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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/28818686/methyleugenol-and-selected-oxidative-metabolites-affect-dna-damage-signalling-pathways-and-induce-apoptosis-in-human-colon-tumour-ht29-cells
#1
Isabel Anna Maria Groh, Melanie Esselen
Previously the food carcinogen methyleugenol was found to be cytotoxic and genotoxic in multiple cell lines and in primary hepatocytes. In this study, the question addressed was whether methyleugenol and the selected oxidative metabolites, 1'-hydroxymethyleugenol, methyleugenol-2',3'-epoxide, and 3'-oxomethylisoeugenol trigger a DNA damage response in the human colon carcinoma HT29 cell line. Most notably investigations by flow cytometry revealed that the metabolites induce an accumulation of HT29 cells in the G2 phase of the cell cycle...
August 14, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28818099/biosemantics-guided-gene-expression-profiling-of-sj%C3%A3-gren-s-syndrome-a-comparative-analysis-with-systemic-lupus-erythematosus-and-rheumatoid-arthritis
#2
Nirav R Shah, Braxton D Noll, Craig B Stevens, Michael T Brennan, Farah B Mougeot, Jean-Luc C Mougeot
BACKGROUND: Sjögren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These autoimmune diseases mostly affect women. In this study, concept profile analysis (CPA) and gene expression meta-analysis were used to identify genes potentially involved in SS pathogenesis. METHODS: Human genes associated with SS, SLE, and RA were identified using the CPA tool, Anni 2.1. The differential mRNA expression of genes common to SS and SLE (SS-SLE) was determined in female peripheral blood mononuclear cells (PBMCs) using NCBI-GEO2R...
August 17, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28814980/cooperative-effect-of-chidamide-and-chemotherapeutic-drugs-induce-apoptosis-by-dna-damage-accumulation-and-repair-defects-in-acute-myeloid-leukemia-stem-and-progenitor-cells
#3
Yin Li, Yan Wang, Yong Zhou, Jie Li, Kai Chen, Leisi Zhang, Manman Deng, Suqi Deng, Peng Li, Bing Xu
BACKGROUND: Many conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed. RESULTS: We report that a low-dose chidamide, a novel orally active benzamide-type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34(+)CD38(-) KG1α cells, CD34(+)CD38(-) Kasumi cells, and primary refractory or relapsed AML CD34(+) cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28813415/cdk4-6-inhibition-triggers-anti-tumour-immunity
#4
Shom Goel, Molly J DeCristo, April C Watt, Haley BrinJones, Jaclyn Sceneay, Ben B Li, Naveed Khan, Jessalyn M Ubellacker, Shaozhen Xie, Otto Metzger-Filho, Jeremy Hoog, Matthew J Ellis, Cynthia X Ma, Susanne Ramm, Ian E Krop, Eric P Winer, Thomas M Roberts, Hye-Jung Kim, Sandra S McAllister, Jean J Zhao
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28807995/regulation-of-the-cell-cycle-and-inflammatory-arthritis-by-the-transcription-cofactor-lbh-gene
#5
Shinji Matsuda, Deepa Hammaker, Katharyn Topolewski, Karoline J Briegel, David L Boyle, Steven Dowdy, Wei Wang, Gary S Firestein
Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined...
August 14, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28806116/systemic-therapy-for-stage-iv-non-small-cell-lung-cancer-american-society-of-clinical-oncology-clinical-practice-guideline-update
#6
Nasser Hanna, David Johnson, Sarah Temin, Sherman Baker, Julie Brahmer, Peter M Ellis, Giuseppe Giaccone, Paul J Hesketh, Ishmael Jaiyesimi, Natasha B Leighl, Gregory J Riely, Joan H Schiller, Bryan J Schneider, Thomas J Smith, Joan Tashbar, William A Biermann, Gregory Masters
Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development...
