gebhart/patrepeval huggingface dataset:
Discovery and development of CP-724714, a selective HER2 receptor tyrosine kinase inhibitor (2004)

3122 Background: The HER2 (neu/erbB2) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary and stomach. Amplification of the HER2 gene and over-expression of this membrane receptor tyrosine kinase has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients and disease free survival. Methods: Novel compounds were evaluated as inhibitors of recombinant HER2 tyrosine kinase-catalyzed phosphorylation of poly-glu/tyr and of the EGF-induced autophosphorylation of cellular epidermal growth factor receptor or a chimeric protein consisting of the EGFR extracellular domain/HER2 intracellular domain. The title inhibitor was further evaluated for its ability to reduce HER2 phosphorylation and growth in human tumor xenografts of athymic mice. Results: CP-724,714, a potent, orally active HER2 inhibitor, was identified and characterized for further development. This compound inhibits HER2 kinase (IC50 3.8 ng/ml) and is selective for HER2 vs. HER1, HER4 and other tyrosine kinases examined. CP-724714 reduces EGF-induced HER2 receptor phosphorylation in NIH 3T3 cells expressing a chimeric receptor consisting of the EGFR extracellular domain and the HER2 intracellular domain (IC50 15 ng/ml) and the growth of SKBr3 cells (IC50 25 ng/ml). Pre-clinical findings suggest that CP-724,714 is an orally bio-available compound with moderate clearance (11–12 ml/min/kg), and a low probability of drug:drug interactions. It reduces HER2 autophosphorylation of tumors in vivo (ED50 ∼ 19 mg/kg, EC50 ∼ 980 ng/ml), after oral administration to athymic mice bearing FRE erbB2 tumors (Fisher rat embryonic fibroblasts over-expressing HER2), and inhibited the growth of these tumors as well as human tumor xenografts. In nonclinical toxicology studies up to 1-month in duration, CP-724,714 was relatively well-tolerated in both Sprague-Dawley rats and Beagle dogs. Conclusions: CP-724714 is a novel HER2 inhibitor now in Phase I clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
A branching dendritic model of a rodent CA3 pyramidal neurone. (1994)

1. We constructed a branching dendritic compartmental model of a CA3 pyramidal neurone, using experimental data from guinea-pig and rat cells obtained in vitro. The goal was to understand interactions between synaptic events impinging on dendritic branches and voltage- and calcium-dependent currents. The model contained sixty-four soma-dendrite (SD) compartments, an axon initial segment (IS), and four axonal compartments. There were six active conductances in the SD membrane, including a sodium conductance (gNa) and a high-threshold calcium conductance (gCa), with kinetic properties similar to those reported in a previous study. 2. The distribution of conductance densities across the IS and SD was adjusted by testing the model response to antidromic stimulation and current pulses or sustained currents injected into the soma or apical dendrites. As before, gNa was concentrated on and near the soma with lower density in the dendrites, while gCa had a higher density in apical dendrites than at the soma. 3. The model predicts that CA3 pyramidal neurones in media blocking synaptic transmission should fire a burst of action potentials following antidromic stimulation. This was confirmed experimentally in hippocampal slices. 4. Both in the model and in guinea-pig neurones, dendritic IPSCs can delay the onset of bursting. If an IPSC begins soon enough after the first fast action potential, the later burst envelope is attenuated. This effect results from suppression of dendritic Ca2+ electrogenesis. 5. The model predicts that an appropriately timed dendritic IPSC (after the first somatic spike but before the dendritic Ca2+ spike) may suppress the transient local [Ca2+] signal, while having a negligible effect on the electrical output of the neurone. This phenomenon has been reported in guinea-pig Purkinje cells. 6. We conclude that active dendritic currents are critical for regulation of the electrical output of CA3 pyramidal neurones. We suggest also that dendritic [Ca2+] signals might be controlled in individual dendrites independently of action potential outputs, an effect of possible importance for synaptic plasticity.
Oxidation Behavior of High Strength Chain-Extended Polyethylene Fibers (1988)

