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Aurora kinase

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https://www.readbyqxmd.com/read/29147626/functional-t-cells-targeting-tumor-associated-antigens-are-predictive-for-recurrence-free-survival-of-patients-with-radically-operated-non-small-cell-lung-cancer
#1
Seyer Safi, Yoshikane Yamauchi, Anchana Rathinasamy, Slava Stamova, Martin Eichhorn, Arne Warth, Geraldine Rauch, Hendrik Dienemann, Hans Hoffmann, Philipp Beckhove
In this prospective study, we examined postoperative follow-up and preoperative IFN-γ T cell responses against 14 non-small cell lung cancer (NSCLC)-associated antigens in the blood of 51 patients with NSCLC, 7 patients with benign pulmonary tumors, and 10 tumor-free patients by enzyme-linked immunospot assay. The phenotype and function of T cells specific for tumor-associated antigens (TAAs) in the blood or tumor tissue of 9 NSCLC patients were characterized in detail using TNF-α, IL-2, and IFN-γ cytokine capture assays...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29147452/the-effect-of-aurora-kinase-inhibitor-on-adhesion-and-migration-in-human-breast-cancer-cells-and-clinical-implications
#2
Huishan Zhao, Sioned Owen, Eleri L Davies, Wen G Jiang, Tracey A Martin
Background: The Aurora kinase family is comprised of highly conserved serine/threonine protein kinases that are known to be crucial in the regulation of the cell cycle. Aberrant expression of Aurora kinases has been demonstrated in certain malignancies. We aimed to examine the expression of Aurora kinases in human breast cancer tissues and to investigate the cellular impact of Aurora kinases inhibitor on breast cancer cells. Methods: The expression of Aurora kinase A/B/C was individually examined in tumor specimens (n = 106) and normal tissues (n = 29) from breast cancer patients using quantitative real-time PCR (Q-PCR) and immunohistochemistry...
October 2017: World Journal of Oncology
https://www.readbyqxmd.com/read/29146887/targeted-therapy-of-gastroenteropancreatic-neuroendocrine-tumours-preclinical-strategies-and-future-targets
#3
Elke Tatjana Aristizabal Prada, Christoph J Auernhammer
Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mTOR-inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression free survival due to tumor resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP-system are needed. This paper reviews preclinical research models and signaling pathways in NETs of the GEP-system...
November 16, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29141582/a-novel-interaction-between-kinase-activities-in-regulation-of-cilia-formation
#4
Nicole DeVaul, Katerina Koloustroubis, Rong Wang, Ann O Sperry
BACKGROUND: The primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle...
November 15, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/29129699/deguelin-an-aurora-b-kinase-inhibitor-exhibits-potent-anti-tumor-effect-in-human-esophageal-squamous-cell-carcinoma
#5
Xinfang Yu, Qi Liang, Wenbin Liu, Li Zhou, Wei Li, Haidan Liu
Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers. In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients. Depleting of Aurora B blunted the malignant phenotypes in ESCC cells. Importantly, we demonstrated that a natural compound, deguelin, has a profound anti-tumor effect on ESCC via inhibiting Aurora B activity...
November 3, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29122619/aurora-a-functional-single-nucleotide-polymorphism-snp-correlates-with-clinical-outcome-in-patients-with-advanced-solid-tumors-treated-with-alisertib-an-investigational-aurora-a-kinase-inhibitor
#6
Huifeng Niu, Hyunjin Shin, Feng Gao, Jacob Zhang, Brittany Bahamon, Hadi Danaee, Bohuslav Melichar, Russell J Schilder, Robert L Coleman, Gerald Falchook, Antoine Adenis, Kian Behbakht, Angela DeMichele, Elizabeth Claire Dees, Kimberly Perez, Ursula Matulonis, Piotr Sawrycki, Dirk Huebner, Jeffrey Ecsedy
BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428)...
