gebhart/patrepeval huggingface dataset:
Activity-dependent disinhibition. II. Effects of extracellular potassium, furosemide, and membrane potential on ECl- in hippocampal CA3 neurons (1989)

1. Single-electrode voltage-clamp recordings were made from CA3 pyramidal cells in organotypic hippocampal slice cultures for measurement of membrane currents underlying both the gamma-aminobutyric acid (GABA)-mediated, Cl- -dependent inhibitory postsynaptic potential (IPSC), evoked in response to stimulation of the mossy fiber pathway, and responses to iontophoretically applied GABA. Their reversal potentials are presumed to equal the equilibrium potential for Cl- (37). Mechanisms underlying activity-dependent increases in the intracellular concentration of Cl- ([Cl-]i) were investigated by describing active and passive pathways for Cl- influx and efflux. 2. During 99-s applications of GABA, driving force declined by 51% due to increases in [Cl-]i; thus passive Cl- influx through GABA-activated pathways can significantly affect [Cl-]i. 3. Decreasing the extracellular K+ concentration ([K+]o) from 5.8 to 1 mM caused a rapid hyperpolarizing shift in the mean IPSC reversal potential (EIPSC) from -67.6 to -81.9 mV, even when membrane potential (Vm) was maintained constant and depolarized with respect to EIPSC. 4. Decreasing [K+]o from 5.8 to 1 mM caused a rapid hyperpolarizing shift in the mean GABA reversal potential (EGABA) from -64.7 to -81.1 mV, even when Vm was maintained constant and depolarized with respect to EGABA. Reducing the extracellular Cl- concentration from 153 to 89 mM, while maintaining [K+]o constant at 1 mM, shifted the mean EGABA from -81.1 to -66.2 mV, an amount close to that predicted by the Nernst equation for Cl-. We conclude that reducing [K+]o caused a hyperpolarizing shift in EGABA and EIPSC by decreasing [Cl-]i. 5. The shift of EIPSC and EGABA upon alteration of [K+]o did not result from contamination of the responses by additional K+-mediated components because it was unaffected by block of K+ channels with intracellular Cs+. 6. Reducing the extracellular Na+ concentration from 141 to 70 mM had no effect on EGABA. 7. Furosemide, bath-applied at 5 X 10(-4) M while holding Vm depolarized with respect to EIPSC, caused a rapid, reversible decrease in IPSC driving force averaging 69%, consistent with the presence of a furosemide-sensitive outward Cl- -transport system. 8. Reducing [K+]o from 5.8 to 1 mM in the presence of 5 X 10(-4) M furosemide produced a smaller shift of EIPSC from -61.0 to -71.2 mV, however, after washout of furosemide from [K+]o = 1 mM saline, EIPSC shifted further to -89.8 mV.(ABSTRACT TRUNCATED AT 400 WORDS)
Phosphoramidate Tantalum Complexes for Room‐Temperature CH Functionalization: Hydroaminoalkylation Catalysis (2013)

A cooled reaction: Phosphoramidate–ClTaMe3 complexes promote the first example of room-temperature hydroaminoalkylation catalysis. This reaction can be realized under solvent-free conditions and with challenging substrates such as styrenes and dialkyl amines. When using a vinylsilane substrate, for the first time the linear regioisomer is obtained preferentially using a Group 5 metal. TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent‐induced apoptosis (2001)

DNA topoisomerase inhibitors are effective chemotherapeutic agents on several solid tumor cells. They induce a specific signaling cascade that executes an active cell death process (apoptosis), including caspase activation, and the blockage of the signaling is associated with drug-resistance of tumor cells. However, little is known about the initial signal transduction induced by the agents. In the present study, we screened genes that are initially upregulated in caspase-independent manner. We found that the activating transcription factor 3 (ATF3) protein, a repressor of cyclic-AMP responsive element (CRE)-dependent transcription, was strongly induced among CRE-BP/ATF members and subsequently accumulated in nuclei following camptothecin or etoposide treatment. During induction of apoptosis, the accumulation and the nuclear translocation of ATF3 coincided with the activation of caspase protease and were not inhibited by the broad caspase inhibitor Z-VAD-fmk, indicating that ATF3 induction is not a downstream event of caspase activation. When stably or transiently overexpressed, ATF3 markedly accelerated the drug-induced apoptosis and enhanced caspase protease activation. ATF3 strongly downregulated CRE-dependent transcription, while ATF3 did not affect the expression levels of Bcl-2, Bcl-x, or Bax. Our present results indicate that ATF3 plays a critical role in accelerating caspase protease activation and apoptosis. Since CRE-dependent transcription functions as cell survival signaling, ATF3 could control the upstream signaling of apoptosis by repressing CRE-dependent gene expression of cell survival factors.
Cloning and characterization of human tumor cell interstitial collagenase. (1990)

