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https://www.readbyqxmd.com/read/28777004/whole-exome-sequencing-identify-the-6q12-q16-linkage-region-and-a-candidate-gene-ttk-for-pulmonary-nontuberculous-mycobacterial-disease
#1
Fei Chen, Eva P Szymanski, Kenneth N Olivier, Xinyue Liu, Hervé Tettelin, Steven M Holland, Priya Duggal
RATIONALE: Pulmonary nontuberculous mycobacterial (PNTM) disease often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism. OBJECTIVES: To map the genes associated with PNTM, whole-exome sequencing (WES) was conducted in 12 PNTM families and 57 sporadic cases recruited at the NIH Clinical Center during 2001-2013...
August 4, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28759042/inhibition-of-the-spindle-assembly-checkpoint-kinase-mps-1-as-a-novel-therapeutic-strategy-in-malignant-mesothelioma
#2
A Szymiczek, M Carbone, S Pastorino, A Napolitano, M Tanji, M Minaai, I Pagano, J M Mason, H I Pass, M R Bray, T W Mak, H Yang
Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity...
July 31, 2017: Oncogene
https://www.readbyqxmd.com/read/28751540/ttk-inhibitors-as-a-targeted-therapy-for-ctnnb1-%C3%AE-catenin-mutant-cancers
#3
Guido J R Zaman, Jeroen A D M de Roos, Marion A A Libouban, Martine B W Prinsen, Jos de Man, Rogier C Buijsman, Joost C M Uitdehaag
The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small molecule inhibitors. While the first TTK inhibitors have entered phase 1 dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of pre-clinical and clinical TTK inhibitors from different chemical series on a panel of sixty-six genetically characterized cell lines derived from different tumors (Oncolines)...
July 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28726638/understanding-inhibitor-resistance-in-mps1-kinase-through-novel-biophysical-assays-and-structures
#4
Yoshitaka Hiruma, Andre Koch, Nazila Hazraty, Foteini Tsakou, Rene H Medema, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described...
July 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28661474/mutant-p53-dictates-the-oncogenic-activity-of-c-abl-in-triple-negative-breast-cancers
#5
Chevaun D Morrison, Jenny C Chang, Ruth A Keri, William P Schiemann
We recently established c-Abl as a potent suppressor of triple-negative breast cancer (TNBC) progression through its reactivation of a p53:p21 signaling axis coupled to senescence. Moreover, we observed co-expression of p53 and c-Abl to be essential for normal mammary epithelial cell physiology, as this relationship is lost upon breast cancer progression. Cytoplasmic c-Abl activity is markedly increased in some TNBCs and contributes to disease progression; however, the mechanisms underlying these events remain largely unknown...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28601573/upregulation-of-cyclin-b1-plays-potential-roles-in-the-invasiveness-of-pituitary-adenomas
#6
Peng Zhao, Pengfei Zhang, Wei Hu, Hongyun Wang, Guoqiang Yu, Zhuang Wang, Chuzhong Li, Jiwei Bai, Yazhuo Zhang
Predicting aggressive or malignant behavior of pituitary adenomas (PAs) remains challenging. Aberrant expression of cyclin B1 (CCNB1) occurred in various tumors including PAs. Our study was aimed to explore its roles in the development of PAs aggressiveness. According to the integrated analysis, the expression of CCNB1 was evaluated. Following bioinformatics analysis was performed to uncover the pathways CCNB1 involved in and the upstream transcriptional regulation factors. The mRNA expression of CCNB1 was verified by qRT-PCR...
June 7, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28588715/aurka-mrna-expression-is-an-independent-predictor-of-poor-prognosis-in-patients-with-non-small-cell-lung-cancer
#7
Ahmed S K Al-Khafaji, Michael W Marcus, Michael P A Davies, Janet M Risk, Richard J Shaw, John K Field, Triantafillos Liloglou
Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and β-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC)...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28550121/bcl6-represses-antiviral-resistance-in-follicular-t-helper-cells
#8
Tohti Amet, Young Min Son, Li Jiang, In Su Cheon, Su Huang, Samir K Gupta, Alexander L Dent, Luis J Montaner, Qigui Yu, Jie Sun
Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells...
