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Yoshitaka Hiruma, Andre Koch, Shreya Dharadhar, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase...
October 3, 2016: Proteins
Petra Hudler, Nina Kocevar Britovsek, Snjezana Frkovic Grazio, Radovan Komel
BACKGROUND: Malignant transformation of normal gastric cells is a complex and multistep process, resulting in development of heterogeneous tumours. Susceptible genetic background, accumulation of genetic changes, and environmental factors play an important role in gastric carcinogenesis. Single nucleotide polymorphisms (SNPs) in mitotic segregation genes could be responsible for inducing the slow process of accumulation of genetic changes, leading to genome instability. PATIENTS AND METHODS: We performed a case-control study of polymorphisms in mitotic kinases TTK rs151658 and BUB1B rs1031963 and rs1801376 to assess their effects on gastric cancer risk...
September 1, 2016: Radiology and Oncology
Maciej Tarnowski, Michał Czerewaty, Anna Deskur, Krzysztof Safranow, Wojciech Marlicz, Elżbieta Urasińska, Mariusz Z Ratajczak, Teresa Starzyńska
Background. While cancer/testis antigens (CTAs) are restricted in postnatal tissues to testes and germ line-derived cells, their role in cancer development and the clinical significance of their expression still remain to be better defined. Objective. The aim of this study was to investigate the level of CTA expression in colon samples from patients with colorectal cancer (CRC) in relation to patient clinical status. Methods. Forty-five patients with newly diagnosed colorectal cancer were included in the study...
2016: Disease Markers
Gwo-Jen Liaw
Histone deacetylation plays an important role in transcriptional repression. Previous results showed that the genetic interaction between ttk and rpd3, which encodes a class I histone deacetylase, is required for tll repression. This study investigated the molecular mechanism by which Ttk69 recruits Rpd3. Using yeast two-hybrid screening and datamining, one novel protein was found that weakly interacts with Ttk69 and Sin3A, designated as Protein interacting with Ttk69 and Sin3A (Pits). Pits protein expressed in the early stages of embryos and bound to the region of the tor response element in vivo...
2016: Scientific Reports
Ruoyu Miao, Yan Wu, Haohai Zhang, Huandi Zhou, Xiaofeng Sun, Eva Csizmadia, Lian He, Yi Zhao, Chengyu Jiang, Rebecca A Miksad, Tahereh Ghaziani, Simon C Robson, Haitao Zhao
Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo...
2016: Scientific Reports
Lamis Hammoud, Jessica R Adams, Amanda J Loch, Richard C Marcellus, David E Uehling, Ahmed Aman, Christopher Fladd, Trevor D McKee, Christine E B Jo, Rima Al-Awar, Sean E Egan, Janet Rossant
Blood vessels are formed through vasculogenesis, followed by remodeling of the endothelial network through angiogenesis. Many events that occur during embryonic vascular development are recapitulated during adult neoangiogenesis, which is critical to tumor growth and metastasis. Current antiangiogenic tumor therapies, based largely on targeting the vascular endothelial growth factor pathway, show limited clinical benefits, thus necessitating the discovery of alternative targets. Here we report the development of a robust embryonic stem cell-based vascular differentiation assay amenable to small-molecule screens to identify novel modulators of angiogenesis...
October 11, 2016: Stem Cell Reports
Joost C M Uitdehaag, Jeroen A D M de Roos, Martine B W Prinsen, Nicole Willemsen-Seegers, Judith R F de Vetter, Jelle Dylus, Antoon M van Doornmalen, Jeffrey Kooijman, Masaaki Sawa, Suzanne J C van Gerwen, Jos de Man, Rogier C Buijsman, Guido J R Zaman
Cancer cell line panels are important tools to characterize the in vitro activity of new investigational drugs. Here we present the inhibition profiles of 122 anti-cancer agents in proliferation assays with 44 or 66 genetically characterized cancer cell lines from diverse tumor tissues (Oncolines™). The library includes 29 cytotoxics, 68 kinase inhibitors and 11 epigenetic modulators. For 38 compounds this is the first comparative profiling in a cell line panel. By strictly maintaining optimized assay protocols, biological variation was kept to a minimum...
September 1, 2016: Molecular Cancer Therapeutics
Erika Gunnar, Caroline Bivik, Annika Starkenberg, Stefan Thor
Neural progenitors typically divide asymmetrically to renew themselves, while producing daughters with more limited potential. In the Drosophila embryonic ventral nerve cord, neuroblasts initially produce daughters that divide once to generate two neurons/glia (type I proliferation mode). Subsequently, many neuroblasts switch to generating daughters that differentiate directly (type 0). This programmed type I>0 switch is controlled by Notch signaling, triggered at a distinct point of lineage progression in each neuroblast...