August 14, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28793172/tropomyosin-receptor-kinase-a-expression-on-merkel-cell-carcinoma-cells
#7
Ulrike Wehkamp, Sophie Stern, Sandra Krüger, Axel Hauschild, Christoph Röcken, Friederike Egberts
Importance: Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor frequently associated with the Merkel cell polyomavirus. Immune checkpoint therapy showed remarkable results, although not all patients are responsive to this therapy. Anti-tropomyosin receptor kinase A (TrkA)-targeted treatment has shown promising results in several tumor entities. Objective: To determine TrkA expression in MCC as a rationale for potential targeted therapy. Design, Setting, and Participants: This case series study investigated the MCC specimens of 55 patients treated at the Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany, from January 1, 2005, through December 31, 2015...
August 9, 2017: JAMA Dermatology
https://www.readbyqxmd.com/read/28791382/potential-role-of-zeb1-as-a-dna-repair-regulator-in-colorectal-cancer-cells-revealed-by-cancer-associated-promoter-profiling
#8
Miao Wang, Su-Fei He, Lei-Lei Liu, Xiao-Xia Sun, Fan Yang, Qian Ge, Wei-Kang Wong, Jing-Yan Meng
Besides being a key contributor to epithelial‑to‑mesenchymal transition (EMT) activation and stemness maintenance, zinc finger E-box binding homeobox 1 (ZEB1) is also a crucial inducer of chemoresistance and radioresistance. Unlike the clear mechanism that mediates its effect on EMT and dedifferentiation, the mechanism of how ZEB1 promotes chemo- and radio-resistance remains to be elucidated. It has been previously reported that ZEB1 promotes DNA double-strand break clearance by enhancing the deubiquitylating activity of ubiquitin-specific peptidase (USP)7 on checkpoint kinase 1, which is an important step during DNA repair...
August 8, 2017: Oncology Reports
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
#9
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/28767408/integration-of-genomic-transcriptomic-and-functional-profiles-of-aggressive-osteosarcomas-across-multiple-species
#10
Lara E Davis, Sophia Jeng, Matthew N Svalina, Elaine Huang, Janét Pittsenbarger, Emma L Cantor, Noah Berlow, Bernard Seguin, Atiya Mansoor, Shannon K McWeeney, Charles Keller
In complex, highly unstable genomes such as in osteosarcoma, targeting aberrant checkpoint processes (metabolic, cell cycle or immune) may prove more successful than targeting specific kinase or growth factor signaling pathways. Here, we establish a comparative oncology approach characterizing the most lethal osteosarcomas identified in a biorepository of tumors from three different species: human, mouse and canine. We describe the development of a genetically-engineered mouse model of osteosarcoma, establishment of primary cell cultures from fatal human tumors, and a biorepository of osteosarcoma surgical specimens from pet dogs...
July 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28763796/the-metabolic-regulator-mtorc1-controls-terminal-myeloid-differentiation
#11
Pui Y Lee, David B Sykes, Sarah Ameri, Demetrios Kalaitzidis, Julia F Charles, Nathan Nelson-Maney, Kevin Wei, Pierre Cunin, Allyn Morris, Astrid E Cardona, David E Root, David T Scadden, Peter A Nigrovic
Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage...
May 26, 2017: Science Immunology
https://www.readbyqxmd.com/read/28761748/new-treatment-options-for-metastatic-renal-cell-carcinoma
#12
REVIEW
Alejo Rodriguez-Vida, Thomas E Hutson, Joaquim Bellmunt, Michiel H Strijbos
During the last decade, the treatment of advanced or metastatic renal cell carcinoma (RCC) was revolutionised with the advent of antiangiogenic drugs and tyrosine-kinase inhibitors. Several agents targeting the vascular endothelial growth factor (VEGF) pathway (sunitinib, bevacizumab, pazopanib, axitinib) or the mammalian target of rapamycin pathway (temsirolimus, everolimus) were since then progressively approved for first-line or later-line use in the treatment of patients with advanced RCC and became the new standard of care...
2017: ESMO Open
https://www.readbyqxmd.com/read/28761743/checkpoint-inhibitors-in-the-treatment-of-urological-malignancies
#13
REVIEW
Lazar S Popovic, Gorana Matovina-Brko, Maja Popovic
Checkpoint inhibitors are monoclonal antibodies attach to several different receptors on T-cells or tumour cells expressing receptors for cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and their ligand (PD-L1). Since 2010, numerous trials on different tumour types have been conducted, which was resulted in these drugs being approved for the treatment of melanoma, lung cancer, Hodgkin's lymphoma and head and neck cancers. Urological cancers, especially urothelial and renal-cell carcinomas, are immunogenic tumours...