May 26, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28545358/molecular-imaging-of-tumor-angiogenesis-and-therapeutic-effects-with-dual-bioluminescence
#9
Ran Wang, Kaiyue Zhang, Hongyan Tao, Wei Du, Di Wang, Ziwei Huang, Manqian Zhou, Yang Xu, Yuebing Wang, Na Liu, Hui Wang, Zongjin Li
BACKGROUND: Angiogenesis is critical for the growth of tumor by supplying nutrients and oxygen that exacerbates the metastasis and progression of cancer. Noninvasive imaging of angiogenesis during the tumor therapeutic processes may provide novel opportunities for image-guided tumor management. OBJECTIVE: Here, we want to develop a mouse animal model for assessing cancer progression and angiogenesis in the same individuals by molecular imaging. METHODS: Breast cancer model was developed with mouse breast cancer cell line 4T1 carrying a reporter system encoding a triple fusion (TF) reporter gene consisting of renilla luciferase (Rluc), red fluorescent protein (RFP) and herpes simplex virus truncated thymidine kinase (HSV-ttk) in transgenic mice, which expressed firefly luciferase (Fluc) under the promoter of vascular endothelial growth factor receptor 2 (Vegfr2-luc)...
May 23, 2017: Current Pharmaceutical Biotechnology
https://www.readbyqxmd.com/read/28539250/target-residence-time-guided-optimization-on-ttk-kinase-results-in-inhibitors-with-potent-anti-proliferative-activity
#10
Joost C M Uitdehaag, Jos de Man, Nicole Willemsen-Seegers, Martine B W Prinsen, Marion A A Libouban, Jan Gerard Sterrenburg, Joeri J P de Wit, Judith R F de Vetter, Jeroen A D M de Roos, Rogier C Buijsman, Guido J R Zaman
The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis)...
July 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28474358/e2f1-interactive-with-brca1-pathway-induces-hcc-two-different-small-molecule-metabolism-or-cell-cycle-regulation-via-mitochondrion-or-cd4-t-to-cytosol
#11
Qingchun Chen, Lin Wang, Minghu Jiang, Juxiang Huang, Zhenfu Jiang, Haitao Feng, Zhili Ji
Breast cancer 1 (BRCA1) and E2F transcription factor 1 (E2F1) are related to metabolism and cell cycle regulation. However, the corresponding mechanism is not clear in HCC. High BRCA1 direct pathway was constructed with 11 molecules from E2F1 feedback-interactive network in HCC by GRNInfer based on 39 Pearson mutual positive corelation CC ≥0.25 molecules with E2F1. Integration of GRNInfer with GO, KEGG, BioCarta, GNF_U133A, UNIGENE_EST, Disease, GenMAPP databases by DAVID and MAS 3.0, E2F1 feedback-interactive BRCA1 indirect mitochondrion to cytosol pathway was identified as upstream LAPTM4B activation, feedback UNG, downstream BCAT1-HIST1H2AD-TK1 reflecting protein, and DNA binding with enrichment of small molecule metabolism; The corresponding BRCA1 indirect membrane to cytosol pathway as upstream CCNB2-NUSAP1 activation, feedback TTK-HIST1H2BJ-CENPF, downstream MCM4-TK1 reflecting ATP, and microtubule binding with enrichment of CD4+T-related cell cycle regulation in HCC...
May 5, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28427185/transcriptional-landscape-of-human-cancers
#12
Mengyuan Li, Qingrong Sun, Xiaosheng Wang
The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415765/stable-aneuploid-tumors-cells-are-more-sensitive-to-ttk-inhibition-than-chromosomally-unstable-cell-lines
#13
Marion A A Libouban, Jeroen A D M de Roos, Joost C M Uitdehaag, Nicole Willemsen-Seegers, Sara Mainardi, Jelle Dylus, Jos de Man, Bastiaan Tops, Jules P P Meijerink, Zuzana Storchová, Rogier C Buijsman, René H Medema, Guido J R Zaman
Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes...
