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Hughes, Timothy,Saglio, Giuseppe,Branford, Susan,Soverini, Simona,Kim, Dong-Wook,Mü,ller, Martin C,Martinelli, Giovanni,Cortes, Jorge,Beppu, Lan,Gottardi, Enrico,Kim, Dongho,Erben, Philipp,Shou, Y Grune Stratton ; American Society of Clinical Onco 2009 Journal of clinical oncology Vol.27 No.25
<P>PURPOSE: Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. PATIENTS AND METHODS: Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. RESULTS: Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. CONCLUSION: For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.</P>
Stress-induced alterations in hippocampal plasticity, place cells, and spatial memory.
Kim, Jeansok J,Lee, Hongjoo J,Welday, Adam C,Song, Eunyoung,Cho, Jeiwon,Sharp, Patricia E,Jung, Min W,Blair, Hugh T National Academy of Sciences 2007 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.104 No.46
<P>Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans and animals. The present study investigated the ensuing effects of 2-h variable 'audiogenic' stress on three related levels of hippocampal functions in rats: long-term potentiation, place cell activity, and spatial memory. In agreement with prior findings, we observed that stress reduced the magnitude of Schaffer collateral/commissural-Cornu Ammonis field 1 long-term potentiation in vitro, and selectively impaired spatial memory on a hidden platform version of the Morris water maze task. We also observed that stress impaired the stability of firing rates (but not firing locations) of place cells recorded from dorsal Cornu Ammonis field 1 in rats foraging freely on a novel open-field platform located in a familiar surrounding room. These findings suggest that stress-induced modifications in synaptic plasticity may prevent the storage of stable 'rate maps' by hippocampal place cells, which in turn may contribute to spatial memory impairments associated with stress.</P>
Lee, B.C.,Kim, M.S.,Pae, M.,Yamamoto, Y.,Eberle, D.,Shimada, T.,Kamei, N.,Park, H.S.,Sasorith, S.,Woo, J.,You, J.,Mosher, W.,Brady, Hugh J.M.,Shoelson, Steven E.,Lee, J. Cell Press 2016 Cell metabolism Vol.23 No.4
<P>Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNF alpha, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNF alpha, and thereby contribute to the development of obesity-induced insulin resistance.</P>
Mü,ller, Martin C.,Cortes, Jorge E.,Kim, Dong-Wook,Druker, Brian J.,Erben, Philipp,Pasquini, Ricardo,Branford, Susan,Hughes, Timothy P.,Radich, Jerald P.,Ploughman, Lynn,Mukhopadhyay, Jaydip,Hochh American Society of Hematology 2009 Blood Vol.114 No.24
<B>Abstract</B><P>Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM; among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.</P>
Lee, Shin Jung C.,Lee, Jong Wha,Lee, Hong Hee,Seo, Jongcheol,Noh, Dong Hun,Ko, Young Ho,Kim, Kimoon,Kim, Hugh I. American Chemical Society 2013 The Journal of physical chemistry B Vol.117 No.29
<P>An investigation of the host–guest chemistry of cucurbit[<I>n</I>]uril (CB[<I>n</I>], <I>n</I> = 6 and 7) with α,ω-alkyldiammonium guests (H<SUB>2</SUB>N(CH<SUB>2</SUB>)<SUB><I>x</I></SUB>NH<SUB>2</SUB>, <I>x</I> = 4, 6, 8, 10, and 12) both in solution and in the gas phase elucidates their intrinsic host–guest properties and the contribution of solvent water. Isothermal titration calorimetry and nuclear magnetic resonance measurements indicate that all alkyldiammonium cations have inclusion interactions with CB[<I>n</I>] except for the CB[7]–tetramethylenediamine complex in aqueous solution. The electrospray ionization of mixtures of CB[<I>n</I>] and the alkyldiammonium guests reflects their solution phase binding constants. Low-energy collision-induced dissociations indicate that, after the transfer of the CB[<I>n</I>]–alkyldiammonium complex to the gas phase, its stability is no longer correlated with the binding properties