tbuckley/cabot-search huggingface dataset:
Abstract 1660: Unraveling isoform selectivities of a broad class of HDAC inhibitors with QM/MM molecular dynamics simulations
Authors: Jung-Hsin Lin
Journal: Cancer Research (2018)

Abstract Therapeutics that have been used by large populations and showed limited or little adverse effects can be good candidates for cancer chemo-prevention. As an example of such therapeutics, statins, i.e., HMG-CA reductase inhibitors, have been widely prescribed for lowering the blood cholesterol level and for treating cardiovascular diseases. In 2008, we discovered that statins are moderate inhibitors of histone deacetylases (HDACs), which provides an epigenetic mechanism for their efficacy in cancer prevention. HDACs have been long recognized for as an important class of therapeutic targets, and these enzymes utilize a Zn2+ ion at its active site for catalysis. Subsequently, in our 2013 J. Med. Chem. article, we showed that we are able to strengthen this epigenetic mechanism and designed more potent and effective therapeutic agents for cancer prevention and treatment, including cancer metastasis, and published in Clin. Cancer Res. in 2016. To investigate the structure-activity relationships of a broad class of HDAC inhibitors with distinct chemical moieties, we have conducted QM/MM molecular dynamics simulations of several systems of HDAC isoforms bound with various ligands. In contrast to molecular dynamics simulations with classical force fields, which always rendered over-coordinated configurations of the Zn2+ at the active site, with the coordination numbers (CN) to be either 6 or 7, in our QM/MM molecular dynamics simulations, the CNs of Zn2+ remain 4 or 5. With the structural and energetics analysis from these QM/MM molecular dynamics simulations, we are able to delineate the origins of isoform-selectivity of different HDAC inhibitors, including the aforementioned HMGR-HDAC dual-action inhibitors that we recently developed. Citation Format: Jung-Hsin Lin. Unraveling isoform selectivities of a broad class of HDAC inhibitors with QM/MM molecular dynamics simulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1660.
Abstract 4788: Preclinical evaluation of E-191, a highly selective EGFR T790M inhibitor
Authors: Liu Xile, Lihong Hu, Charles Z Ding, Weifeng Mao, Liqing Wang, Xiaohe Shi, Chaofeng Long, Xiaoxin Chen, Haijun Li, Xing Liu, Zhuowei Liu
Journal: Cancer Research (2018)

Abstract Objective: Patients of non-small cell lung cancer (NSCLC) with activating EGFR mutations initially respond to the first generation reversible EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib. However, most of the patients acquire resistance within 10~16 months. The most common mechanism of resistance is the EGFR T790M mutation. In addition, selectivity of the EGFR inhibitors is important, as inhibition of EGFR wild type can lead to dose limiting toxicities, including rash and diarrhea. This may be the reason why the second generation irreversible EGFR inhibitors, such as afatinib, which also inhibit EGFRWT, is not widely used. Here, we disclose our clinical candidate compound E-191 as a novel irreversible inhibitor that potently inhibits the resistance mutant forms of EGFR with a good selectivity sparing EGFRWT. Method: The anti-proliferative activity of E-191 was evaluated in NCI-H1975 (EGFRT790M/L58R), HCC827 (EGFRd746-750), and A431 (EGFRWT) cell lines. Daily oral administration of E-191 at 3 doses was used to evaluate the in vivo anti-tumor activity in three cell-derived tumor xenograft (CDX) models, NCI-H1975, HCC827, and Ba/F3 (EGFRT790M /d746-750). The in vivo selectivity was evaluated in the A431 (EGFRWT) CDX model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204). Result: E-191 displayed potent anti-proliferative activity in the EGFR mutant cell lines NCI-H1975 (IC50 = 22 nM) and HCC827 (IC50=1.9 nM), and a much less potent activity in the EGFRWT A431 cell line (IC50 = 531 nM). E-191 has about 24 fold selectivity for EGFRT790M over EGFRWT. E-191 potently inhibited tumor growth at all doses tested (P&amp;lt;0.001) in the NCI-H1975, HCC827 and Ba/F3 (EGFRT790M /d746-750) models, while significantly less so in the A431 model. Western blot analysis of the tumor samples in the NCI-H1975 model study showed that E-191 inhibited p-EGFR (Y1068), p-AKT (Ser473), and p-ERK (Thr202/Tyr204), indicating that the tumor growth inhibition was through inhibition of the resistant mutant EGFR. Conclusion: We have demonstrated with in vitro and in vivo preclinical models that E-191 is a selective inhibitor of the resistance mutant forms of EGFR, potently inhibiting EGFRT790M but not EGFRWT. These results make us believe that E-191 has a good potential in the clinic for the treatment of resistant EGFR driven NSCLC. Citation Format: Liu Xile, Lihong Hu, Charles Z Ding, Weifeng Mao, Liqing Wang, Xiaohe Shi, Chaofeng Long, Xiaoxin Chen, Haijun Li, Xing Liu, Zhuowei Liu. Preclinical evaluation of E-191, a highly selective EGFR T790M inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4788.
Abstract 128: NKILA lncRNA promotes tumor immune evasion by mediating activation-induced cell death in tumor-specific CTLs
Authors: Erwei Song
Journal: Cancer Research (2018)

