO2. Additional experiments were conducted in order to determine if this NO2 formation mechanism is a function of how the nickel oxide cluster anions are formed. It was observed that a significantly different reaction occurs when nickel clusters are allowed to oxidize at room temperature and are then reacted with nitric oxide.
Mechanisms of β-Cell Death in Type 2 Diabetes (2005)

A decrease in the number of functional insulin-producing beta-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in beta-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of beta-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-kappaB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of beta-cell secretory function and cell turnover. Thus, the mechanisms regulating beta-cell proliferation, apoptosis, and function are inseparable processes.
Specific Activity (2016)

From 1967 onwards, a number of documents prepared by the IUPAC/C-QUCC and IFCC/C-QU (from 1996-01-01 C-NPU), with input from many clinical laboratory scientists worldwide, and consistent with standards promulgated by authoritative international scientific organisations, have been published. Because of the importance of a consistent terminology in clinical chemistry and because these documents are often published in journals that may not be readily accessible, the C-NPU has prepared a glossary containing those terms considered of particular interest to the clinical chemistry and clinical laboratory science communities. The glossary has been compiled from definitions taken from published documents of the C-NPU. Also it contains a number of terms, and their definitions, considered relevant to the practice of clinical chemistry, taken from the official documents of other commissions of IUPAC and of international scientific organisations such as the International Organisation for Standardisation, the International Bureau of Weights and Measures and the International Union of Biochemistry and Molecular Biology.
Synergistic sputtering effects during ion bombardment with two ion species (1995)

The modification of the sputtering yield during ion bombardment with two ion species of different masses is studied with the dynamic Monte Carlo code T−DYN. Specifically, the sputtering yield of low mass targets with low to medium mass primary ions is substantially enhanced when a second ion species of higher mass is introduced. This enhancement is due to the incorporation of the heavier ion species into the target material thus changing significantly the collision cascade behavior of the primary ions. As a result, the energy deposited at the surface is increased and hence the sputtering yield is also increased. This sputter yield enhancement is found to be a function of the ion energy, angle of incidence, masses and atomic densities of the two ion species, steady state concentration of the secondary ion species at the surface (primary to secondary ion ratio), etc. The effect is found to be most pronounced at low energies where the sputter yield enhancement is predicted to increase by a factor of 2 or more. The mechanisms of the sputter yield enhancement as well as the modification of the energy deposition function are discussed in detail.
Diffusion in Co90Fe10/Ru multilayers (2003)

Signal degradation in spin-valve structures is today a concern for long-term stability of data storage devices. One of the possible degradation mechanisms of spin-valve structures in disk drive applications could be thermally activated diffusion between constituent layers. In order to predict and control performance degradation, the interdiffusion coefficients for all bilayers in the spin-valve structure will have to be determined. Here we report results from a Co90Fe10/Ru interface, common in many spin-valve structures. The diffusion in (0002) oriented polycrystalline Co90Fe10/Ru multilayers has been measured and quantified by x-ray reflectivity in the temperature range of 450–540 °C. The bulk diffusion in this case is described by an activation energy of Ea=4.95 eV and a prefactor of D0=6.43×10−9 m2/s. No grain boundary diffusion was detected in the large-grain structure dominated by high symmetry grain boundaries at the temperature interval in this study. For a spin-valve structure that contains Co90Fe10/Ru interfaces it is clear that with the absence of grain boundary diffusion and a very high activation energy to bulk diffusion degradation will first take place at another interface, or by another phenomenon.
Immunoglobulin-like PapD chaperone caps and uncaps interactive surfaces of nascently translocated pilus subunits. (1991)

Molecular chaperones are found in the cytoplasm of bacteria and in various cellular compartments in eukaryotes to maintain proteins in nonnative conformations that permit their secretion across membranes or assembly into oligomeric structures. Virtually nothing, however, has been reported about a similar requirement for molecular chaperones in the periplasm of Gram-negative bacteria. We used the well-characterized P pilus biogenesis system in Escherichia coli as a model to elucidate the mechanism of action of a periplasmic chaperone, PapD, which is specifically required for P pilus biogenesis. PapD probably associates with at least six P pilus subunits after their secretion across the cytoplasmic membrane, but PapD is not incorporated into the pilus. We used purified periplasmic complex that PapD forms with the PapG adhesin to investigate the function of interactions between the chaperone and its targets. We demonstrated that PapD binds to PapG to form a stable, discrete bimolecular complex and that, unlike cytoplasmic chaperones, the periplasmic PapD chaperone maintained PapG in a native-like conformation. Bound PapD in the complex was displaced by free PapD in vitro; however, the in vivo release of subunits to the nascent pilus is probably driven by an ATP-independent mechanism involving the outer membrane protein PapC. In addition, the binding of PapD to PapG in vitro prevented aggregation of PapG. We propose that the function of PapD and other periplasmic pilus chaperones is to partition newly translocated pilus subunits into assembly-competent complexes and thereby prevent nonproductive aggregation of the subunits in the periplasm. These data provide important information for understanding the mechanism of action of this general class of chaperones that function in the periplasmic space.
Botulinum Toxin as a Biological Weapon (2001)