The resistance to oxidation of polyethylene fiber intended for engineering applications has been compared with that of conventional polyethylene films. The highly ordered fiber was appreciably more resistant to γ-initiated oxidation and somewhat more resistant to photo-oxidation. Oxidation products from the γ-initiated oxidation were quite highly ordered with respect to the fiber axis as shown by polarized infrared spectroscopy. Photo-oxidation products showed random orientation, possibly as a result of the more extensive chain scission that must accompany the photo-process. Despite the higher resistance of γ-radiation damage of the chain-extended fiber structure as compared to unoriented film, the irradiated fiber did show a slow post-irradiation oxidation.
Flexible bandwidth and bit-rate programmability in future optical networks (2012)

Recent progress in network equipment allows trade-offs to be made between the optical bandwidth, distance-reach, and bit-rate for given optical data channels. We discuss methods to increase the utilization of network resources and thereby to lower the network's cost-per-bit of transport.
Murein-metabolizing enzymes from Escherichia coli: existence of a second lytic transglycosylase (1992)

In addition to the soluble lytic transglycosylase, a murein-metabolizing enzyme with a molecular mass of 70 kDa (Slt70), Escherichia coli possesses a second lytic transglycosylase, which has been described as a membrane-bound lytic transglycosylase (Mlt; 35 kDa; EC 3.2.1.-). The mlt gene, which supposedly encodes Mlt, was cloned, and the complete nucleotide sequence was determined. The open reading frame, identified on a 1.7-kb SalI-PstI fragment, codes for a protein of 323 amino acids (M(r) = 37,410). Two transmembrane helices and one membrane-associated helix were predicted in the N-terminal half of the protein. Lysine and arginine residues represent up to 15% of the amino acids, resulting in a calculated isoelectric point of 10.0. The deduced primary structure did not show significant sequence similarity to Slt70 from E. coli. High-level expression of the presumed mlt gene was not paralleled by an increase in murein hydrolase activity. To clarify the identity of the second transglycosylase, we purified an enzyme with the specificity of a transglycosylase from an E. coli slt deletion strain. The completely soluble transglycosylase, with a molecular mass of approximately 35 kDa, was designated Slt35. Its determined 26 N-terminal amino acids showed similarity to a segment in the middle of the Slt70 primary structure. Polyclonal anti-Mlt antibodies, which had been used for the isolation of the mlt gene, were found to cross-react with Mlt as well as with Slt35, suggesting that the previously described Mlt preparation was contaminated with Slt35. We conclude that the second transglycosylase of E. coli is not a membrane-bound protein but rather is a soluble protein.
Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival (2011)

Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.
[IL-18 and IL-18 receptor]. (1998)

Interleukin-18 (IL-18) is a recently cloned cytokine, produced from activated macrophages, including Kupffer cells. IL-18 is originally called interferon-gamma inducing factor (IGIF), due to its action to induce IFN-gamma production from Th 1 cells and NK cells. However, recent studies suggested that, IL-18 also enhances expression of FasL and NK activity as well as GM-CSF production. These data revealed this novel cytokine is pleiotropic. Recently, cDNA encoding human IL-18 receptor (IL-18R) was cloned. And, we had cloned murine IL-18R cDNA by RT-PCR, using human IL-18R sequence. Northern blot analysis of cytoplasmic RNA from T cells stimulated with IL-12 clearly demonstrated that, T cells stimulated with IL-12 induced high level of IL-18R-mRNA, whereas non-stimulated T cells did not have. Interestingly, we had several reports, indicated the involvement of IL-18 on the progressions of pathogenicity in chronic inflammatory diseases, including endotoxin-shock, hepatitis and autoimmune-diabetes. We need further studies to reveal physiological roles of this novel cytokine in various inflammatory or autoimmune diseases.
Project OART: WDM, EDFAs and mixed data rates in a real-world testbed (1994)

