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https://www.readbyqxmd.com/read/29149186/cell-cycle-time-series-gene-expression-data-encoded-as-cyclic-attractors-in-hopfield-systems
#1
Anthony Szedlak, Spencer Sims, Nicholas Smith, Giovanni Paternostro, Carlo Piermarocchi
Modern time series gene expression and other omics data sets have enabled unprecedented resolution of the dynamics of cellular processes such as cell cycle and response to pharmaceutical compounds. In anticipation of the proliferation of time series data sets in the near future, we use the Hopfield model, a recurrent neural network based on spin glasses, to model the dynamics of cell cycle in HeLa (human cervical cancer) and S. cerevisiae cells. We study some of the rich dynamical properties of these cyclic Hopfield systems, including the ability of populations of simulated cells to recreate experimental expression data and the effects of noise on the dynamics...
November 17, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29147457/oxidative-stress-delays-prometaphase-metaphase-of-the-first-cleavage-in-mouse-zygotes-via-the-mad2l1-mediated-spindle-assembly-checkpoint
#2
Que Wu, Zhiling Li, Yue Huang, Diting Qian, Man Chen, Wanfen Xiao, Bin Wang
In zygotes, DNA damage delays the first cleavage to enable repair. Our previous study found that 0.03 mM hydrogen peroxide (H2O2) was the minimum concentration required for induction of oxidative DNA damage in mouse zygotes and that this represented the most similar situation to the clinical phenomenon. In this study, we quantified the cleavage rates of cells in blastocysts at different developmental stages, followed by immunofluorescence to detect activation of γ-H2A histone family member X (a marker of DNA damage) in zygotes to confirm that oxidative DNA damage was induced in H2O2-treated zygotes...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29100415/the-e2f-activators-control-multiple-mitotic-regulators-and-maintain-genomic-integrity-through-sgo1-and-bubr1
#3
Miyoung Lee, Yainyrette Rivera-Rivera, Carlos S Moreno, Harold I Saavedra
The E2F1, E2F2, and E2F3a transcriptional activators control proliferation. However, how the E2F activators regulate mitosis to maintain genomic integrity is unclear. Centrosome amplification (CA) and unregulated spindle assembly checkpoint (SAC) are major generators of aneuploidy and chromosome instability (CIN) in cancer. Previously, we showed that overexpression of single E2F activators induced CA and CIN in mammary epithelial cells, and here we show that combined overexpression of E2F activators did not enhance CA...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29036655/mfib-a-repository-of-protein-complexes-with-mutual-folding-induced-by-binding
#4
Erzsébet Fichó, István Reményi, István Simon, Bálint Mészáros
Motivation: It is commonplace that intrinsically disordered proteins (IDPs) are involved in crucial interactions in the living cell. However, the study of protein complexes formed exclusively by IDPs is hindered by the lack of data and such analyses remain sporadic. Systematic studies benefited other types of protein-protein interactions paving a way from basic science to therapeutics; yet these efforts require reliable datasets that are currently lacking for synergistically folding complexes of IDPs...
November 15, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29025594/gene-expression-profiling-pathway-analysis-and-subtype-classification-reveal-molecular-heterogeneity-in-hepatocellular-carcinoma-and-suggest-subtype-specific-therapeutic-targets
#5
Rahul Agarwal, Jitendra Narayan, Amitava Bhattacharyya, Mayank Saraswat, Anil Kumar Tomar
A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28991472/the-discovery-of-a-dual-ttk-protein-kinase-cdc2-like-kinase-clk2-inhibitor-for-the-treatment-of-triple-negative-breast-cancer-initiated-from-a-phenotypic-screen
#6
Jennifer R Riggs, Mark Nagy, Jan Elsner, Paul Erdman, Dan Cashion, Dale Robinson, Roy Harris, Dehua Huang, Lida Tehrani, Gordafaried Deyanat-Yazdi, Rama Krishna Narla, Xiaohui Peng, Tam Tran, Leo Barnes, Terra Miller, Jason Katz, Yang Tang, Ming Chen, Mehran F Moghaddam, Sogole Bahmanyar, Barbra Pagarigan, Silvia Delker, Laurie LeBrun, Philip P Chamberlain, Andrew Calabrese, Stacie S Canan, Katerina Leftheris, Dan Zhu, John F Boylan
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties...
