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https://www.readbyqxmd.com/read/28337968/crispr-cas9-mutagenesis-invalidates-a-putative-cancer-dependency-targeted-in-on-going-clinical-trials
#1
Ann Lin, Christopher J Giuliano, Nicole M Sayles, Jason M Sheltzer
The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types...
March 24, 2017: ELife
https://www.readbyqxmd.com/read/28323497/potential-mechanisms-underlying-cdk5-related-osteosarcoma-progression
#2
Hang-Xing Bao, Qing Bi, Yong Han, Chen Zhao, Hai Zou
OBJECTIVES: Identification of new prognostic biomarkers and therapeutic targets is of crucial importance for patients with osteosarcoma. Cyclin-dependent kinase 5 (CDK5) is overexpressed in several tumor types. However, the exact role CDK5 plays in osteosarcoma is still unknown. METHODS: In this study, we explored the association between CDK5 expression and the prognosis of osteosarcoma patients using publicly available gene expression datasets. Potential molecular mechanisms underlying its pro-malignant role in cancer progression were also discussed...
March 21, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28319600/early-and-late-factors-impacting-patient-and-graft-outcome-in-pediatric-liver-transplantation-summary-of-an-espghan-monothematic-conference
#3
Valérie A McLin, Upton Allen, Olivia Boyer, John Bucuvalas, Michele Colledan, Maria-Cristina Cuturi, Lorenzo d'Antiga, Dominique Debray, Antal Dezsofi, Jean de Ville de Goyet, Anil Dhawan, Ozlem Durmaz, Christine Falk, Sandy Feng, Björn Fischler, Stéphanie Franchi-Abella, Esteban Frauca, Rainer Ganschow, Stephen Gottschalk, Nedim Hadzic, Loreto Hierro, Simon Horslen, Stefan Hubscher, Vincent Karam, Deirdre Kelly, Britta Maecker-Kolhoff, George Mazariegos, Patrick McKiernan, Anette Melk, Valerio Nobili, Funda Ozgenç, Raymond Reding, Marco Sciveres, Khalid Sharif, Piotr Socha, Christian Toso, Pietro Vajro, Anita Verma, Barbara E Wildhaber, Ulrich Baumann
As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications...
March 17, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28275243/the-microrna-expression-signature-of-small-cell-lung-cancer-tumor-suppressors-of-mir-27a-5p-and-mir-34b-3p-and-their-targeted-oncogenes
#4
Keiko Mizuno, Hiroko Mataki, Takayuki Arai, Atsushi Okato, Kazuto Kamikawaji, Tomohiro Kumamoto, Tsubasa Hiraki, Kazuhito Hatanaka, Hiromasa Inoue, Naohiko Seki
Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous...
March 9, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28260099/identification-of-prognostic-genes-in-kidney-renal-clear-cell-carcinoma-by-rna%C3%A2-seq-data-analysis
#5
Yanqin Gu, Linfeng Lu, Lingfeng Wu, Hao Chen, Wei Zhu, Yi He
The present study aimed to analyze RNA-seq data of kidney renal clear cell carcinoma (KIRC) to identify prognostic genes. RNA‑seq data were downloaded from The Cancer Genome Atlas. Feature genes with a coefficient of variation (CV) >0.5 were selected using the genefilter package in R. Gene co‑expression networks were constructed with the WGCNA package. Cox regression analysis was performed using the survive package. Furthermore, a functional enrichment analysis was conducted using Database for Annotation, Visualization and Integrated Discovery tools...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28237943/kinome-profiling-identifies-druggable-targets-for-novel-hcmv-antivirals
#6
Kyle C Arend, Erik M Lenarcic, Heather A Vincent, Naim Rashid, Eric Lazear, Ian M McDonald, Thomas S K Gilbert, Michael P East, Laura E Herring, Gary L Johnson, Lee Graves, Nathaniel J Moorman
Human cytomegalovirus (HCMV) is a significant cause of disease in immunecompromised adults and immune naive newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals...