August 30, 2016: Development
Shu Chen, Yang Wang, Chunxia Ni, Ge Meng, Xiaofang Sheng
Glioma is a malignant cancer with high mortality. A key prognostic factor of glioma is radiosensitivity. It has also been known that microRNAs (miR) significantly contribute to the development of glioma. miR-132 has been previously reported to inhibit tumor growth in some cancers, but not well studied in glioma. It is necessary to understand the association between miR-132 and glioma, including miR-132 expression in glioma, effects of miR-132 on cancer metastasis and radiosensitivity, and the involved molecular mechanism...
August 10, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Manoj B Parmar, Bárbara E Arteaga Ballesteros, Timothy Fu, Remant Bahadur Kc, Hamidreza Montazeri Aliabadi, Judith C Hugh, Raimar Löbenberg, Hasan Uludağ
Conventional breast cancer therapies have significant limitations that warrant a search for alternative therapies. Short-interfering RNA (siRNA), delivered by polymeric biomaterials and capable of silencing specific genes critical for growth of cancer cells, holds great promise as an effective and more specific therapy. Here, we employed amphiphilic polymers and silenced the expression of two cell cycle proteins, TTK and CDC20, and the anti-apoptosis protein survivin to determine the efficacy of polymer-mediated siRNA treatment in breast cancer cells as well as side effects in non-malignant cells in vitro...
July 28, 2016: Journal of Biomedical Materials Research. Part A
Yong Liu, Radoslaw Laufer, Narendra Kumar Patel, Grace Ng, Peter B Sampson, Sze-Wan Li, Yunhui Lang, Miklos Feher, Richard Brokx, Irina Beletskaya, Richard Hodgson, Olga Plotnikova, Donald E Awrey, Wei Qiu, Nickolay Y Chirgadze, Jacqueline M Mason, Xin Wei, Dan Chi-Chia Lin, Yi Che, Reza Kiarash, Graham C Fletcher, Tak W Mak, Mark R Bray, Henry W Pauls
This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency...
July 14, 2016: ACS Medicinal Chemistry Letters
Yannis Emmanuel Mavromatakis, Andrew Tomlinson
As cells proceed along their developmental pathways they make a series of sequential cell fate decisions. Each of those decisions needs to be made in a robust manner so there is no ambiguity in the state of the cell as it proceeds to the next stage. Here we examine the decision made by the Drosophila R7 precursor cell to become a photoreceptor and ask how the robustness of that decision is achieved. The transcription factor Tramtrack (Ttk) inhibits photoreceptor assignment, and previous studies found that the RTK-induced degradation of Ttk was critically required for R7 specification...
July 2016: PLoS Genetics
Radoslaw Laufer, Sze-Wan Li, Yong Liu, Grace Ng, Yunhui Lang, Miklos Feher, Richard Brokx, Irina Beletskaya, Richard Hodgson, Guodong Mao, Olga Plotnikova, Donald E Awrey, Jacqueline M Mason, Xin Wei, Dan Chi-Chia Lin, Yi Che, Reza Kiarash, Brian Madeira, Graham C Fletcher, Tak W Mak, Mark R Bray, Henry W Pauls
TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0...
August 1, 2016: Bioorganic & Medicinal Chemistry Letters
Julia Varga, László Dobson, Gábor E Tusnády
UNLABELLED: The TOPDOM database-originally created as a collection of domains and motifs located consistently on the same side of the membranes in α-helical transmembrane proteins-has been updated and extended by taking into consideration consistently localized domains and motifs in globular proteins, too. By taking advantage of the recently developed CCTOP algorithm to determine the type of a protein and predict topology in case of transmembrane proteins, and by applying a thorough search for domains and motifs as well as utilizing the most up-to-date version of all source databases, we managed to reach a 6-fold increase in the size of the whole database and a 2-fold increase in the number of transmembrane proteins...
