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https://www.readbyqxmd.com/read/28092460/a-three-dimensional-lymphatic-endothelial-cell-tube-formation-assay-to-identify-novel-kinases-involved-in-lymphatic-vessel-remodeling
#1
T Jessica Gambino, Steven P Williams, Carol Caesar, Daniel Resnick, Cameron J Nowell, Rae H Farnsworth, Marc G Achen, Steven A Stacker, Tara Karnezis
The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes...
January 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28092155/discovery-of-first-in-class-potent-and-orally-bioavailable-eed-inhibitor-with-robust-anti-cancer-efficacy
#2
Ying Huang, Jeff Zhang, Zhengtian Yu, Hailong Zhang, Youzhen Wang, Andreas Lingel, Wei Qi, X Justin Gu, Kehao Zhao, Michael David Shultz, Long Wang, Xingnian Fu, Yongfeng Sun, Qiong Zhang, Xiangqing Jiang, Jiang-Wei Zhang, Chunye Zhang, Ling Li, Jue Zeng, Lijian Feng, Chao Zhang, Yueqin Liu, Man Zhang, Lijun Zhang, Mengxi Zhao, Zhenting Gao, Xianghui Liu, Douglas Fang, Haibing Guo, Yuan Mi, Tobias Gabriel, Michael P Dillon, Peter Atadja, Counde Oyang
Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit Polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (Tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective and orally bioavailable EED inhibitor EED226 (compound 43)...
January 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28087713/functional-genomics-reveals-that-tumors-with-activating-phosphoinositide-3-kinase-mutations-are-dependent-on-accelerated-protein-turnover
#3
Teresa Davoli, Kristen E Mengwasser, Jingjing Duan, Ting Chen, Camilla Christensen, Eric C Wooten, Anthony N Anselmo, Mamie Z Li, Kwok-Kin Wong, Kristopher T Kahle, Stephen J Elledge
Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28076663/synthesis-and-biological-evaluation-of-novel-amidinourea-and-triazine-congeners-as-inhibitors-of-mda-mb-231-human-breast-cancer-cell-proliferation
#4
Daniele Castagnolo, Rosemary Bass, Sarah Jenkinson, Jennifer Wright, Tora Smulders-Srinivasan, Jamie C Marshall
A series of novel amidinourea derivatives has been synthesised and the new compounds have been evaluated as inhibitors of MDA-MB-231 human breast cancer cell proliferation. In addition, a second series of triazine derivatives designed as rigid congeners of the amidinoureas was synthesised as well and the compounds were evaluated for their antiproliferative activity. Among the two series, the amidinourea 3d emerged as a potent anticancer hit compound with IC50 = 0.76 micormolar comparable to tamoxifen.
January 11, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28075508/differences-in-access-to-and-use-of-electronic-personal-health-information-between-rural-and-urban-residents-in-the-united-states
#5
Alexandra J Greenberg, Danielle Haney, Kelly D Blake, Richard P Moser, Bradford W Hesse
PURPOSE: The increase in use of health information technologies (HIT) presents new opportunities for patient engagement and self-management. Patients in rural areas stand to benefit especially from increased access to health care tools and electronic communication with providers. We assessed the adoption of 4 HIT tools over time by rural or urban residency. METHODS: Analyses were conducted using data from 7 iterations of the National Cancer Institute's Health Information National Trends Survey (HINTS; 2003-2014)...
January 11, 2017: Journal of Rural Health
https://www.readbyqxmd.com/read/28068087/design-of-a-biased-potent-small-molecule-inhibitor-of-the-bromodomain-and-phd-finger-containing-brpf-proteins-suitable-for-cellular-and-in-vivo-studies
#6
Niall Igoe, Elliott D Bayle, Oleg Fedorov, Cynthia Tallant, Pavel Savitsky, Catherine Rogers, Dafydd R Owen, Gauri Deb, Tim C P Somervaille, David M Andrews, Neil Jones, Anne Cheasty, Hamish Ryder, Paul E Brennan, Susanne Müller, Stefan Knapp, Paul V Fish
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines...
January 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28067996/virtual-screening-sar-and-discovery-of-5-indole-3-yl-2-2-nitrophenyl-amino-1-3-4-oxadiazole-as-a-novel-bcl-2-inhibitor
#7
Noha I Ziedan, Rania Hamdy, Alessandra Cavaliere, Malamati Kourti, Filippo Prencipe, Andrea Brancale, Arwyn T Jones, Andrew D Westwell
A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with sub-micromolar IC50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa)...