June 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28395636/ttk-chitra-tilting-disc-heart-valve-model-tc2-an-assessment-of-fatigue-life-and-durability
#14
N N Subhash, Adathala Rajeev, Sreedharan Sujesh, C V Muraleedharan
Average age group of heart valve replacement in India and most of the Third World countries is below 30 years. Hence, the valve for such patients need to be designed to have a service life of 50 years or more which corresponds to 2000 million cycles of operation. The purpose of this study was to assess the structural performance of the TTK Chitra tilting disc heart valve model TC2 and thereby address its durability. The TC2 model tilting disc heart valves were assessed to evaluate the risks connected with potential structural failure modes...
April 1, 2017: Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine
https://www.readbyqxmd.com/read/28386672/malignancy-in-pheochromocytoma-or-paraganglioma-integrative-analysis-of-176-cases-in-tcga
#15
Yong Joon Suh, Ji-Young Choe, Hyo Jin Park
Methods of diagnosing malignant pheochromocytoma (PCC) or paraganglioma (PGL) are needed. However, there are no reliable histopathologic criteria to distinguish malignant PCC/PGLs. The recent genomic analysis of The Cancer Genome Atlas (TCGA) provides in-depth information enabling more accurate diagnosis of disease entities. Therefore, we investigated genomic expression differences and mutational differences of malignant PCC/PGLs with TCGA. As of December 2014, TCGA had acquired multigenomic analysis of 176 PCC/PGL samples...
June 2017: Endocrine Pathology
https://www.readbyqxmd.com/read/28380042/genetic-and-pharmacological-inhibition-of-ttk-impairs-pancreatic-cancer-cell-line-growth-by-inducing-lethal-chromosomal-instability
#16
Jeran K Stratford, Feng Yan, Rebecca A Hill, Michael B Major, Lee M Graves, Channing J Der, Jen Jen Yeh
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28370201/a-phase-1-study-of-amg-900-an-orally-administered-pan-aurora-kinase-inhibitor-in-adult-patients-with-acute-myeloid-leukemia
#17
MULTICENTER STUDY
Hagop M Kantarjian, Michael W Schuster, Nitin Jain, Anjali Advani, Elias Jabbour, Erick Gamelin, Erik Rasmussen, Gloria Juan, Abraham Anderson, Vincent F Chow, Gregory Friberg, Florian D Vogl, Mikkael A Sekeres
Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule)...
July 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28316214/-expression-of-tyrosine-and-threonine-protein-kinase-in-carcinogenic-process-of-colorectal-cancer-and-its-relationship-with-prognosis
#18
X L Zhang, W X Han, Y M Ma, H W Y Baohan, X H Zhao, H Y Wang
Objective: To investigate the expression of TTK (tyrosine and threonine protein kinase) in the process of colorectal cancer (CRC) development and its relationship to prognosis in CRC patients. Methods: Colitis-associated colon cancer model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in C57BL/6 mice. Mice at four different stages of colon cancer development were obtained, named AD1 (inflammation of the recovery), AD2 (mild dysplasia), AD3 (adenoma) and AD4 (adenocarcinoma), as well as negative control (no treatment)...
March 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-the-growth-of-hepatocellular-carcinoma-cells-via-the-accumulation-of-chromosomal-instability
#19
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
June 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28270606/functional-characterization-of-cfi-402257-a-potent-and-selective-mps1-ttk-kinase-inhibitor-for-the-treatment-of-cancer
#20
Jacqueline M Mason, Xin Wei, Graham C Fletcher, Reza Kiarash, Richard Brokx, Richard Hodgson, Irina Beletskaya, Mark R Bray, Tak W Mak
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
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