gebhart/patrepeval huggingface dataset:
Discovery of a Novel, Potent, and Orally Active Nonpeptide Antagonist of the Human Luteinizing Hormone-Releasing Hormone (LHRH) Receptor (1998)

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTDiscovery of a Novel, Potent, and Orally Active Nonpeptide Antagonist of the Human Luteinizing Hormone-Releasing Hormone (LHRH) ReceptorNobuo Cho, Masataka Harada, Toshihiro Imaeda, Takashi Imada, Hirokazu Matsumoto, Yoji Hayase, Satoshi Sasaki, Shuichi Furuya, Nobuhiro Suzuki, Shoichi Okubo, Kazuhiro Ogi, Satoshi Endo, Haruo Onda, and Masahiko FujinoView Author Information Discovery Research Division, Takeda Chemical Industries, Ltd., 10 Wadai Tsukuba, Ibaraki 300-4293, Japan, and Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85 Jusohonmachi 2-chome Yodogawa-ku, Osaka 532-8686, Japan Cite this: J. Med. Chem. 1998, 41, 22, 4190–4195Publication Date (Web):October 7, 1998Publication History Received17 June 1998Published online7 October 1998Published inissue 1 October 1998https://pubs.acs.org/doi/10.1021/jm9803673https://doi.org/10.1021/jm9803673rapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views834Altmetric-Citations121LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Antagonists,Inhibition,Peptides and proteins,Receptors,Rodent models Get e-Alerts
Synergistic Combination of Novel Tubulin Inhibitor ABI-274 and Vemurafenib Overcomes Vemurafenib Acquired Resistance in BRAFV600E Melanoma (2013)

Acquired clinical resistance to vemurafenib, a selective BRAF(V600E) inhibitor, arises frequently after short-term chemotherapy. Because inhibitions of targets in the RAF-MEK-ERK pathway result in G(0)-G(1) cell-cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell-cycle arrest and progress to the subsequent G(2)-M phase. We hypothesized that a combined therapy using vemurafenib with a G(2)-M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next, we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in the G(1)-G(2)-M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of extracellular signal-regulated kinase (ERK) phosphorylation. Finally, in vivo coadministration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in patients with melanoma who inevitably become resistant to current vemurafenib therapy.
Dry Powder Inhalers: An Overview (2005)

Dry powder inhalers (DPIs) are a widely accepted inhaled delivery dosage form, particularly in Europe, where they currently are used by a large number of patients for the delivery of medications to treat asthma and chronic obstructive pulmonary disease. The acceptance of DPIs in the United States after the slow uptake following the introduction of the Serevent Diskus in the late 1990s has been driven in large part by the enormous success in recent years of the Advair Diskus. This combination of 2 well-accepted drugs in a convenient and simple-to-use device has created an accepted standard in pulmonary delivery and disease treatment that only a few years ago could not have been anticipated. The DPI offers good patient convenience, particularly for combination therapies, and also better compliance. The design and development of any powder drug-delivery system is a highly complex task. Optimization of the choice of formulation when matched with device geometry is key. The use of particle engineering to create a formulation matched to a simple device is being explored, as is the development of active powder devices in which the device inputs the energy, making it simpler for patients to receive the correct dose. Patient interface issues are also critically important. However, one of the most important factors in pulmonary delivery from a DPI is the requirement for a good-quality aerosol, in terms of the aerosol's aerodynamic particle size, and its potential to consistently achieve the desired lung deposition in vivo.
Irradiation of chemically crosslinked ultrahigh molecular weight polyethylene (1996)

Acetabular cups for artificial hip joints were prepared by compression molding of ultrahigh molecular weight polyethylene in the presence of peroxide. Peroxide crosslinking led to a decrease in the degree of crystallinity, peak melting temperature, and recrystallization temperature, as well as decreased crystal perfection and size. Peroxide crosslinked cups were sterilized with gamma rays at room temperature in air atmosphere to an average dose of 3.4 Mrad. Irradiation produced further crosslinking in amorphous regions plus extensive chain scission of taut tie molecules and led to increased crystallinity and crystal perfection. A significant increase in carbonyl concentration was determined for irradiated specimens. In general, peroxide crosslinking reduces the effect of irradiation on the crosslinked network, because chemical crosslinking stabilizes chain fragments resulting from radiolytic scission and suppresses recrystallization of broken chains from amorphous regions. Wear rates were much lower for chemically crosslinked cups, which showed about one-fifth of the wear of control cups for the period from 0.5 to 1.0 million cycles. © 1996 John Wiley & Sons, Inc.
Underwater thrust and power generation using flexible piezoelectric composites: an experimental investigation toward self-powered swimmer-sensor platforms (2011)