September 1, 2016: Bioinformatics
Mutsunori Murahashi, Yasuki Hijikata, Kazunari Yamada, Yoshihiro Tanaka, Junji Kishimoto, Hiroyuki Inoue, Tomotoshi Marumoto, Atsushi Takahashi, Toshihiko Okazaki, Kazuyoshi Takeda, Masakazu Hirakawa, Hiroshi Fujii, Shinji Okano, Masaru Morita, Eishi Baba, Kazuhiro Mizumoto, Yoshihiko Maehara, Masao Tanaka, Koichi Akashi, Yoichi Nakanishi, Koji Yoshida, Takuya Tsunoda, Kazuo Tamura, Yusuke Nakamura, Kenzaburo Tani
We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks...
May 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Grazyna Janikowska, Tomasz Janikowsk, Alina Pyka, Adam Wilczok, Urszula Mazurek
Cyclosporin A is an immunosuppressant drug that is used not only in solid transplant rejection, but also in moderate and severe forms of psoriasis, pyoderma, lupus or arthritis. Serious side effects of the drug such as skin cancer or gingival hyperplasia probably start with the latent proliferation process. Little is known about the influence of cyclosporin A on molecular signaling in epidermal tissue. Thus, the aim of this study was to estimate the influence of cyclosporin A on the process of proliferation in normal human dermal fibroblasts...
January 2016: Acta Poloniae Pharmaceutica
Alberto Ocaña, Javier Pérez-Peña, Ana Alcaraz-Sanabria, Verónica Sánchez-Corrales, Cristina Nieto-Jiménez, Arnoud J Templeton, Bostjan Seruga, Atanasio Pandiella, Eitan Amir
INTRODUCTION: Accurate assessment of prognosis in early stage ovarian cancer is challenging resulting in suboptimal selection of patients for adjuvant therapy. The identification of predictive markers for cytotoxic chemotherapy is therefore highly desirable. Protein kinases are important components in oncogenic transformation and those relating to cell cycle and mitosis control may allow for identification of high-risk early stage ovarian tumors. METHODS: Genes with differential expression in ovarian surface epithelia (OSE) and ovarian cancer epithelial cells (CEPIs) were identified from public datasets and analyzed with dChip software...
April 19, 2016: Oncotarget
Giovanna Maria Pierantoni, Andrea Conte, Cinzia Rinaldo, Mara Tornincasa, Raffaele Gerlini, Davide Valente, Antonella Izzo, Alfredo Fusco
The High Mobility Group A1 proteins (HMGA1) are nonhistone chromatinic proteins with a critical role in development and cancer. We have recently reported that HMGA1 proteins are able to increase the expression of spindle assembly checkpoint (SAC) genes, thus impairing SAC function and causing chromosomal instability in cancer cells. Moreover, we found a significant correlation between HMGA1 and SAC genes expression in human colon carcinomas. Here, we report that mouse embryonic fibroblasts null for the Hmga1 gene show downregulation of Bub1, Bub1b, Mad2l1 and Ttk SAC genes, and present several features of chromosomal instability, such as nuclear abnormalities, binucleation, micronuclei and karyotypic alterations...
2016: Cell Cycle
Ram Bhupal Reddy, Anupama Rajan Bhat, Bonney Lee James, Sindhu Valiyaveedan Govindan, Rohit Mathew, D R Ravindra, Naveen Hedne, Jeyaram Illiayaraja, Vikram Kekatpure, Samanta S Khora, Wesley Hicks, Pramila Tata, Moni A Kuriakose, Amritha Suresh
The head and neck squamous cell carcinoma (HNSCC) transcriptome has been profiled extensively, nevertheless, identifying biomarkers that are clinically relevant and thereby with translational benefit, has been a major challenge. The objective of this study was to use a meta-analysis based approach to catalog candidate biomarkers with high potential for clinical application in HNSCC. Data from publically available microarray series (N = 20) profiled using Agilent (4X44K G4112F) and Affymetrix (HGU133A, U133A_2, U133Plus 2) platforms was downloaded and analyzed in a platform/chip-specific manner (GeneSpring software v12...
2016: PloS One
Sriganesh Srihari, Murugan Kalimutho, Samir Lal, Jitin Singla, Dhaval Patel, Peter T Simpson, Kum Kum Khanna, Mark A Ragan
UNLABELLED: Copy number alterations (CNAs) are thought to account for 85% of the variation in gene expression observed among breast tumours. The expression of cis-associated genes is impacted by CNAs occurring at proximal loci of these genes, whereas the expression of trans-associated genes is impacted by CNAs occurring at distal loci. While a majority of these CNA-driven genes responsible for breast tumourigenesis are cis-associated, trans-associated genes are thought to further abet the development of cancer and influence disease outcomes in patients...
March 2016: Molecular BioSystems
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