An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.
Mutational analysis of muscle nicotinic acetylcholine receptor subunit assembly. (1990)

The structural elements required for normal maturation and assembly of the nicotinic acetylcholine receptor alpha subunit were investigated by expression of mutated subunits in transfected fibroblasts. Normally, the wild-type alpha subunit acquires high affinity alpha bungarotoxin binding in a time-dependent manner; however, mutation of the 128 and/or 142 cysteines to either serine or alanine, as well as deletion of the entire 14 amino acids in this region abolished all detectable high affinity binding. Nonglycosylated subunits that had a serine to glycine mutation in the consensus sequence also did not efficiently attain high affinity binding to toxin. In contrast, mutation of the proline at position 136 to glycine or alanine, or a double mutation of the cysteines at position 192 and 193 to serines had no effect on the acquisition of high affinity toxin binding. These data suggest that a disulfide bridge between cysteines 128 and 142 and oligosaccharide addition at asparagine 141 are required for the normal maturation of alpha subunit as assayed by high affinity toxin binding. The unassembled wild-type alpha subunit expressed in fibroblasts is normally degraded with a t1/2 of 2 h; upon assembly with the delta subunit, the degradation rate slows significantly (t1/2 greater than 13 h). All mutated alpha subunits retained the capacity to assemble with a delta subunit coexpressed in fibroblasts; however, mutated alpha subunits that were not glycosylated or did not acquire high affinity toxin binding were rapidly degraded (t1/2 = 20 min to 2 h) regardless of whether or not they assembled with the delta subunit. Assembly and rapid degradation of nonglycosylated acetylcholine receptor (AChR) subunits and subunit complexes were also observed in tunicamycin-treated BC3H-1 cells, a mouse musclelike cell line that normally expresses functional AChR. Hence, rapid degradation may be one form of regulation assuring that only correctly processed and assembled subunits accumulate, and ultimately make functional receptors in AChR-expressing cells.
Detection of insulin synthesis in mammalian anterior pituitary cells by immunohistochemistry and demonstration of insulin-related transcripts by in situ RNA-DNA hybridization. (1986)

Insulin or highly homologous transcripts is shown to be synthesized in cultures of mammalian anterior pituitary cells using cloned insulin-specific cDNA probes and nucleic acid cytochemistry. The insulin-hybridizing cells are less abundant than the growth hormone-producing cells, occurring in the cultures at approximately one tenth the frequency. Immunocytochemistry demonstrates that insulin or insulin-like proteins is also synthesized by the cultured pituitary cells and that the insulin immunoreactivity is contained within secretory granules. It appears that many of these secretory granules are concentrated around the periphery of the cell, unlike the insulin-containing granules in pancreatic B-cells.
ACS2, a Saccharomyces Cerevisiae Gene Encoding Acetyl-Coenzyme A Synthetase, Essential for Growth on Glucose (1995)

In Saccharomyces cerevisiae, the conversion of pyruvate to acetyl-coenzyme A may proceed directly via the pyruvate dehydrogenase complex (PDH) or indirectly via the so-called PDH bypass, which requires the sequential action of pyruvate decarboxylase, acetaldehyde dehydrogenase and acetyl-coenzyme A synthetase. The relative contribution of both pathways to the rate of acetyl-coenzyme A synthesis varies in an unknown way with cultural conditions. To determine the possible role of acetyl-coenzyme A synthetase in this central part of metabolism, we have analyzed the genes encoding this enzyme. Disruption of the recently cloned ACS1 gene [De Virgilio, C., Burckert, N., Barth, G., Neuhaus, J., Boller, T. & Wiemken, A. (1992) Yeast 8, 1043-1051] did not cause an apparent phenotype, except for a prolonged lag-phase during growth on glucose or C2 compounds such as acetate and ethanol. In fact, a product from a different gene is responsible for acetyl-coenzyme A formation in the acs1 mutant. We cloned a second gene encoding acetyl-coenzyme A synthetase, which we called ACS2. Inactivation of this gene caused inability to grow on media containing glucose, but not on media with acetate or ethanol as the sole carbon source. This indicates that ACS2 is essential for growth on glucose in batch cultures. The acs1-acs2 double mutant was not viable. The role of both genes in glucose metabolism and acetate or ethanol metabolism is discussed.