in solution. Gas phase structures obtained from density functional theory calculations, which support the results from the ion mobility measurements, and molecular dynamics simulated structures in water provide a detailed understanding of the solvated complexes. In the gas phase, the binding properties of complexation mostly depend on the ion–dipole interactions. However, the ion–dipole integrity is strongly affected by hydrogen bonding with water molecules in the aqueous condition. Upon the inclusion of water molecules, the intrinsic characteristics of the host–guest binding are dominated by entropic-driven thermodynamics.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jpcbfk/2013/jpcbfk.2013.117.issue-29/jp4053874/production/images/medium/jp-2013-053874_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jp4053874'>ACS Electronic Supporting Info</A></P>
Lee, Jong Wha,Heo, Sung Woo,Lee, Shin Jung C.,Ko, Jae Yoon,Kim, Hyungjun,Kim, Hugh I. Springer-Verlag 2013 Journal of the American Society for Mass Spectrome Vol.24 No.1
<P>We report mechanistic studies of structural changes of ubiquitin (Ub) by host-guest chemistry with cucurbit[6]uril (CB[6]) using electrospray ionization mass spectrometry (ESI-MS) combined with circular dichroism spectroscopy and molecular dynamics (MD) simulation. CB[6] binds selectively to lysine (Lys) residues of proteins. Low energy collision-induced dissociation (CID) of the protein-CB[6] complex reveals CB[6] binding sites. We previously reported (<I>Anal. Chem.</I> 2011, 83, 7916-7923) shifts in major charge states along with Ub-CB[6] complexes in the ESI-MS spectrum with addition of CB[6] to Ub from water. We also reported that CB[6] is present only at Lys<SUB>6</SUB> or Lys<SUB>11</SUB> in high charge state (+13) complex. In this study, we provide additional information to explain unique conformational change mechanisms of Ub by host-guest chemistry with CB[6] compared with solvent-driven conformational change of Ub. Additional CID study reveals that CB[6] is bound only to Lys<SUB>48</SUB> and Lys<SUB>63</SUB> in low charge state (+7) complex. MD simulation studies reveal that the high charge state complexes are attributed to the CB[6] bound to Lys<SUB>11</SUB>. The complexation prohibits salt bridge formation between Lys<SUB>11</SUB> and Glu<SUB>34</SUB> and induces conformational change of Ub. This results in formation of high charge state complexes in the gas phase. Then, by utilizing stronger host-guest chemistry of CB[6] with pentamethylenediamine, refolding of Ub via detaching CB[6] from the protein is performed. Overall, this study gives an insight into the mechanism of denatured Ub ion formation via host-guest interactions with CB[6]. Furthermore, this provides a direction for designing function-controllable supramolecular system comprising proteins and synthetic host molecules.</P> [FIG OMISSION]</BR>
Supramolecular Inhibition of Amyloid Fibrillation by Cucurbit[7]uril
Lee, Hong Hee,Choi, Tae Su,Lee, Shin Jung C.,Lee, Jong Wha,Park, Junghong,Ko, Young Ho,Kim, Won Jong,Kim, Kimoon,Kim, Hugh I. WILEY‐VCH Verlag 2014 Angewandte Chemie Vol.126 No.29
<P><B>Abstract</B></P><P>Amyloid fibrils are insoluble protein aggregates comprised of highly ordered β‐sheet structures and they are involved in the pathology of amyloidoses, such as Alzheimer’s disease. A supramolecular strategy is presented for inhibiting amyloid fibrillation by using cucurbit[7]uril (CB[7]). CB[7] prevents the fibrillation of insulin and β‐amyloid by capturing phenylalanine (Phe) residues, which are crucial to the hydrophobic interactions formed during amyloid fibrillation. These results suggest that the Phe‐specific binding of CB[7] can modulate the intermolecular interaction of amyloid proteins and prevent the transition from monomeric to multimeric states. CB[7] thus has potential for the development of a therapeutic strategy for amyloidosis.</P>