2017: ESMO Open
https://www.readbyqxmd.com/read/28759820/winning-the-battle-but-losing-the-war-mechanisms-and-morphology-of-cancer-therapy-associated-cardiovascular-toxicity
#14
REVIEW
Carolyn Kwak Glass, Richard N Mitchell
In the United States, the lifetime risk of a cancer diagnosis is nearly 40%; in 2016, that represents almost 1.6 million new patients, and despite advances in early diagnosis and treatment, roughly 35% will ultimately die of their malignancy. Fortunately, the number of patients living with a cancer diagnosis also continues to expand, anticipated to be more than 19 million in less than a decade. In calculating the relative risks and benefits of therapy, it is therefore important to consider the morbidity and mortality associated with antitumor therapy itself...
June 30, 2017: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
https://www.readbyqxmd.com/read/28759042/inhibition-of-the-spindle-assembly-checkpoint-kinase-mps-1-as-a-novel-therapeutic-strategy-in-malignant-mesothelioma
#15
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/28756137/survival-of-patients-with-advanced-metastatic-melanoma-the-impact-of-novel-therapies-update-2017
#16
REVIEW
Selma Ugurel, Joachim Röhmel, Paolo A Ascierto, Keith T Flaherty, Jean Jacques Grob, Axel Hauschild, James Larkin, Georgina V Long, Paul Lorigan, Grant A McArthur, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Claus Garbe
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma...
July 27, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28751929/the-preconditioning-of-berberine-suppresses-hydrogen-peroxide-induced-premature-senescence-via-regulation-of-sirtuin-1
#17
Xiaofei Zhu, Haodi Yue, Xiaofang Guo, Jingyi Yang, Jingshuo Liu, Jiangtao Liu, Ruijie Wang, Wenjuan Zhu
With a long history of application in Chinese traditional medicine, berberine (BBR) was reported to exhibit healthspan-extending properties in some age-related diseases, such as type 2 diabetes and atherosclerosis. However, the antiaging mechanism of BBR is not completely clear. By means of hydrogen peroxide- (H2O2-) induced premature cellular senescence model, we found that a low-concentration preconditioning of BBR could resist premature senescence in human diploid fibroblasts (HDFs) measured by senescence-associated β-galactosidase (SA-β-gal), accompanied by a decrease in loss of mitochondrial membrane potential and production of intracellular reactive oxygen species (ROS)...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28751540/ttk-inhibitors-as-a-targeted-therapy-for-ctnnb1-%C3%AE-catenin-mutant-cancers
#18
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/28745928/low-dose-decitabine-enhances-chidamide-induced-apoptosis-in-adult-acute-lymphoblast-leukemia-especially-for-p16-deleted-patients-through-dna-damage
#19
Pengcheng Shi, Leisi Zhang, Kai Chen, Zhiwu Jiang, Manman Deng, Jie Zha, Xutao Guo, Peng Li, Bing Xu
AIM: To investigate the combined action of decitabine (DAC) with chidamide (CS055) on acute lymphoblastic leukemia (ALL) cells. MATERIALS & METHODS: ALL cell lines as well as primary cells from 17 ALL patients were subjected to different treatments and thereafter cell counting Kit-8 (CCK-8) assay, flow cytometry and western blot were employed to determine IC50, apoptosis and checkpoint kinase 1 and γH2A.X expression. RESULTS: Low-dose DAC combined with CS055 could effectively kill ALL cells by the reduction of cell viability and induction of apoptosis...
July 26, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28745064/therapeutic-potential-of-investigational-chk-1-inhibitors-for-the-treatment-of-solid-tumors
#20
Hani M Babiker, Ali McBride, Laurence S Cooke, Daruka Mahadevan
For several decades' cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules. Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors...
July 30, 2017: Expert Opinion on Investigational Drugs
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