February 25, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28214016/melk-expression-in-ovarian-cancer-correlates-with-poor-outcome-and-its-inhibition-by-otssp167-abrogates-proliferation-and-viability-of-ovarian-cancer-cells
#7
Reto S Kohler, Henriette Kettelhack, Alexandra M Knipprath-Mészaros, André Fedier, Andreas Schoetzau, Francis Jacob, Viola Heinzelmann-Schwarz
OBJECTIVE: Maternal embryonic leucine-zipper kinase (MELK) shows oncogenic properties in basal-like breast cancer, a cancer subtype sharing common molecular features with high-grade serous ovarian cancer. We examined the potential of MELK as a molecular and pharmacological target for treatment of epithelial ovarian cancer (EOC). METHODS/MATERIALS: Bioinformatic analysis was performed on nine OC transcriptomic data sets totaling 1241 patients. Effects of MELK depletion by shRNA or inhibition by OTSSP167 in cell lines were assessed by colony formation and MTT (proliferation) assays, Western blotting (apoptosis), and flow cytometry (cell cycle analysis)...
February 14, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#8
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28191039/elevated-transcriptional-levels-of-aldolase-a-aldoa-associates-with-cell-cycle-related-genes-in-patients-with-nsclc-and-several-solid-tumors
#9
Fan Zhang, Jie-Diao Lin, Xiao-Yu Zuo, Yi-Xuan Zhuang, Chao-Qun Hong, Guo-Jun Zhang, Xiao-Jiang Cui, Yu-Kun Cui
BACKGROUND: Aldolase A (ALDOA) is one of the glycolytic enzymes primarily found in the developing embryo and adult muscle. Recently, a new role of ALDOA in several cancers has been proposed. However, the underlying mechanism remains obscure and inconsistent. In this study, we tried to investigate ALDOA-associated (AA) genes using available microarray datasets to help elucidating the role of ALDOA in cancer. RESULTS: In the dataset of patients with non-small-cell lung cancer (NSCLC, E-GEOD-19188), 3448 differentially expressed genes (DEGs) including ALDOA were identified, in which 710 AA genes were found to be positively associated with ALDOA...
2017: BioData Mining
https://www.readbyqxmd.com/read/27920471/identification-of-il11ra-and-melk-amplification-in-gastric-cancer-by-comprehensive-genomic-profiling-of-gastric-cancer-cell-lines
#10
Danielle Queiroz Calcagno, Sylvia Santomi Takeno, Carolina Oliveira Gigek, Mariana Ferreira Leal, Fernanda Wisnieski, Elizabeth Suchi Chen, Taíssa Maíra Thomaz Araújo, Eleonidas Moura Lima, Maria Isabel Melaragno, Samia Demachki, Paulo Pimentel Assumpção, Rommel Rodriguez Burbano, Marília Cardoso Smith
AIM: To identify common copy number alterations on gastric cancer cell lines. METHODS: Four gastric cancer cell lines (ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR analysis. RESULTS: The amplification of 9p13...
November 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27915972/resistance-to-cell-death-and-its-modulation-in-cancer-stem-cells
#11
Ahmad R Safa
Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs...
2016: Critical Reviews in Oncogenesis
https://www.readbyqxmd.com/read/27867630/melk-kinase-holds-promise-as-a-new-radiosensitizing-target-and-biomarker-in-triple-negative-breast-cancer
#12
COMMENT
Carlos S Moreno
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27827310/cardiovascular-phenotypes-in-children-with-ckd-the-4c-study
#13
Franz Schaefer, Anke Doyon, Karolis Azukaitis, Aysun Bayazit, Nur Canpolat, Ali Duzova, Ana Niemirska, Betul Sözeri, Daniela Thurn, Ali Anarat, Bruno Ranchin, Mieczyslav Litwin, Salim Caliskan, Cengiz Candan, Esra Baskin, Ebru Yilmaz, Sevgi Mir, Marietta Kirchner, Anja Sander, Dieter Haffner, Anette Melk, Elke Wühl, Rukshana Shroff, Uwe Querfeld
BACKGROUND AND OBJECTIVES: Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m(2). The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity...