Fiber-based flexible piezoelectric composites offer several advantages to use in energy harvesting and biomimetic locomotion. These advantages include ease of application, high power density, effective bending actuation, silent operation over a range of frequencies, and light weight. Piezoelectric materials exhibit the well-known direct and converse piezoelectric effects. The direct piezoelectric effect has received growing attention for low-power generation to use in wireless electronic applications while the converse piezoelectric effect constitutes an alternative to replace the conventional actuators used in biomimetic locomotion. In this paper, underwater thrust and electricity generation are investigated experimentally by focusing on biomimetic structures with macro-fiber composite piezoelectrics. Fish-like bimorph configurations with and without a passive caudal fin (tail) are fabricated and compared. The favorable effect of having a passive caudal fin on the frequency bandwidth is reported. The presence of a passive caudal fin is observed to bring the second bending mode close to the first one, yielding a wideband behavior in thrust generation. The same smart fish configuration is tested for underwater piezoelectric power generation in response to harmonic excitation from its head. Resonant piezohydroelastic actuation is reported to generate milli-newton level hydrodynamic thrust using milli-watt level actuation power input. The average actuation power requirement for generating a mean thrust of 19 mN at 6 Hz using a 10 g piezoelastic fish with a caudal fin is measured as 120 mW. This work also discusses the feasibility of thrust generation using the harvested energy toward enabling self-powered swimmer-sensor platforms with comparisons based on the capacity levels of structural thin-film battery layers as well as harvested solar and vibrational energy.
Pharmacologic therapy for inflammatory bowel disease refractory to steroids (2015)

Although corticosteroids are an effective treatment for induction of remission in inflammatory bowel disease (IBD), many patients are dependent on or refractory to corticosteroids. This review is based on scrutinizing current literature with emphasis on randomized controlled trials, meta-analyses, and Cochrane reviews on the management of IBD refractory to corticosteroids. Based on this evidence, we propose algorithms and optimization strategies for use of immunomodulator and biologic therapy in IBD refractory to corticosteroids.
Transgenic Mice with Immunoglobulin Genes (1987)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Pathogenesis of Dengue: Challenges to Molecular Biology (1988)

Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.
Expression profiling of cyclin B1 and D1 in cervical carcinoma. (2006)

Our results were consistent with the concept that up-regulation of cyclin B1 expression occurred in cervical cancer and an aberrant expression of cyclin B1 might play an important role in cervical carcinogenesis.
Discovery of aminoacyl-tRNA synthetase activity through cell-surface display of noncanonical amino acids (2006)

The incorporation of noncanonical amino acids into recombinant proteins in Escherichia coli can be facilitated by the introduction of new aminoacyl-tRNA synthetase activity into the expression host. We describe here a screening procedure for the identification of new aminoacyl-tRNA synthetase activity based on the cell surface display of noncanonical amino acids. Screening of a saturation mutagenesis library of the E. coli methionyl-tRNA synthetase (MetRS) led to the discovery of three MetRS mutants capable of incorporating the long-chain amino acid azidonorleucine into recombinant proteins with modest efficiency. The Leu-13 --> Gly (L13G) mutation is found in each of the three MetRS mutants, and the MetRS variant containing this single mutation is highly efficient in producing recombinant proteins that contain azidonorleucine.
Treatment of Deep Cartilage Defects in the Knee with Autologous Chondrocyte Transplantation (1994)

Cultured autologous chondrocytes can be used to repair deep cartilage defects in the femorotibial articular surface of the knee joint.
Progranulin Does Not Bind Tumor Necrosis Factor (TNF) Receptors and Is Not a Direct Regulator of TNF-Dependent Signaling or Bioactivity in Immune or Neuronal Cells (2013)