A full-length complementary DNA (cDNA) for interstitial collagenase was isolated from an A2058 melanoma cDNA library using the pCD-X Okayama-Berg vector. The tumor interstitial collagenase cDNA was sequenced and compared to the published sequences for human fibroblast collagenase. The sequence for the tumor collagenase has two DNA base pairs which differ from the sequence of normal fibroblast collagenase. Restriction enzyme digestion of a specific DNA fragment produced by polymerase chain reaction amplification of genomic DNA from human placenta resolves a discrepancy in the previously reported DNA and amino acid sequences for the fibroblast collagenase. A high level of expression of interstitial collagenase message was found in human A2058 melanoma cells by Northern blot analysis, and this level was slightly increased by phorbol ester (phorbol myristate acetate) stimulation. Interstitial collagenase mRNA expression was significantly decreased by treatment with either transforming growth factor-beta 1 or retinoic acid in A2058 melanoma cells. A high level of the collagenase protein secreted into conditioned media was identified by Western blotting. As shown by gelatin zymogram analysis interstitial collagenase was one of at least two metalloproteinases secreted by this same cell line. Thus, human melanoma cells can directly produce interstitial collagenase without a requirement for host cell interaction.
Control of methionine biosynthesis in Escherichia coli by proteolysis (2000)

Most bacterial proteins are stable, with half-lives considerably longer than the generation time. In Escherichia coli, the few exceptions are unstable regulatory proteins. The results presented here indicate that the first enzyme in methionine biosynthesis - homoserine trans-succinylase (HTS) - is unstable and subject to energy-dependent proteolysis. The enzyme is stable in triple mutants defective in Lon-, HslVU- and ClpP-dependent proteases. The instability of the protein is determined by the amino-terminal part of the protein, and its removal or substitution by the N-terminal part of beta-galactosidase confers stability. The effect of the amino-terminal segment is not caused by the N-end rule, as substitution of the first amino acid does not affect the stability of the protein. HTS is the first biosynthetic E. coli enzyme shown to have a short half-life and may represent a group of biosynthetic enzymes whose expression is controlled by proteolysis. Alternatively, the proteolytic processing of HTS may be unique to this enzyme and could reflect its central role in regulating bacterial growth, especially at elevated temperatures.
Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (2017)

Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.
Detection of novel cancer‐testis antigen‐specific T‐cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma (2008)

We recently identified three HLA-A2402-restricted epitope peptides derived from cancer-testis antigens (CTA), TTK protein kinase (TTK), lymphocyte antigen 6 complex locus K (LY6K), and insulin-like growth factor (IGF)-II mRNA binding protein 3 (IMP-3) for the development of immunotherapies against esophageal squamous cell carcinoma (ESCC). In order to evaluate their immunotherapeutic potential in ESCC patients, we estimated by ELISPOT assay the TTK-, LY6K-, or IMP-3-specific T-cell immune responses in tumor-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL), and peripheral blood lymphocytes (PBL) expanded from 20HLA-A2402 (+) ESCC patients, and correlated their immune activity with the expression levels of TTK, LY6K, and IMP-3, and MHC class I in the tumors. Induction of TTK-antigen specific T-cell response in TIL to the peptide-pulsed target cells was detected in 14 out of 20 (70%) cases, while LY6K or IMP-3 specific T-cell activity was observed in 11 of 20 (55%) or in eight of 20 (40%) cases, respectively. Furthermore, T-cell activity in RLNL and PBL was detectable in the similar proportion of the 20 ESCC patients. Interestingly, CTA-specific T-cell immune response was found in 13 of 14 (93%) TIL obtained from ESCC tumors with strong MHC class I expression, while it could be observed only in two of six (33%) TIL from ESCC tumors with weak MHC class I expression. These results strongly suggest the pre-existence of specific T-cell responses to HLA-A24-restricted epitope peptides from TTK, LY6K, and IMP-3 in ESCC patients. Monitoring antigen-specific T-cell responses, as well as the expression levels of MHC class I and epitope CTA in tumors, should be a selection index for application of cancer vaccine therapies to the patients who are likely to show good immune response.
Bone marrow stroma‐mediated resistance to FLT3 inhibitors in FLT3‐ITD AML is mediated by persistent activation of extracellular regulated kinase (2013)