January 6, 2017: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/27798878/expression-of-maternal-embryonic-leucine-zipper-kinase-melk-correlates-to-malignant-potentials-in-hepatocellular-carcinoma
#14
Kiyokazu Hiwatashi, Shinichi Ueno, Masahiko Sakoda, Satoshi Iino, Koji Minami, Keiichi Yonemori, Yuka Nishizono, Hiroshi Kurahara, Yuko Mataki, Kosei Maemura, Hiroyuki Shinchi, Shoji Natsugoe
BACKGROUND/AIM: Maternal embryonic leucine zipper kinase (MELK) is categorized as a member of AMP-activated protein kinase families. Various MELK-associated cellular and biological processes affect multiple stages of tumorigenesis. The aim of the present study was to clarify the relationship between MELK expression and hepatocellular carcinoma (HCC) clinicopathological features. MATERIALS AND METHODS: In thirty conserved frozen primary HCC and non-HCC samples MELK mRNA expression was examined by quantitative real-time polymerase chain reaction (PCR)...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27715411/the-impact-of-autophagy-on-the-development-of-senescence-in-primary-tubular-epithelial-cells
#15
Arpita Baisantry, Sagar Bhayana, Christoph Wrede, Jan Hegermann, Hermann Haller, Anette Melk, Roland Schmitt
Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC...
November 2016: Cell Cycle
https://www.readbyqxmd.com/read/27693640/melk-is-an-oncogenic-kinase-essential-for-early-hepatocellular-carcinoma-recurrence
#16
Hongping Xia, Shik Nie Kong, Jianxiang Chen, Ming Shi, Karthik Sekar, Veerabrahma Pratap Seshachalam, Muthukumar Rajasekaran, Brian Kim Poh Goh, London Lucien Ooi, Kam M Hui
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival...
September 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27600870/biased-%C3%AE-opioid-receptor-agonists-diversely-regulate-lateral-mobility-and-functional-coupling-of-the-receptor-to-its-cognate-g-proteins
#17
COMPARATIVE STUDY
Barbora Melkes, Lucie Hejnova, Jiri Novotny
There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2...
December 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27574806/kinase-gene-expression-profiling-of-metastatic-clear-cell-renal-cell-carcinoma-tissue-identifies-potential-new-therapeutic-targets
#18
Pooja Ghatalia, Eddy S Yang, Brittany N Lasseigne, Ryne C Ramaker, Sara J Cooper, Dongquan Chen, Sunil Sudarshan, Shi Wei, Arjun S Guru, Amy Zhao, Tiffiny Cooper, Deborah L Della Manna, Gurudatta Naik, Richard M Myers, Guru Sonpavde
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets...
2016: PloS One
https://www.readbyqxmd.com/read/27540718/anti-myeloma-activity-of-melk-inhibitor-ots167-effects-on-drug-resistant-myeloma-cells-and-putative-myeloma-stem-cell-replenishment-of-malignant-plasma-cells
#19
A T Stefka, J-H Park, Y Matsuo, S Chung, Y Nakamura, A J Jakubowiak, S Rosebeck
No abstract text is available yet for this article.
August 19, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27528663/mitotic-melk-eif4b-signaling-controls-protein-synthesis-and-tumor-cell-survival
#20
Yubao Wang, Michael Begley, Qing Li, Hai-Tsang Huang, Ana Lako, Michael J Eck, Nathanael S Gray, Timothy J Mitchison, Lewis C Cantley, Jean J Zhao
The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle...
August 30, 2016: Proceedings of the National Academy of Sciences of the United States of America
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