October 16, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29115879/design-synthesis-and-biological-activity-of-n-4-phenylsubstituted-7h-pyrrolo-2-3-d-pyrimidin-4-amines-as-dual-inhibitors-of-aurora-kinase-a-and-epidermal-growth-factor-receptor-kinase
#7
Sonali Kurup, Bradley McAllister, Pavlina Liskova, Trusha Mistry, Anthony Fanizza, Dan Stanford, Jolanta Slawska, Ulrich Keller, Alexander Hoellein
Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/29109080/central-leptin-regulates-heart-lipid-content-by-selectively-increasing-ppar-%C3%AE-%C3%AE-expression
#8
Cristina Mora, Cristina Pintado, Blanca Rubio, Lorena Mazuecos, Virginia Lopez, Alejandro Fernandez, Aurora Salamanca, Brenda Barcena, Teresa Fernandez-Agullo, Carmen Arribas, Nilda Gallardo, Antonio Andres
The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective up-regulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and their target genes, adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), pyruvate dehydrogenase kinase 4 (PDK4), and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization...
November 6, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/29104076/solid-cancer-treatment-with-aurora-kinase-inhibitors-towards-a-personalized-medicine
#9
Salvatore Ulisse
No abstract text is available yet for this article.
October 31, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29100089/de-novo-mutations-in-protein-kinase-genes-camk2a-and-camk2b-cause-intellectual-disability
#10
Sébastien Küry, Geeske M van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C Towne, Megan T Cho, Trine E Prescott, Melissa A Ploeg, Stephan Sanders, Holly A F Stessman, Aurora Pujol, Ben Distel, Laurie A Robak, Jonathan A Bernstein, Anne-Sophie Denommé-Pichon, Gaëtan Lesca, Elizabeth A Sellars, Jonathan Berg, Wilfrid Carré, Øyvind Løvold Busk, Bregje W M van Bon, Jeff L Waugh, Matthew Deardorff, George E Hoganson, Katherine B Bosanko, Diana S Johnson, Tabib Dabir, Øystein Lunde Holla, Ajoy Sarkar, Kristian Tveten, Julitta de Bellescize, Geir J Braathen, Paulien A Terhal, Dorothy K Grange, Arie van Haeringen, Christina Lam, Ghayda Mirzaa, Jennifer Burton, Elizabeth J Bhoj, Jessica Douglas, Avni B Santani, Addie I Nesbitt, Katherine L Helbig, Marisa V Andrews, Amber Begtrup, Sha Tang, Koen L I van Gassen, Jane Juusola, Kimberly Foss, Gregory M Enns, Ute Moog, Katrin Hinderhofer, Nagarajan Paramasivam, Sharyn Lincoln, Brandon H Kusako, Pierre Lindenbaum, Eric Charpentier, Catherine B Nowak, Elouan Cherot, Thomas Simonet, Claudia A L Ruivenkamp, Sihoun Hahn, Catherine A Brownstein, Fan Xia, Sébastien Schmitt, Wallid Deb, Dominique Bonneau, Mathilde Nizon, Delphine Quinquis, Jamel Chelly, Gabrielle Rudolf, Damien Sanlaville, Philippe Parent, Brigitte Gilbert-Dussardier, Annick Toutain, Vernon R Sutton, Jenny Thies, Lisenka E L M Peart-Vissers, Pierre Boisseau, Marie Vincent, Andreas M Grabrucker, Christèle Dubourg, Wen-Hann Tan, Nienke E Verbeek, Martin Granzow, Gijs W E Santen, Jay Shendure, Bertrand Isidor, Laurent Pasquier, Richard Redon, Yaping Yang, Matthew W State, Tjitske Kleefstra, Benjamin Cogné, Slavé Petrovski, Kyle Retterer, Evan E Eichler, Jill A Rosenfeld, Pankaj B Agrawal, Stéphane Bézieau, Sylvie Odent, Ype Elgersma, Sandra Mercier
Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration...