Abstract Activation-induced cell death (AICD) of T lymphocytes may be exploited by cancers to eliminate cytotoxic T cells (CTLs). However, the mechanisms underlying AICD in tumor specific CTLs remain unknown. Here, we demonstrated excessive apoptosis of tumor antigen-specific CTLs in breast and lung cancers. Interestingly, NKILA, an NFκB-interacting lncRNA, mediates AICD of CTLs by inhibiting NFκB activities after their activation. Mechanistically, NKILA promoter is closed for transcription by histone deacetylation in resting T cells, while calcium influx by TCR signaling activates calmodulin to remove the deacetylase from NKILA promoter and enhances its transcription. In vivo, administering CTLs with NKILA silencing to immunocompromised mice with breast cancer patient-derived xenografts (PDXs) effectively inhibits PDX growth by increasing CTL infiltration. Clinically, NKILA was overexpressed in the tumor-specific CTLs of breast and lung cancers, which was associated with less CTL infiltration in the tumors and shorter patient survival. Our findings present the first evidence that AICD in tumor-specific CTLs is crucial to cancer immune evasion, and targeting NKILA in CTLs emerges as a novel antitumor immunotherapy. Citation Format: Erwei Song. NKILA lncRNA promotes tumor immune evasion by mediating activation-induced cell death in tumor-specific CTLs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 128.
Abstract 5672: Facile generation of single-cell transcriptome and immune repertoire freshly isolated from clinical tumor specimens
Authors: Junjie Zhu, Ameen A. Salahudeen, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Grace X. Zheng, Dhananjay Wagh, John Coller, Chiara Sabatti, Calvin J. Kuo
Journal: Cancer Research (2018)

Abstract Immunotherapies including cell-based therapies generate deep and durable responses in patients with chemotherapy-refractory cancers. However, in solid tumors, particularly those with stereotypic driver mutations and resultant neoantigens, the clonality and cell states of tumor-infiltrating lymphocytes (TILs) remain poorly understood. Here, we use a droplet-based 5' single-cell RNA-sequencing (scRNA-seq) to simultaneously profile transcriptome and immune repertoire of the same cells, enabling the phenotypic characterization (including cytotoxic and helper T, B, T regulatory and exhausted T cells) of each clonotype. We performed scRNA-seq on unsorted and CD45+-FACS sorted cells from fresh clinical samples of multiple tissue types, including lung, liver and kidney, and obtained on average tens of thousands of cells per sample. We demonstrated that high-quality single-cell suspension can be rapidly and reliably generated from clinical samples. We devised different diversity metrics to appropriately classify the immune repertoire within samples, and cross samples of different tissues. We observed distinct cell type compositions and, more importantly, context-specific T-cell clonal expansion patterns, suggesting the activation of different molecular programs in these tumors. In addition, comparison of non-small cell lung cancer (NSCLC) tumors varying by histology type and patient smoking status showed differences among these phenotypes, suggesting a potential link between immune microenvironments and cancer etiology. In summary, we provide a proof of concept for rapid generation of large number of single-cell transcriptomes of TILs paired with their corresponding TCR cDNA sequence in fresh tumor samples across different tissue types. Further analysis with this methodology on larger clinical cohorts will provide robust correlative prognostic markers of clinical phenotypes of immunotherapy responses. Our analysis strategy of TCR sequences among large clinical cohorts across multiple tumor types will facilitate cell-based therapeutic efforts, including CAR T cell or autologous T cell therapies. Citation Format: Junjie Zhu, Ameen A. Salahudeen, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Grace X. Zheng, Dhananjay Wagh, John Coller, Chiara Sabatti, Calvin J. Kuo. Facile generation of single-cell transcriptome and immune repertoire freshly isolated from clinical tumor specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5672.
Activation of Mitochondrial ATP-Sensitive K+ Channel for Cardiac Protection Against Ischemic Injury Is Dependent on Protein Kinase C Activity
Authors: YigangWang, KyojiHirai, MuhammadAshraf
Journal: Circulation Research (1999)