January 9, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28064007/protein-based-nanotoxicology-assessment-strategy
#8
Marlene Pedersen Elnegaard, Markus List, Helle Christiansen, Steffen Schmidt, Jan Mollenhauer, Ines Block
The nanomaterial community calls for standardized in vitro assays to determine nanoparticle toxicity in the effort to reduce the number of in vivo validation experiments. We demonstrate that chip-based protein detection is suitable for assessing toxicity and may complement traditional assays to improve selection of primary hits for subsequent analysis. As nanodrug mimics, we analyzed the effect of transiently transfected siRNAs in MCF7 breast cancer cells and normal MCF12A breast cells, resembling a differential screen...
January 5, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28059163/phosphoproteomic-comparison-of-pik3ca-and-pten-signalling-identifies-the-nucleotidase-nt5c-as-a-novel-akt-substrate
#9
Larissa S Moniz, Silvia Surinova, Essam Ghazaly, Lorena Gonzalez Velasco, Syed Haider, Juan Carlos Rodríguez-Prados, Inma M Berenjeno, Claude Chelala, Bart Vanhaesebroeck
To identify novel effectors and processes regulated by PI3K pathway activation, we performed an unbiased phosphoproteomic screen comparing two common events of PI3K deregulation in cancer: oncogenic Pik3ca mutation (Pik3ca(H1047R)) and deletion of Pten. Using mouse embryonic fibroblast (MEF) models that generate inducible, low-level pathway activation as observed in cancer, we quantified 7566 unique phosphopeptides from 3279 proteins. A number of proteins were found to be differentially-regulated by Pik3ca(H1047R) and Pten loss, suggesting unique roles for these two events in processes such as vesicular trafficking, DNA damage repair and RNA splicing...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28057719/structure-and-inhibitor-specificity-of-the-pctaire-family-kinase-cdk16
#10
Sarah E Dixon-Clarke, Saifeldin N Shehata, Tobias Krojer, Timothy D Sharpe, Frank von Delft, Kei Sakamoto, Alex N Bullock
CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent protein kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has an unique consensus substrate phosphorylation motif compared to conventional CDKs. To elucidate the structure and inhibitor binding properties of this atypical CDK we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits...
January 5, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28049589/a-triple-exon-skipping-luciferase-reporter-assay-identifies-a-new-clk-inhibitor-pharmacophore
#11
Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C Sambucetti, Thomas R Webb
The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors...
December 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28048635/su-f-t-184-3d-range-modulator-for-scanned-particle-therapy-development-monte-carlo-simulations-and-measurements
#12
Y Simeonov, P Penchev, T Printz Ringbaek, S Brons, U Weber, K Zink
PURPOSE: Active raster scanning in particle therapy results in highly conformal dose distributions. Treatment time, however, is relatively high due to the large number of different iso-energy layers used. By using only one energy and the so called 3D range-modulator irradiation times of a few seconds only can be achieved, thus making delivery of homogeneous dose to moving targets (e.g. lung cancer) more reliable. METHODS: A 3D range-modulator consisting of many pins with base area of 2...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28048287/th-d-brc-00-educational-point-counter-point-has-photon-rt-hit-the-limits
#13
Bulent Aydogan
: Interest in proton therapy has increased dramatically in the past couple of years, especially in the United States. There certainly is an important place for proton therapy in the arsenal of cancer treatments. Its dosimetric advantage and potential for low toxicity makes it the perfect partner for photons and other cancer treatment modalities. Often there is a belief that the new technology ought to be better but many believe that they should be widely adopted in the clinic only after evidence has shown that they are at least as safe and efficacious as existing technologies, which are often less expensive...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28047053/we-h-bra-06-experimental-investigation-of-rbe-for-lung-cancer-cell-lines-as-a-function-of-dose-and-let-in-proton-helium-and-carbon-beams
#14
D Patel, L Bronk, F Guan, C Peeler, D Mirkovic, D Grosshans, O Jakel, A Abdollahi, U Titt, R Mohan
PURPOSE: Investigate and quantify the effect of dose and LET on the RBE of protons, helium and carbon ions. METHODS: High throughput, high accuracy experimental setups were custom designed to investigate the Relative Biological Effectiveness (RBE) dependence on the dose and Linear Energy Transfer (LET) values for proton, helium and carbon ion beams. The experiment was conducted at the HIT facility in collaboration with the DKFZ in Heidelberg/Germany. Clonogenic assays of two human lung cancer cell lines, H460 and H1437, were investigated in this study...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28045487/probing-the-allosteric-role-of-the-%C3%AE-5-subunit-of-%C3%AE-3%C3%AE-4%C3%AE-5-nicotinic-acetylcholine-receptors-by-functionally-selective-modulators-and-ligands
#15
Caroline Ray, Erik J Soderblom, Yushi Bai, F Ivy Carroll, Marc G Caron, Larry S Barak
Nicotinic acetylcholine receptors regulate the nicotine dependence encountered with cigarette smoking, and this has stimulated a search for drugs binding the responsible receptor subtypes. Studies link a gene cluster encoding for α3β4α5-D398N nicotinic acetylcholine receptors to lung cancer risk as well as link a second mutation in this cluster to an increased risk for nicotine dependence. However, there are currently no recognized drugs for discriminating α3β4α5 signaling. In this study we describe the development of homogenous HEK-293 cell clones of α3β4 and α3β4α5 receptors appropriate for drug screening and characterizing biochemical and pharmacological properties of incorporated α5 subunits...