November 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29097609/recent-advances-of-cell-cycle-inhibitor-therapies-for-pediatric-cancer
#11
REVIEW
Christopher C Mills, E A Kolb, Valerie B Sampson
This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the cross-talk of signals activated by cell-cycle arrest, as well as pediatric-focused drug development, are critical for the advancement of drugs for rare childhood diseases...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29078282/rad52-phosphorylation-by-ipl1-and-mps1-contributes-to-mps1-kinetochore-localization-and-spindle-assembly-checkpoint-regulation
#12
Gyubum Lim, Won-Ki Huh
Rad52 is well known as a key factor in homologous recombination. Here, we report that Rad52 has functions unrelated to homologous recombination in Saccharomyces cerevisiae; it plays a role in the recruitment of Mps1 to the kinetochores and the maintenance of spindle assembly checkpoint (SAC) activity. Deletion of RAD52 causes various phenotypes related to the dysregulation of chromosome biorientation. Rad52 directly affects efficient operation of the SAC and accurate chromosome segregation. Remarkably, by using an in vitro kinase assay, we found that Rad52 is a substrate of Ipl1/Aurora and Mps1 in yeast and humans...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29074977/the-translation-of-cyclin-b1-and-b2-is-differentially-regulated-during-mouse-oocyte-reentry-into-the-meiotic-cell-cycle
#13
Seung Jin Han, João Pedro Sousa Martins, Ye Yang, Min Kook Kang, Enrico Maria Daldello, Marco Conti
Control of protein turnover is critical for meiotic progression. Using RiboTag immunoprecipitation, RNA binding protein immunoprecipitation, and luciferase reporter assay, we investigated how rates of mRNA translation, protein synthesis and degradation contribute to the steady state level of Cyclin B1 and B2 in mouse oocytes. Ribosome loading onto Ccnb1 and Mos mRNAs increases during cell cycle reentry, well after germinal vesicle breakdown (GVBD). This is followed by the translation of reporters containing 3' untranslated region of Mos or Ccnb1 and the accumulation of Mos and Cyclin B1 proteins...
October 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074706/aurora-a-activation-in-mitosis-promoted-by-bugz
#14
Yuejia Huang, Teng Li, Stephanie C Ems-McClung, Claire E Walczak, Claude Prigent, Xueliang Zhu, Xuemin Zhang, Yixian Zheng
Protein phase separation or coacervation has emerged as a potential mechanism to regulate biological functions. We have shown that coacervation of a mostly unstructured protein, BuGZ, promotes assembly of spindle and its matrix. BuGZ in the spindle matrix binds and concentrates tubulin to promote microtubule (MT) assembly. It remains unclear, however, whether BuGZ could regulate additional proteins to promote spindle assembly. In this study, we report that BuGZ promotes Aurora A (AurA) activation in vitro. Depletion of BuGZ in cells reduces the amount of phosphorylated AurA on spindle MTs...
October 26, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29070411/chemical-space-big-data-challenge-for-molecular-diversity
#15
Mahendra Awale, Ricardo Visini, Daniel Probst, Josep Arús-Pous, Jean-Louis Reymond
Chemical space describes all possible molecules as well as multi-dimensional conceptual spaces representing the structural diversity of these molecules. Part of this chemical space is available in public databases ranging from thousands to billions of compounds. Exploiting these databases for drug discovery represents a typical big data problem limited by computational power, data storage and data access capacity. Here we review recent developments of our laboratory, including progress in the chemical universe databases (GDB) and the fragment subset FDB-17, tools for ligand-based virtual screening by nearest neighbor searches, such as our multi-fingerprint browser for the ZINC database to select purchasable screening compounds, and their application to discover potent and selective inhibitors for calcium channel TRPV6 and Aurora A kinase, the polypharmacology browser (PPB) for predicting off-target effects, and finally interactive 3D-chemical space visualization using our online tools WebDrugCS and WebMolCS...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/29065986/critical-risk-benefit-assessment-of-the-novel-anti-cancer-aurora-a-kinase-inhibitor-alisertib-mln8237-a-comprehensive-review-of-the-clinical-data
#16
REVIEW
Yaman Tayyar, Luqman Jubair, Sora Fallaha, Nigel A J McMillan
BACKGROUND: Many current anticancer chemotherapeutics suffer from significant side effects, which have led to the exploration of more targeted therapies. This resulted in the exploration of inhibitors of Aurora A kinase as a potential anti-cancer treatment. Alisertib (MLN8237) has proven to be a potent Aurora A kinase inhibitor that had the highest safety profile among its therapeutic family. Phase I/II/III clinical trials with Alisertib have been carried out and reported promising efficacy, yet serious side effects...