Pacific Bell, Lawrence Livermore National Laboratory (LLNL), and the University of California at Berkeley have established a joint fiber testbed located in the San Francisco Bay Area. The fiber to be used in the trial is representative of Pacific Bell`s current fiber plant. This ongoing project is a year long collaboration involving the wavelength division multiplexing (WDM) of data and video on a link using erbium doped fiber amplifiers (EDFA). Designated Project OART. for Optical Amplifier Reliability Trial, this project will provide the Network, Technology District of Pacific Bell a valuable testbed for gathering information and experience with future network designs that will use WDM, EDFs, and the simultaneous transmission of high-speed digital and video information. LLN`s interest in this link is driven by a need to evaluate various future means of interconnecting high performance users With high performance storage and computation sites over remote connections. The OART link will consist of a four channel WDM system on a pair of fibers over a link amplified by two pairs of EDFAs. Three wavelengths will be data communication channels transmitted between LLNL in Livermore and UCB in Berkeley at a distance of 98 km. A fourth channel of video will be carried from a Pacific Bell test facility in Concord on 73 km of fiber to a video lab at LLNL.
An effective technique and practical utility for approximate query processing (2015)

This dissertation studies efficient and effective approximate query processing for decision support systems. A novel method that enables fast query processing and reliable approximation even in highly selective queries is proposed and evaluated. Also, utility software that enables the implementation of the proposed method in databases and enables the execution of approximate query processing in SQL is developed as part of this research.
Synthesis and effect of shortened oostatic decapeptide (TMOF) analogs with isosteric structures on reproduction of Neobellieria bullata (2001)

Oligopeptides 2a-2d derived from the oostatic decapeptide (TMOF) sequence, H-Tyr-Asp-Pro-Ala-Pro-Pro-Pro-Pro-Pro-Pro-OH (1a) and containing isosteric structures were synthesized and assayed to determine their effect during reproduction in the flesh fly Neobellieria bullata. The N-terminal linear tetra- and pentapeptides 2a, 2b containing the Pro-psi[CH2O]Ala isosteric linkage affect egg development in 80-90% of ovarioles resulting in some resorbed egg chambers, abnormal yolk deposition, the formation of large eggs with irregular yolk granules and proliferation of follicular epithelium. In comparison with their nonisosteric precursors 1b, 1c they exhibit even more accelerated oostatic activity. However, peptides 2c, 2d containing a Pro-psi[CH2S]Ala isosteric linkage are less active.
Species-specific Inhibition of Porphobilinogen Synthase by 4-Oxosebacic Acid (2002)

Porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of 5-aminolevulinic acid (ALA), an essential step in tetrapyrrole biosynthesis. 4-Oxosebacic acid (4-OSA) and 4,7-dioxosebacic acid (4,7-DOSA) are bisubstrate reaction intermediate analogs for PBGS. We show that 4-OSA is an active site-directed irreversible inhibitor for Escherichia coli PBGS, whereas human, pea, Pseudomonas aeruginosa, and Bradyrhizobium japonicum PBGS are insensitive to inhibition by 4-OSA. Some variants of human PBGS (engineered to resemble E. coli PBGS) have increased sensitivity to inactivation by 4-OSA, suggesting a structural basis for the specificity. The specificity of 4-OSA as a PBGS inhibitor is significantly narrower than that of 4,7-DOSA. Comparison of the crystal structures for E. coli PBGS inactivated by 4-OSA versus 4,7-DOSA shows significant variation in the half of the inhibitor that mimics the second substrate molecule (A-side ALA). Compensatory changes occur in the structure of the active site lid, which suggests that similar changes normally occur to accommodate numerous hybridization changes that must occur at C3 of A-side ALA during the PBGS-catalyzed reaction. A comparison of these with other PBGS structures identifies highly conserved active site water molecules, which are isolated from bulk solvent and implicated as proton acceptors in the PBGS-catalyzed reaction.
A Perspective on Cancer Cell Metastasis (2011)

Metastasis causes most cancer deaths, yet this process remains one of the most enigmatic aspects of the disease. Building on new mechanistic insights emerging from recent research, we offer our perspective on the metastatic process and reflect on possible paths of future exploration. We suggest that metastasis can be portrayed as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a metastatic lesion at that distant site. Although much remains to be learned about the second phase, we feel that an understanding of the first phase is now within sight, due in part to a better understanding of how cancer cell behavior can be modified by a cell-biological program called the epithelial-to-mesenchymal transition.
LH Response (in vivo and in vitro) to an LHRH Agonist Administered to Domestic Male Cats (2003)