Progranulin (PGRN) is a secreted glycoprotein expressed in neurons and glia that is implicated in neuronal survival on the basis that mutations in the GRN gene causing haploinsufficiency result in a familial form of frontotemporal dementia (FTD). Recently, a direct interaction between PGRN and tumor necrosis factor receptors (TNFR I/II) was reported and proposed to be a mechanism by which PGRN exerts anti-inflammatory activity, raising the possibility that aberrant PGRN-TNFR interactions underlie the molecular basis for neuroinflammation in frontotemporal lobar degeneration pathogenesis. Here, we report that we find no evidence for a direct physical or functional interaction between PGRN and TNFRs. Using coimmunoprecipitation and surface plasmon resonance (SPR) we replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the interaction between PGRN and TNFRs. Recombinant PGRN or transfection of a cDNA encoding PGRN did not antagonize TNF-dependent NFκB, Akt, and Erk1/2 pathway activation; inflammatory gene expression; or secretion of inflammatory factors in BV2 microglia and bone marrow-derived macrophages (BMDMs). Moreover, PGRN did not antagonize TNF-induced cytotoxicity on dopaminergic neuroblastoma cells. Last, co-addition or pre-incubation with various N- or C-terminal-tagged recombinant PGRNs did not alter lipopolysaccharide-induced inflammatory gene expression or cytokine secretion in any cell type examined, including BMDMs from Grn+/- or Grn-/- mice. Therefore, the neuroinflammatory phenotype associated with PGRN deficiency in the CNS is not a direct consequence of the loss of TNF antagonism by PGRN, but may be a secondary response by glia to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identified.
Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata (2007)

Macrophage accumulation participates decisively in the development and exacerbation of atherosclerosis. Circulating monocytes, the precursors of macrophages, display heterogeneity in mice and humans, but their relative contribution to atherogenesis remains unknown. We report here that the Ly-6C(hi) monocyte subset increased dramatically in hypercholesterolemic apoE-deficient mice consuming a high-fat diet, with the number of Ly-6C(hi) cells doubling in the blood every month. Ly-6C(hi) monocytes adhered to activated endothelium, infiltrated lesions, and became lesional macrophages. Hypercholesterolemia-associated monocytosis (HAM) developed from increased survival, continued cell proliferation, and impaired Ly-6C(hi) to Ly-6C(lo) conversion and subsided upon statin-induced cholesterol reduction. Conversely, the number of Ly-6C(lo) cells remained unaffected. Thus, we believe that Ly-6C(hi) monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis.
Vaccination Strategies for an Influenza Pandemic (2005)

Vaccination offers the best opportunity to prevent disease and death in a pandemic, but there will be limitations on the timeliness and availability of vaccine [1]. Optimistic projections are that it could take at least 6 months for the first pandemic vaccine doses to be prooduced after the identification of a pandemic strain. Global influenza-vaccine production capacity has nearly doubled over the preceding decade, and increased demand for annual influenza vaccine will continue to
Readthrough of dystrophin stop codon mutations induced by aminoglycosides (2004)

We report the translational readthrough levels induced by the aminoglycosides gentamicin, amikacin, tobramycin, and paromomycin for eight premature stop codon mutations identified in Duchenne's and Becker's muscular dystrophy patients. In a transient transfection reporter assay, aminoglycoside treatment results show that one stop codon mutation is suppressed significantly better (up to 10% stop codon readthrough) than the others; five show lower but statistically significant suppression (< 2% stop codon readthrough); and two appear refractory to aminoglycoside treatment. Readthrough levels do not substantially vary between different sources of gentamicin, and, for this set of mutations, the efficiency of termination at the premature stop codon mutation does not appear to correlate with disease severity.
The Neisseria Lipooligosaccharide-Specific α-2,3-Sialyltransferase Is a Surface-Exposed Outer Membrane Protein (2002)

Neisseria gonorrhoeae and Neisseria meningitidis express an approximately 43-kDa alpha-2,3-sialyltransferase (Lst) that sialylates the surface lipooligosaccharide (LOS) by using exogenous (in all N. gonorrhoeae strains and some N. meningitidis serogroups) or endogenous (in other N. meningitidis serogroups) sources of 5'-cytidinemonophospho-N-acetylneuraminic acid (CMP-NANA). Sialylation of LOS can protect N. gonorrhoeae and N. meningitidis from complement-mediated serum killing and from phagocytic killing by neutrophils. The precise subcellular location of Lst has not been determined. We confirm and extend previous studies by demonstrating that Lst is located in the outer membrane and is surface exposed in both N. gonorrhoeae and N. meningitidis. Western immunoblot analysis of subcellular fractions of N. gonorrhoeae strain F62 and N. meningitidis strain MC58 not subset 3 (an acapsulate serogroup B strain) performed with rabbit antiserum raised against recombinant Lst revealed an approximately 43-kDa protein exclusively in outer membrane preparations of both pathogens. Inner membrane, periplasmic, cytoplasmic, and culture supernatant fractions were devoid of Lst, as determined by Western blot analysis. Consistent with this finding, outer membrane fractions of N. gonorrhoeae were significantly enriched for sialyltransferase enzymatic activity. A trace of enzymatic activity was detected in inner membrane fractions, which may have represented Lst in transit to the outer membrane or may have represented inner membrane contamination of outer membrane preparations. Subcellular preparations of an isogenic lst insertion knockout mutant of N. gonorrhoeae F62 (strain ST01) expressed neither a 43-kDa immunoreactive protein nor sialyltransferase activity. Anti-Lst rabbit antiserum bound to whole cells of N. meningitidis MC58 not subset 3 and wild-type N. gonorrhoeae F62 but not to the Lst mutant ST01, indicating the surface exposure of the enzyme. Although the anti-Lst antiserum avidly bound enzymatically active, recombinant Lst, it inhibited Lst (sialyltransferase) activity by only about 50% at the highest concentration of antibody used. On the contrary, anti-Lst antiserum did not inhibit sialylation of whole N. gonorrhoeae cells in the presence of exogenous CMP-NANA, suggesting that the antibody did not bind to or could not access the enzyme active site on the surface of viable Neisseria cells. Taken together, these results indicate that Lst is an outer membrane, surface-exposed glycosyltransferase. To our knowledge, this is the first demonstration of the localization of a bacterial glycosyltransferase to the outer membrane of gram-negative bacteria.
The effect of a thin coating of polymethylmethacrylate on the torsional fatigue strength of the cement‐metal interface (1992)

