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RISS 인기검색어
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- 저자 : Rachel Tan (검색결과 3 건)
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Tan, Li,Wang, Jun,Tanizaki, Junko,Huang, Zhifeng,Aref, Amir R.,Rusan, Maria,Zhu, Su-Jie,Zhang, Yiyun,Ercan, Dalia,Liao, Rachel G.,Capelletti, Marzia,Zhou, Wenjun,Hur, Wooyoung,Kim, NamDoo,Sim, Taebo,G National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.45
<P><B>Significance</B></P><P>Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for the treatment of various cancers. All currently approved kinase inhibitors eventually are rendered useless by the emergence of drug-resistant tumors. We used structure-based drug design to develop the first, to our knowledge, selective, next-generation covalent FGFR inhibitors that can overcome the most common form of kinase inhibitor resistance, the mutation of the so-called “gatekeeper” residue located in the ATP-binding pocket. We also describe a novel kinase inhibitor design strategy that uses a single electrophile to target covalently cysteines that are located in different positions within the ATP-binding pocket. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance.</P><P>The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.</P>
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Russell Body Lesions of the Colon: Case Report and Literature Review
( W. Keith Tan ),( Rachel Smith ),( Anthony George ),( Anita Gibbons ),( Syed Shaukat ),( Rizwan Kassam ),( Phil Roberts ) 대한소화기학회 2021 대한소화기학회지 Vol.77 No.6
Russell bodies (RB) are rare manifestations within the lower gastrointestinal tract. To date, there are only three other reported cases of RB lesions of the colon; two were polyps, and the third was a case of a multifocal RB lesion of the gastrointestinal tract. This paper reports a case of a tubulovillous adenoma with RB of the sigmoid colon in a patient diagnosed incidentally as part of the UK National Health Service Bowel Cancer Screening Programme. A thorough hematological investigation is required to exclude hematological malignancies because of its association with plasma cell neoplasm. These lesions should undergo clonality analysis to exclude the monoclonal proliferation of plasma cells. Ideally, a bone marrow aspirate and investigations for amyloidosis should be performed to exclude underlying hematological malignancies. (Korean J Gastroenterol 2021;77:309-312)
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배종석,Michele Ferguson,Rachel Tan,Eneida Mioshi,Neil Simon,James Burrell,Steve Vucic,John R. Hodges,Matthew C Kiernan,Michael Hornberger 대한신경과학회 2016 Journal of Clinical Neurology Vol.12 No.2
Background and Purpose Tis study investigated the structural and functional changes in the motor system in amyotrophic lateral sclerosis (ALS; n=25) and behavioral-variant frontotemporal dementia (bvFTD; n=17) relative to healthy controls (n=37). Methods Structural changes were examined using a region-of-interest approach, applying voxel-based morphometry for gray-matter changes and difusion tensor imaging for white-matter changes. Functional changes in the motor system were elucidated using threshold-tracking transcranial magnetic stimulation (TMS) measurements of upper motor-neuron excitability. Results The structural analyses showed that in ALS there were more white-matter changes in the corticospinal and motor-cortex regions and more gray-matter changes in the cerebellum in comparison to controls. bvFTD showed substantial gray- and white-matter changes across virtually all motor-system regions compared to controls, although the brainstem was afected less than the other regions. Direct comparisons across patient groups showed that the gray- and white-matter motor-system changes inclusive of the motor cortex were greater in bvFTD than in ALS. By contrast, the functional integrity of the motor system was more adversely afected in ALS than in bvFTD, with both patient groups showing increased excitability of upper motor neurons compared to controls. Conclusions Cross-correlation of structural and functional data further revealed a neural dissociation of diferent motor-system regions and tracts covarying with the TMS excitability across both patient groups. Te structural and functional motor-system integrities appear to be dissociated between ALS and bvFTD, which represents useful information for the diagnosis of motor-system changes in these two disorders.
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