A consistent pattern of response has been observed when FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have been used as monotherapy to treat patients with relapsed or refractory FLT3- internal tandem duplication (ITD) acute myeloid leukaemia (AML). Circulating blasts are cleared from the peripheral blood, while bone marrow blasts are either unaffected or are cleared from the marrow at a much slower rate. We used an in vitro model of FLT3-ITD AML blasts co-cultured with normal human bone marrow stromal cells to investigate the basis for this dichotomous response pattern to FLT3 inhibitors. We have found that in blasts on stroma, potent FLT3 inhibition predominantly results in cell cycle arrest rather than apoptosis. The anti-apoptotic effect is mediated through a combination of direct cell-cell contact and soluble factors. The addition of exogenous FLT3 ligand (FL) augments the protection, primarily by shifting the 50% inhibitory concentration for FLT3 inhibition upwards. Cytokine-activated extracellular regulated kinase (ERK), rather than STAT5, appears to be the most important downstream signalling protein mediating the protective effect, and inhibition of MEK significantly abrogates stromal-mediated resistance. These findings explain the phenomenon of peripheral blood versus bone marrow blast responses and suggest that the combination of potent FLT3 inhibition and MEK inhibition is a promising strategy for the treatment of FLT3-ITD AML.
Synthesis of yohimbines. II. Alternative route to alloyohimbine alkaloids (1973)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of yohimbines. II. Alternative route to alloyohimbine alkaloidsLaszlo Toke, Zsuzsa Gombos, Gabor Blasko, Katalin Hont, Lajos Szabo, Jozsef Tamas, and Csaba SzantayCite this: J. Org. Chem. 1973, 38, 14, 2501–2509Publication Date (Print):July 1, 1973Publication History Published online1 May 2002Published inissue 1 July 1973https://pubs.acs.org/doi/10.1021/jo00954a017https://doi.org/10.1021/jo00954a017research-articleACS PublicationsRequest reuse permissionsArticle Views210Altmetric-Citations22LEARN 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 Get e-Alerts
Update on combined-modality treatment options for pancreatic cancer. (2003)

Cancer of the pancreas remains a formidable challenge in oncology. This malignancy ranks as the fourth leading cause of cancer death in the United States in 2003, with an estimated 30,700 new cases to be diagnosed and 30,000 deaths. Although gains have been achieved in the clinical management of these patients, this malignancy is rarely curable. Long-term survival is limited to patients undergoing resection. For patients with localized but unresectable malignancy, radiation therapy combined with fluorouracil, gemcitabine (Gemzar), or paclitaxel has shown modest improvements in survival and symptom palliation. However, there has been significant progress in the diagnostic evaluation of pancreatic cancer patients, which has aided clinicians in caring for these patients and in selecting therapies. The use of computed tomography, endoscopic ultrasonography, and laparoscopy techniques will be discussed. Newer techniques of radiation therapy, such as intraoperative electron-beam radiation therapy and three-dimensional conformal radiation therapy, with the integration of new biologically targeted agents may provide new avenues of research and progress in this disease.
Molecular diversity of heparan sulfate (2001)

Heparan sulfate (HS) appeared early in metazoan evolution. As such, many of the structural motifs (variably sulfated disaccharide subunits) that characterize HS (and heparin) were established early on and have been preserved in modern organisms. Thus, many of the biological functions associated with HS either occurred early in evolution or have depended on the subsequent evolution of the protein ligands that bind to the polysaccharide. Today, we know of literally hundreds of heparin-binding proteins, and many interactions have profound consequences in vertebrate and invertebrate physiology. This Perspective aims to provide an overview of HS structure, function, and biosynthesis and to set the stage for discussing the relationship between structure and function of these fascinating molecules and how altered HS biosynthesis and catabolism can lead to human disorders.
Inhibition of Transforming Growth Factor-β1–induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA (2006)

Overexpression of the inhibitory Smad, Smad7, is used frequently to implicate the Smad pathway in cellular responses to transforming growth factor beta (TGF-beta) signaling; however, Smad7 regulates several other proteins, including Cdc42, p38MAPK, and beta-catenin. We report an alternative approach for more specifically disrupting Smad-dependent signaling using a peptide aptamer, Trx-SARA, which comprises a rigid scaffold, the Escherichia coli thioredoxin A protein (Trx), displaying a constrained 56-amino acid Smad-binding motif from the Smad anchor for receptor activation (SARA) protein. Trx-SARA bound specifically to Smad2 and Smad3 and inhibited both TGF-beta-induced reporter gene expression and epithelial-to-mesenchymal transition in NMuMG murine mammary epithelial cells. In contrast to Smad7, Trx-SARA had no effect on the Smad2 or 3 phosphorylation levels induced by TGF-beta1. Trx-SARA was primarily localized to the nucleus and perturbed the normal cytoplasmic localization of Smad2 and 3 to a nuclear localization in the absence of TGF-beta1, consistent with reduced Smad nuclear export. The key mode of action of Trx-SARA was to reduce the level of Smad2 and Smad3 in complex with Smad4 after TGF-beta1 stimulation, a mechanism of action consistent with the preferential binding of SARA to monomeric Smad protein and Trx-SARA-mediated disruption of active Smad complexes.
The mRNA (guanine-7-)methyltransferase domain of the vaccinia virus mRNA capping enzyme. Expression in Escherichia coli and structural and kinetic comparison to the intact capping enzyme. (1994)