January 3, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28042453/design-and-synthesis-of-selective-small-molecule-inhibitors-of-coactivator-associated-arginine-methyltransferase-1-carm1
#16
H Ü Kaniskan, M S Eram, J Liu, D Smil, M L Martini, Y Shen, V Santhakumar, P J Brown, C Arrowsmith, M Vedadi, J Jin
Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα...
September 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/28035731/what-cancer-means-to-the-patients-and-their-primary-caregivers-in-the-family-accounted-korean-context-a-dyadic-interpretation
#17
Ansuk Jeong, Ji Yeong M An, Jong Hyock Park, Keeho Park
OBJECTIVE: When cancer hits a family, the entire family members start to adapt to the new status. This study aimed to investigate the main issue of the family with cancer patient and their way of solving it. METHODS: In-depth interviews were conducted as a qualitative research. 33 participants described their experience either as cancer patients or as family caregivers. RESULTS: Guided by the Grounded Theory, we identified the main concern of the families being primary caregiver selection...
December 30, 2016: Psycho-oncology
https://www.readbyqxmd.com/read/28030798/combined-inhibition-of-wee1-and-chk1-gives-synergistic-dna-damage-in-s-phase-due-to-distinct-regulation-of-cdk-activity-and-cdc45-loading
#18
Sissel Hauge, Christian Naucke, Grete Hasvold, Mrinal Joel, Gro Elise Rødland, Petras Juzenas, Trond Stokke, Randi G Syljuåsen
Recent studies have shown synergistic cytotoxic effects of simultaneous Chk1- and Wee1-inhibition. However, the mechanisms behind this synergy are not known. Here, we present a flow cytometry-based screen for compounds that cause increased DNA damage in S-phase when combined with the Wee1-inhibitor MK1775. Strikingly, the Chk1-inhibitors AZD7762 and LY2603618 were among the top candidate hits of 1664 tested compounds, suggesting that the synergistic cytotoxic effects are due to increased S-phase DNA damage...
December 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/28011425/discovery-and-evaluation-of-inhibitors-to-the-immunosuppressive-enzyme-indoleamine-2-3-dioxygenase-1-ido1-probing-the-active-site-inhibitor-interactions
#19
Petr Tomek, Brian D Palmer, Jack U Flanagan, Chuanwen Sun, Emma L Raven, Lai-Ming Ching
High expression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) for a broad range of malignancies is associated with poor patient prognosis, and the enzyme is a validated target for cancer intervention. To identify novel IDO1 inhibitors suitable for drug development, 1597 compounds in the National Cancer Institute Diversity Set III library were tested for inhibitory activity against recombinant human IDO1. We retrieved 35 hits that inhibited IDO1 activity >50% at 20 μM. Five structural filters and the PubChem Bioassay database were used to guide the selection of five inhibitors with IC50 between 3 and 12 μM for subsequent experimental evaluation...
December 13, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28008665/discovery-of-novel-potent-nuclear-factor-kappa-b-inhibitors-ikk-%C3%AE-via-extensive-ligand-based-modeling-and-virtual-screening
#20
Mahmoud A Al-Sha'er, Inas S Almazari, Mutasem O Taha
Inhibitor kappa-B kinase-beta (IKK-β) controls the activation of nuclear transcription factor kappa-B and has been linked to inflammation and cancer. Therefore, inhibitors of this kinase should have potent anti-inflammatory and anticancer properties. Accordingly, we explored the pharmacophoric space of 218 IKK-β inhibitors to identify high-quality binding models. Subsequently, genetic algorithm-based quantitative structure activity relationship (QSAR) analysis was employed to select the best possible combination of pharmacophoric models and physicochemical descriptors that explain bioactivity variation among training compounds...
December 23, 2016: Journal of Molecular Recognition: JMR
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