Abstract—Protein kinase C (PKC) is involved in the second messenger signaling cascade during ischemic and Ca2+ preconditioning. Given that the pharmacological activation of mitochondrial ATP-sensitive K+ (mitoKATP) channels also mimics preconditioning, the mechanisms linking PKC activation and mitoKATP channels remain to be established. We hypothesize that PKC activity is important for the opening of the mitoKATP channel. To examine this, a specific opener of the mitoKATP channel, diazoxide, was used in conjunction with subcellular distribution of PKC in a model of ischemia/reperfusion (I/R). Langendorff-perfused rat hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Effects of activation of the mitoKATP channel and other interventions on functional, biochemical, and pathological changes in ischemic hearts were assessed. In hearts treated with diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly improved after I/R; lactate dehydrogenase releas...
Regular Exercise Training Prevents Aortic Valve Disease in Low-Density Lipoprotein–Receptor–Deficient Mice
Authors: YasuharuMatsumoto, VolkerAdams, SaskiaJacob, NormanMangner, GerhardSchuler, AxelLinke
Journal: Circulation (2010)

Background— Regular exercise training (ET) slows the progression of atherosclerotic lesions, reduces oxidative stress, and increases nitric oxide bioavailability, all of which may be expected to improve degenerative aortic valve disease. Methods and Results— Four-week-old low-density lipoprotein–receptor–deficient mice (n=94) were randomly divided into 4 groups: Group 1 (control group), normal diet plus sedentary activity; group 2 (cholesterol group), cholesterol diet plus sedentary activity; group 3 (regular ET group), cholesterol diet plus regular ET (60 min/day, 5 days/week) for 16 weeks; and group 4 (occasional exercise group), cholesterol diet plus occasional ET (1 day/week) for 16 weeks. At 20 weeks of age, histological analysis was performed. A significant increase in aortic valve thickness was evident in the cholesterol group compared with the control group. Importantly, regular but not occasional ET significantly reduced aortic valve thickness compared with the cholesterol group (control 31.3±3.0...
Abstract 2377: Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma
Authors: David Uehling, Babu Joseph, Carly Griffin, Ratheesh Subramaniam, Ayome Abibi, Richard Marcellus, Michael Prakesch, Gennadiy Poda, Methvin Isaac, Chungyee Leung-Hagesteijn, Rodger Tiedemann, Rima Al-awar
Journal: Cancer Research (2018)

Abstract Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapeutic options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. In a kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase GRK6 was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other members of the GRK family, results in decreased survival. Through gene silencing techniques, we determined that a functional GRK6 kinase domain is required for survival of MM cells. These findings helped validate that the kinase domain of GRK6 is a promising target for MM, and therefore encouraged us to embark on an effort to identify potent small molecule kinase inhibitors of GRK6. Toward that end, by screening a focused kinase-directed library of small molecule inhibitors, compounds with moderate potency against GRK6 in biochemical assays were identified. Through this exercise, we discovered that two structurally distinct aminopyrazoles AZ-960 and ASC-082 had modest inhibition of GRK6. By combining structural features of these hits and further optimization we identified the quinazoline analogue OICR9945, a potent GRK6 inhibitor with good selectivity against a panel of diverse kinases and anti-proliferative activity against MM cell lines. Herein, we describe the design, synthesis and early pharmacological characterization of OICR9945 along with structure activity relationships (SAR) of this series against GRK6 and other kinases. Citation Format: David Uehling, Babu Joseph, Carly Griffin, Ratheesh Subramaniam, Ayome Abibi, Richard Marcellus, Michael Prakesch, Gennadiy Poda, Methvin Isaac, Chungyee Leung-Hagesteijn, Rodger Tiedemann, Rima Al-awar. Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2377.
A bone-targeting delivery system carrying osteogenic phytomolecule icaritin prevents osteoporosis in mice
Authors: Le Huang, Xinluan Wang, Huijuan Cao, Ling Li, Dick Ho-Kiu Chow, Li Tian, Heng Wu, Jiayong Zhang, Nan Wang, Lizhen Zheng, Xinsheng Yao, Zhijun Yang, Ling Qin
Journal: Biomaterials (2018)
Abstract 3757: Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine
Authors: Silvia Coma, Jill Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, Candice Lamb, Christos Karamitros, John Blazek, Kendra Garrison, George Georgiou, Mark Manfredi, Xiaoyan Michelle Zhang
Journal: Cancer Research (2018)