The mRNA (guanine-7-)methyltransferase active site of the heterodimeric vaccinia virus mRNA capping enzyme was previously localized to the carboxyl-terminal third of the large subunit, D1R, associated with the small subunit, D12L (Cong, P., and Shuman, S. (1992) J. Biol. Chem. 267, 16424-16429; Higman, M. A., Bourgeois, N., and Niles, E. G. (1992) J. Biol. Chem. 267, 16430-16437). A plasmid was constructed which directs the coexpression of the carboxyl terminus of the D1R subunit from amino acids 498 to 844 and the D12L subunit in Escherichia coli. The mRNA (guanine-7-)methyltransferase catalytic activity in the isolated domain was found to be kinetically equivalent to that present in the intact enzyme. Through mobility shift and ultraviolet photolinkage analyses, both domains were shown to bind RNA in a saturable fashion. RNA binding was localized predominantly to the large subunit, but a low level of linkage of RNA to D12L was also observed. A low, but reproducible, level of mRNA (guanine-7-)methyltransferase activity was detected in the isolated D1R498-844 subunit demonstrating that the active site resides solely within the large subunit of the capping enzyme. This activity is enhanced 30- to 50-fold by the association of the D12L subunit.
Structure−Activity Relationships of Lysophosphatidic Acid:  Conformationally Restricted Backbone Mimetics (1999)

Lysophosphatidic acid (LPA) has associated with it an intriguing cell biology that is thought to be mediated through its interaction with G-protein coupled receptor(s). In an effort to extend the structure-activity relationships of LPA, we have produced a series of LPA analogues in which the glycerol core in LPA was replaced with conformationally restricted aryl substructures. The aryl substructures encompassed aminophenol, resorcinol, dihydroxy benzophenone, and tocopherol systems. The benzophenone moiety was investigated both as a conformationally restricting substructure for LPA and as a possible photoreactive alkylating agent for the LPA receptor(s). All LPA analogues were evaluated for their potency and efficacy in mobilizing calcium ions from internal stores in MDA MB-231 cells. Ten of the 14 analogues exhibited activity in this assay at doses up to 5 microM; none of the compounds exhibited nonreceptor-mediated lytic activity at this maximal concentration. The receptor response showed surprising tolerance for manipulation in the backbone region of LPA, although none of the compounds were equipotent to LPA. This tolerance for a variety of structures has given us new leads into the realization of novel agonists and antagonists of the LPA receptor(s).
Hemodynamic effects of intracoronary VEGF delivery: evidence of tachyphylaxis and NO dependence of response (1997)

Vascular endothelial growth factor (VEGF) has been utilized to improve blood flow in the setting of myocardial or peripheral vascular ischemia. In this investigation we studied the hemodynamic effects of intracoronary VEGF administration. Hemodynamic parameters and Doppler flow wire recordings from the left anterior descending coronary artery were measured after intracoronary infusion of VEGF (1, 10, and 100 micrograms) in 28 intubated pigs. Additional studies were performed using an in vitro isolated microvessel preparation. VEGF produced a highly significant dose-dependent increase in coronary blood flow (maximal 3.51 +/- 0.85-fold) in the absence of significant changes in epicardial artery diameter, a decline in mean arterial pressure (maximal 43%), and a decrease in left ventricular end-diastolic pressure (maximal 52%), all of which could be inhibited by pretreatment with NG-nitro-L-arginine. The increase in coronary flow seen with 10 or 100 micrograms VEGF was significantly greater than the maximal vasodilation achieved with serotonin or nitroglycerin and was equivalent to a maximal adenosine response. In summary, VEGF stimulates nitric oxide (NO)-dependent dilation of coronary microvessels, and repeat administrations of VEGF resulted in rapid development of tachyphylaxis to VEGF as well as serotonin, but not to nitroglycerin or adenosine, which appeared to be secondary to impaired NO production.
Roles of interferon-gamma and interleukin-4 in murine lupus. (1997)

The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
Ionic Liquids—Progress on the Fundamental Issues (2007)

Ionic liquids challenge conventional descriptions of fluids in a variety of ways. In the past, it has been common to oversimplify their behaviour and to ignore the complexity that was possible, given the burgeoning range of ionic liquids available. Here we discuss what is meant by the term ‘ionic liquid’ and some of the key fundamental issues in understanding their properties.