October 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28911857/new-mouse-model-for-inducing-and-evaluating-unilateral-vestibular-deafferentation-syndrome
#7
R Cassel, P Bordiga, D Pericat, C Hautefort, B Tighilet, C Chabbert
BACKGROUND: Unilateral vestibular deafferentation syndrome (uVDS) holds a particular place in the vestibular pathology domain. Due to its suddenness, the violence of its symptoms that often result in emergency hospitalization, and its associated original neurophysiological properties, this syndrome is a major source of questioning for the otoneurology community. Also, its putative pathogenic causes remain to be determined. There is currently a strong medical need for the development of targeted and effective countermeasures to improve the therapeutic management of uVDS...
September 11, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28892033/ultrasound-guided-intracardiac-injection-of-human-mesenchymal-stem-cells-to-increase-homing-to-the-intestine-for-use-in-murine-models-of-experimental-inflammatory-bowel-diseases
#8
Maneesh Dave, Paola Menghini, Keiki Sugi, Rodrigo A Somoza, Zhenghong Lee, Mukesh Jain, Arnold Caplan, Fabio Cominelli
Crohn's disease (CD) is a common chronic inflammatory disease of the small and large intestines. Murine and human mesenchymal stem cells (MSCs) have immunosuppressive potential and have been shown to suppress inflammation in mouse models of intestinal inflammation, even though the route of administration can limit their homing and effectiveness (1)(,)(3)(,)(4)(,)(5). Local application of MSCs to colonic injury models has shown greater efficacy at ameliorating inflammation in the colon. However, there is paucity of data on techniques to enhance the localization of human bone marrow-derived MSCs (hMSCs) to the small intestine, the site of inflammation in the SAMP-1/YitFc (SAMP) model of experimental Crohn's disease...
September 1, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28883705/threonine-and-tyrosine-kinase-may-serve-as-a-prognostic-biomarker-for-gallbladder-cancer
#9
Yuan Xie, Jian-Zhen Lin, An-Qiang Wang, Wei-Yu Xu, Jun-Yu Long, Yu-Feng Luo, Jie Shi, Zhi-Yong Liang, Xin-Ting Sang, Hai-Tao Zhao
AIM: To detect the expression of threonine and tyrosine kinase (TTK) in gallbladder cancer (GBC) specimens and analyze the associations between TTK expression and clinicopathological parameters and clinical prognosis. METHODS: A total of 68 patients with GBC who underwent surgical resection were enrolled in this study. The expression of TTK in GBC tissues was detected by immunohistochemistry. The assessment of TTK expression was conducted using the H-scoring system...
August 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28866503/the-topology-toolkit
#10
Julien Tierny, Guillaume Favelier, Joshua A Levine, Charles Gueunet, Michael Michaux
This system paper presents the Topology ToolKit (TTK), a software platform designed for the topological analysis of scalar data in scientific visualization. While topological data analysis has gained in popularity over the last two decades, it has not yet been widely adopted as a standard data analysis tool for end users or developers. TTK aims at addressing this problem by providing a unified, generic, efficient, and robust implementation of key algorithms for the topological analysis of scalar data, including: critical points, integral lines, persistence diagrams, persistence curves, merge trees, contour trees, Morse-Smale complexes, fiber surfaces, continuous scatterplots, Jacobi sets, Reeb spaces, and more...
August 29, 2017: IEEE Transactions on Visualization and Computer Graphics
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
#11
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
#12
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...
November 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28751540/ttk-inhibitors-as-a-targeted-therapy-for-ctnnb1-%C3%AE-catenin-mutant-cancers
#13
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. Although the first TTK inhibitors have entered phase I 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 preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 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
#14
COMPARATIVE STUDY
Yoshitaka Hiruma, Andre Koch, Nazila Hazraty, Foteini Tsakou, René H Medema, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signaling, 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...
September 1, 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
#15
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
#16
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
#17
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
#18
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...
August 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28545358/molecular-imaging-of-tumor-angiogenesis-and-therapeutic-effects-with-dual-bioluminescence
#19
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
#20
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
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