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排序方式: 共有242条查询结果,搜索用时 15 毫秒
1.
AndrewJ. Stott Michel C. Maillard Vahri Beaumont David Allcock Omar Aziz Alexander H. Borchers Wesley Blackaby Perla Breccia Gillian Creighton-Gutteridge Alan F. Haughan Rebecca E. Jarvis Christopher A. Luckhurst Kim L. Matthews George McAllister Scott Pollack Elizabeth Saville-Stones Amanda J. Van de Poël Huw D. Vater Julie Vann Rachel Williams Dawn Yates Ignacio Muoz-Sanjun Celia Dominguez 《ACS medicinal chemistry letters》2021,12(3):380
Using an iterative structure–activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with a pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding of endogenous class IIa HDAC substrates, we developed a surrogate readout to measure compound effects in vivo, by exploiting the >100-fold selectivity compound 12 exhibits over class I/IIb HDACs. We achieved adequate brain exposure with compound 12 in mice to estimate a class I/IIb deacetylation EC50, using class I substrate H4K12 acetylation and global acetylation levels as a pharmacodynamic readout. We observed excellent correlation between the compound 12 in vivo pharmacodynamic response and in vitro class I/IIb cellular activity. Applying the same relationship to class IIa HDAC inhibition, we estimated the compound 12 dose required to inhibit class IIa HDAC activity, for use in preclinical models of Huntington’s disease. 相似文献
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Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice 总被引:3,自引:3,他引:3
Ulich TR; del Castillo J; Senaldi G; Kinstler O; Yin S; Kaufman S; Tarpley J; Choi E; Kirley T; Hunt P; Sheridan WP 《Blood》1996,87(12):5006-5015
PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis. 相似文献
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Kelsey E Huntington Anna Louie Lanlan Zhou Attila A Seyhan Aaron WP Maxwell Wafik S El-Deiry 《American journal of cancer research》2022,12(1):138
Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer. 相似文献
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Frank Blackaby 《Medicine, conflict, and survival》2013,29(2):133-136
The Gulf War After the Gulf War Edited by St John Kettle and Stephanie Dowrick Pluto Press Australia, 1991, 134pp., Aust$9.95 (from PO. Box 199, Leichhardt, NSW 2040 Australia), ISBN 0–949138–69‐X. United Nations Building A More Democratic United Nations: Proceedings of CAMDUN 1 Edited by Frank Barnaby Frank Cass, London, 1991, 304 + viii pp; ISBN 0–7146–3442–5, £37.50(hbk), ISBN 0–7146–4082–5 £15.00(pbk) Conflict Research Conflict Under The Microscope By Roderick C. Ogley with foreword by Anatol Rapoport Avebury, Aldershot, 1991, 251pp. + xxi, £35.00, ISBN 1–85628–023–3. Human Rights Guatemala: Getting Away With Murder An Americas Watch and Physicians for Human Rights Report PHR, 1991, 87pp., $10.00 (front 58 Day Street, Suite 202, Somerville MA 02144, USA), ISBN 1–56432–024–3. Human Rights Yugoslavia: Mistreatment of Ethnic Albanians A case study report by Physicians for Human Rights and the Johannes Wier Foundation PHR/ Johannes Wier Foundation, 1991, 30 pp., $3.00 (from PHR, 58 Day Street, Suite 202, Somerville MA 02144, USA), ISBN 1–879707–03–9. Pacifism Peace is the Way: A Guide to Pacifist Views and Actions Edited by Cyril Wright and Tony Augarde for the Peace Pledge Union Lutterworth Press, Cambridge, 178pp., £6.95(pbk), ISBN 0–718, 8–2821–6. Arms Spending World Military and Social Expenditures 1991 by Ruth Leger Sivard 14th Edition, World Priorities, Washington DC, 1991, 64pp., ISBN 0–918281–07–5, £7.50 incl p&;p, (available in UK front DFAX Associates, Royal Oak Buildings, Dacre Banks, Summerbridge, Harrogate HG3 4EN). 相似文献
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Masclee AA; Hopman WP; Corstens FH; Rosenbusch G; Jansen JB; Lamers CB 《Radiology》1989,173(2):407-410
Both ultrasonography (US) and cholescintigraphy are used to study gallbladder dynamics. The present study was undertaken to determine whether the two methods provide the same or different information relating to gallbladder emptying. Emptying was simultaneously studied with both methods during infusion of graded physiologic doses of cholecystokinin (CCK) in six healthy subjects. Infusion of stepwise increasing doses of CCK, ranging from 0.03 to 0.5 Ivy dog units per kilogram of body weight per hour (IDU/kg.h), induced significant dose-related increases in plasma CCK, decreases in gallbladder volume assessed with US, and gallbladder emptying assessed with cholescintigraphy. The threshold dose for inducing significant gallbladder emptying was 0.13 IDU/kg.h, as determined with both techniques, indicating similar detection limits. There was a highly significant correlation between decreases in gallbladder volume and decreases in radioactive counts over the gallbladder region, with a tendency toward greater gallbladder responses at sonography during the early phase of gallbladder contraction and toward greater responses at cholescintigraphy during the later phase of gallbladder contraction. It is concluded that these methods can be used interchangeably for the quantitation of gallbladder emptying. 相似文献
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Cranial nerve deficits from various pathologic processes of the head and neck may result in characteristic patterns of denervation muscular atrophy. Such atrophic patterns may be clues to the location and extent of the lesion, particularly when cranial nerves are involved early in the course of the disease process. Thirty-six patients with computed tomographic (CT) evidence of muscular atrophy secondary to pathologic conditions involving the motor division of cranial nerves were examined. Five characteristic denervation muscular atrophy patterns seen on CT scans were identified. In several patients, identification of the muscular atrophy pattern was the only clue to the presence of a pathologic condition. Recognition of these atrophic patterns can prevent misinterpretation of their CT appearance and direct the CT examination to the course of the compromised cranial nerve from the brainstem to its peripheral innervation. 相似文献
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Discovery of novel ansamycins possessing potent inhibitory activity in a cell-based oncostatin M signalling assay 总被引:3,自引:0,他引:3
Stead P Latif S Blackaby AP Sidebottom PJ Deakin A Taylor NL Life P Spaull J Burrell F Jones R Lewis J Davidson I Mander T 《The Journal of antibiotics》2000,53(7):657-663
We describe the isolation and characterisation of novel non-benzoquinone ansamycin metabolites related to geldanamycin from a culture of Streptomyces sp. S6699. The compounds possess potent inhibitory activity in a cell-based assay measuring inhibition of oncostatin M signalling in a reporter cell line utilising a secreted placental alkaline phosphatase (sPAP) readout. In this paper we report the isolation and structure elucidation of the compounds and describe some of their biological properties. 相似文献