Abstract The tryptophan/kynurenine pathway has been clinically validated in several tumor types with small-molecule IDO1 inhibitors in combination with checkpoint inhibition. Indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are upregulated in a number of tumor types, metabolizing tryptophan to form immunosuppressive kynurenine. We are developing Kynureninase (Kynase), a kynurenine depleting enzyme, to treat IDO1 and TDO2 positive tumors. The human Kynase has been successfully engineered to vastly increase catalytic activity and stability toward kynurenine over the wild type enzyme. In mice, Kynase achieved prolonged Kynurenine degradation (≥5 days) in plasma and tumor draining lymph node (TDLN), leading to anti-tumor activity as a single agent and in combination with check point inhibitors in mouse syngeneic tumor models. Kynase demonstrated superior tumor growth inhibition and survival benefit relative to a leading IDO1 inhibitor epacadostat in these models. The effects of Kynase on a number of immune cell types, both in vitro and in vivo, are being investigated. Human Kynase has also shown a favorable PK profile and kynurenine degradation in non-human primates, and Kynase variants are now moving toward development candidate selection for treatment of cancers where both IDO/TDO pathways play a significant immunosuppressive role. Citation Format: Silvia Coma, Jill Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, Candice Lamb, Christos Karamitros, John Blazek, Kendra Garrison, George Georgiou, Mark Manfredi, Xiaoyan Michelle Zhang. Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3757.
DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions
Authors: Beth M. Stadtmueller, Michael D. Bridges, Kim-Marie Dam, Michael T. Lerch, Kathryn E. Huey-Tubman, Wayne L. Hubbell, Pamela J. Bjorkman
Journal: Immunity (2018)

HIV-1 Envelope (Env) mediates viral-host membrane fusion after binding host-receptor CD4 and coreceptor. Soluble envelopes (SOSIPs), designed to mimic prefusion conformational states of virion-bound envelopes, are proposed immunogens for eliciting neutralizing antibodies, yet only static structures are available. To evaluate conformational landscapes of ligand-free, CD4-bound, inhibitor-bound, and antibody-bound SOSIPs, we measured inter-subunit distances throughout spin-labeled SOSIPs using double electron-electron resonance (DEER) spectroscopy and compared results to soluble and virion-bound Env structures, and single-molecule fluorescence resonance energy transfer (smFRET)-derived dynamics of virion-bound Envs. Unliganded SOSIP measurements were consistent with closed, neutralizing antibody-bound structures and shielding of non-neutralizing epitopes, demonstrating homogeneity at Env apex, increased flexibility near Env base, and no evidence for the intra-subunit flexibility near Env apex suggested by smFRET. CD4 binding increased inter-subunit distances and heterogeneity, consistent with rearrangements required for coreceptor binding. Results suggest similarities between SOSIPs and virion-bound Envs and demonstrate DEER's relevance for immunogen design.
Abstract 21025: Wnt/beta Catenin Signaling Regulates Lymphatic Vascular Development
Authors: Sathish Srinivasan, Boksik Cha
Journal: Circulation (2017)

Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.
α1-Adrenergic Stimulation of Sarcolemmal Na+-H+ Exchanger Activity in Rat Ventricular Myocytes
Authors: HiroyukiYokoyama, MasahiroYasutake, MetinAvkiran
Journal: Circulation Research (1998)

Abstract—α1-Adrenoceptor (α1-AR) stimulation increases sarcolemmal Na+-H+ exchanger (NHE) activity. The present study was designed to determine the role(s) of α1-AR subtype(s) in mediating this response. As an index of NHE activity, acid efflux rates (JHs) were determined in single rat ventricular myocytes loaded with the pH-sensitive fluoroprobe carboxy-seminaphthorhodafluor-1 after 2 consecutive intracellular acid pulses in bicarbonate-free medium. JH at pHi 6.90 did not change significantly during the second pulse relative to the first in control cells but increased in a dose-dependent manner when the second pulse occurred in the presence of phenylephrine (nonselective α1-AR agonist) or A61603 (α1A-AR–selective agonist), with EC50 values of 1.24 μmol/L and 3.6 nmol/L, respectively (both agonists given together with 1 μmol/L atenolol). Stimulation of NHE activity by 10 μmol/L phenylephrine was inhibited in a dose-dependent manner by the competitive antagonists prazosin, WB4101, and 5-methylurapidil, wit...
Possible Role of Brain-Derived Neurotrophic Factor in the Pathogenesis of Coronary Artery Disease
Authors: JunyaEjiri, NobutakaInoue, SeiichiKobayashi, RioShiraki, KazunoriOtsui, TomoyukiHonjo, MotonoriTakahashi, YoshitakaOhashi, ShinobuIchikawa, MitsuyasuTerashima, TakaoMori, KojiroAwano, ToshiroShinke, JunyaShite, Ken-ichiHirata, HiroshiYokozaki, SeinosukeKawashima, MitsuhiroYokoyama
Journal: Circulation (2005)

Background— The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear. Methods and Results— To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non–coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non–coronary artery diseas...