November 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29050234/a-small-molecule-inhibitor-targeting-the-aurkc-i%C3%AE%C2%BAb%C3%AE-interaction-decreases-transformed-growth-of-mda-mb-231-breast-cancer-cells
#17
Eun Hee Han, Jin-Young Min, Shin-Ae Yoo, Sung-Joon Park, Yun-Jeong Choe, Hee Sub Yun, Zee-Won Lee, Sun Woo Jin, Hyung Gyun Kim, Hye Gwang Jeong, Hyun Kyoung Kim, Nam Doo Kim, Young-Ho Chung
The Aurora kinases, Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) or meiosis (AURKC). Several Aurora kinase inhibitors are being investigated as novel anticancer therapeutics. Recent studies demonstrated that AURKC activation contributes to breast cancer cell transformation. Therefore, AURKC is both a promising marker and therapeutic target for breast cancer; however, its signaling network has not been fully characterized...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045843/high-throughput-functional-genetic-and-compound-screens-identify-targets-for-senescence-induction-in-cancer
#18
Liqin Wang, Rodrigo Leite de Oliveira, Cun Wang, João M Fernandes Neto, Sara Mainardi, Bastiaan Evers, Cor Lieftink, Ben Morris, Fleur Jochems, Lisa Willemsen, Roderick L Beijersbergen, René Bernards
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045126/characterization-of-three-druggable-hot-spots-in-the-aurora-a-tpx2-interaction-using-biochemical-biophysical-and-fragment-based-approaches
#19
Patrick J McIntyre, Patrick M Collins, Lukáš Vrzal, Kristian Birchall, Laurence H Arnold, Chido Mpamhanga, Peter J Coombs, Selena G Burgess, Mark W Richards, Anja Winter, Václav Veverka, Frank von Delft, Andy Merritt, Richard Bayliss
The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like protein 2) are overexpressed in cancers, and it has been proposed that they work together as an oncogenic holoenzyme. TPX2 is responsible for activating Aurora-A during mitosis, ensuring proper cell division. Disruption of the interface with TPX2 is therefore a potential target for novel anticancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using coprecipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2...
November 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29040668/aurora-kinase-b-a-novel-regulator-of-terf1-binding-and-telomeric-integrity
#20
Foong Lyn Chan, Benjamin Vinod, Karel Novy, Ralf B Schittenhelm, Cheng Huang, Maheshi Udugama, Juan Nunez-Iglesias, Jane I Lin, Linda Hii, Julie Chan, Hilda A Pickett, Roger J Daly, Lee H Wong
AURKB (Aurora Kinase B) is a serine/threonine kinase better known for its role at the mitotic kinetochore during chromosome segregation. Here, we demonstrate that AURKB localizes to the telomeres in mouse embryonic stem cells, where it interacts with the essential telomere protein TERF1. Loss of AURKB function affects TERF1 telomere binding and results in aberrant telomere structure. In vitro kinase experiments successfully identified Serine 404 on TERF1 as a putative AURKB target site. Importantly, in vivo overexpression of S404-TERF1 mutants results in fragile telomere formation...
October 10, 2017: Nucleic Acids Research
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