We investigated plasma luteinizing hormone (LH) concentration in domestic male cats challenged with Luteinizing Hormone Releasing Hormone Analog (LHRH-A) [des Gly 10, (DTrp6)-LHRH ethylamide] that mediates the function of the hypothalamic-pituitary-gonadal axis (HPG). Plasma LH concentrations in cats treated daily with LHRH (10 microg/100 microl/kg/day, subcutaneously-s.c.) for 19 days (LHRH group) and in controls treated with saline (NaCl-0.9%, same volume-SAL group) were chronically studied. LHRH administration (s.c.) for 15 days induced a significant fall (P < 0.05) in plasma LH concentrations during the chronic study. After the 15th day of treatment the groups were divided once more into animals treated with LHRH (10 microg/100 microl/kg) or saline (i.v.), and a time course study (300 min) was performed (acute study). Next, four groups of cats were compared in an acute study involving the s.c./i.v. administration of SAL/SAL, SAL/LHRH, LHRH/SAL, and LHRH/LHRH. The responses of the SAL animals challenged by acute i.v. administration of LHRH (group SAL/LHRH) were significantly higher (P < 0.01) than those of animals treated with LHRH (sc) (group LHRH/LHRH). LH release was also significantly increased in the latter group (P < 0.05), although the effect was short lasting, being recorded only at the first observation (45 min). An in vitro study with the pituitaries was also performed on day 20. Mean (+/-SEM) LH concentrations in the culture medium containing pituitaries with LHRH (10(-7) M) or saline were determined. In vitro analysis of these pituitaries demonstrated a significantly reduced response (P < 0.05) by animals treated sc with LHRH for 19 days. This study represents a source of data for the domestic cat going beyond its own physiology. Serving as a model, this animal provide important information for the study of reproductive physiology in other members of its family (Felidae), almost all of them threatened with extinction.
Amidase coupled with low‐molecular‐mass nitrile hydratase from Rhodococcus rhodochrous J1 (1993)

The cloned 9.4-kb insert of plasmid pNHJ20L containing low-molecular-mass nitrile hydratase (L-NHase) gene from Rhodococcus rhodochrous J1 [Kobayashi, M. et al. (1991) Biochim. Biophys. Acta 1129, 23-33] was digested with various restriction enzymes, and the trimmed fragments were inserted into pUC18 or pUC19. A 1.96-kb EcoRI-SphI region located 1.9-kb downstream of the L-NHase gene was found to be essential for the expression of amidase activity in Escherichia coli; the gene arrangement of the amidase and the NHase in R. rhodochrous J1 differed from those in Rhodococcus species including N-774 and Pseudomonas chlororaphis B23. The nucleotide-determined sequence indicated that the amidase consists of 515 amino acids (54626 Da) and the deduced amino acid sequence of the amidase had high similarity to those of amidases from Rhodococcus species including N-774 and P. chlororaphis B23 and to indole-3-acetamide hydrolase from Pseudomonas savastanoi. The amidase gene modified in the nucleotide sequence upstream from its start codon expressed 8% of the total soluble protein in E. coli under the control of lac promoter. The level of amidase activity in cell-free extracts of E. coli was 0.468 unit/mg using benzamide as a substrate. This amidase was purified to homogeneity from extracts of the E. coli transformant with 30.4% overall recovery. The molecular mass of the enzyme estimated by HPLC was about 110 kDa and the enzyme consists of two subunits identical in molecular mass (55 kDa). The enzyme acted upon aliphatic amides such as propionamide and also upon aromatic amides such as benzamide. The apparent Km values for propionamide and benzamide were 0.48 mM and 0.15 mM, respectively. This amidase was highly specific for the S-enantiomer of 2-phenylpropionamide, but could not recognize the configuration of 2-chloropropionamide. It also catalyzed the transfer of an acyl group from an amide to hydroxylamine to produce the corresponding hydroxamate.
Biosensor-Based Kinetic Characterization of the Interaction between HIV-1 Reverse Transcriptase and Non-nucleoside Inhibitors (2006)

Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs licensed for clinical use: nevirapine, delavirdine, and efavirenz. Mathematical evaluation of the experimental data with several interaction models revealed that the four inhibitors interacted with HIV-1 RT with varying degrees of complexity. The simplest adequate model accounted for two different conformations of the free enzyme, of which only one can bind the inhibitor, consistent with a previously hypothesized population-shift model including a preformation of the NNRTI binding site. In addition, a heterogeneous binding was observed for delavirdine, efavirenz, and MIV-150, indicating that two noncompetitive and kinetically distinct enzyme-inhibitor complexes could be formed. Furthermore, for these compounds, there were indications for ligand-induced conformational changes.
An Activating Mutation in the Kit Receptor Abolishes the Stroma Requirement for Growth of ELM Erythroleukemia Cells, But Does Not Prevent Their Differentiation in Response to Erythropoietin (1998)

We have previously shown that murine ELM erythroleukemia cells can only be grown in vitro in the presence of a stromal feeder layer, or alternatively stem cell factor (SCF), without which they differentiate. When grown in the presence of SCF, ELM cells can still differentiate in response to erythropoietin (Epo), but growth on stroma prevents this. We previously isolated a stroma-independent ELM variant, ELM-I-1, that is also defective in Epo-induced differentiation. We show here that this variant has an activating mutation in the Kit receptor, converting aspartic acid 814 to histidine. Expression of the mutant receptor in stroma-dependent ELM-D cells causes growth factor-independent proliferation and also gives the cells a selective advantage, in terms of proliferation rate and clonegenicity, compared with ELM-D cells grown in optimal amounts of SCF. Expression of the mutant receptor in ELM-D cells also prevents spontaneous differentiation, but not differentiation induced by Epo. Analysis of mitogenic signaling pathways in these cells shows that the mutant receptor induces constitutive activation of p42/p44 mitogen-activated protein kinases. It also selectively inhibits the expression of p66Shc but not the p46/p52 Shc isoforms (as did treatment of ELM cells with SCF), which is of interest, because p66Shc is known to play an inhibitory role in growth factor signaling.
Paracoccus carotinifaciens sp. nov., a new aerobic Gram-negative astaxanthin-producing bacterium (1999)

The strain E-396T, isolated from soil, was Gram-negative, aerobic, orange-pigmented, rod-shaped, motile by peritrichous flagella and astaxanthin-producing. This organism produced carotenoids, mainly astaxanthin, and did not produce bacteriochlorophyll. The ubiquinone system was Q-10. Analysis of the 16S rRNA sequence of strain E-396T showed it to be a member of the alpha-3 subclass of the Proteobacteria, forming a cluster with the species of the genus Paracoccus. On the basis of the production of orange pigments and motility by peritrichous flagella, together with DNA-DNA reassociation data, it is concluded that the new isolate should be classified into a new species of the genus Paracoccus, Paracoccus carotinifaciens sp. nov. The type strain is E-396T (= IFO 16121T).
Human cysticercosis: antigens, antibodies and non-responders. (1980)

Immunoelectrophoresis of sera from patients with brain cysticercosis against a crude antigenic extract from Cysticercus cellulosae indicates that nearly 50% of the patients do not make sufficient antibodies to ostensively precipitate. The other 50% of the patients who do make precipitating antibodies show a very heterogeneous response in the number of antigens they recognize as well as in the type of antigen--as classified by their electrophoretic mobilities. The most favoured, called antigen B, is recognized by 84% of positive sera and corresponds to one or a limited number of antigens isoelectric at pH 8.6. Indirect immunofluorescence with monospecific anti-human immunoglobulins, performed upon the immunoelectrophoretic preparations, reveal that all cysticercus antigens induced the synthesis of antibodies in the immunoglobulin classes in the order G greater than M greater than E greater than A greater than D. Finally, antigen H (an anodic component) seems to favour IgE relative to its ability to induce IgG. Thus, although in natural infection a good proportion of cysticercotic patients do not seem to mount an energetic antibody response against the parasite, giving rise to some speculations about immunosuppression, the fact that 50% do synthesize antibodies allows for some optimistic expectations from vaccination of humans--in view of the good results of vaccination in experimental animals mediated by IgG antibodies. A likely prospect for a human vaccine would be antigen B because it is the most frequently detected by humans, although its immunizing and toxic properties remain to be properly studied.