Recent studies have established that a mechanism of initiation of failure of fixation of cemented femoral components is debonding of the cement-metal interface. Other studies have shown that the torsional forces induced by stair climbing and rising from a chair are very high. Thus, the interface between the femoral prosthesis and the bone cement in total hip arthroplasty (THA) is required to transmit high torsional loads from the metal to the cement in a cyclic shear mode many times per year. These torsional loads likely contribute to the debonding. This study evaluated the efficacy of a thin layer of polymethylmethacrylate (PMMA) precoating in increasing the torsional fatigue strength of the cement-metal interface. Fatigue studies were performed on 15 specimens. Each specimen was tested with and without PMMA precoating. The PMMA precoat significantly and substantially increased the torsional fatigue strength of the cement-metal interface. Thus, PMMA precoating is likely to be a clinical advantage in maintaining the long-term integrity of the cement-prosthesis interface.
Naturally occurring dibenzofurans. Part 1. A synthesis of cannabifuran (1982)

The synthesis of dibenzofurans from diphenyl ethers by non-phenolic oxidative coupling, u.v. irradiation, and by reaction with palladium(II) acetate has been investigated. 9-Isopropyl-6-methyl-3-pentyldibenzofuran-1-ol (cannabifuran)(35), a minor cannabis constituent, has been synthesized by annulation of 4-isopropyl-7-methylbenzofuran-2-carbaldehyde (28) by Wittig reaction with 2-carboxy-1-ethoxycarbonylethyltriphenylphosphorane and ring closure and functional-group modification of the resultant (E)-4-(4-isopropyl-7-methylbenzofuran-2-yl)-3-methoxycarbonylbut-3-enoic acid (29).
Genes encoding core components of the phycobilisome in the cyanobacterium Calothrix sp. strain PCC 7601: occurrence of a multigene family (1988)

The phycobilisome is the major light-harvesting complex of cyanobacteria. It is composed of a central core from which six rods radiate. Allphycocyanin, an alpha beta oligomer (alpha AP and beta AP), is the main component of the core which also contains three other phycobiliproteins (alpha APB, beta 18.3, and L92CM) and a small linker polypeptide (L7.8C). By heterologous DNA hybridization, two EcoRI DNA fragments of 3.5 and 3.7 kilobases have been cloned from the chromatically adapting cyanobacterium Calothrix sp. strain PCC 7601. Nucleotide sequence determination has allowed the identification of five apc genes: apcA1 (alpha AP1), apcA2 (alpha AP2), apcB1 (beta AP1), apcC (L7.8C), and apcE (L92CM). Four of these genes are adjacent on the chromosome and form the apcEA1B1C gene cluster. In contrast, no genes have been found close to the apcA2 gene which is carried by the 3.5-kilobase EcoRI fragment. Transcriptional analysis and 5'-end-mapping experiments were performed. The results obtained demonstrate that the apcEA1B1C gene cluster forms an operon from which segmented transcripts originate, whereas the apcA2 gene behaves as a monocistronic unit. Qualitatively, the same transcripts were identified regardless of the light wavelengths received during cell growth. The deduced amino acid sequences of the apc gene products are very similar to their known homologs of either cyanobacterial or eucaryotic origin. It was interesting, however, that in the apcA1 and apcA2 genes, whose products correspond to alpha-type allophycocyanin subunits, nucleotide sequences were more conserved (67%) than were the deduced amino acid sequences (59%).