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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/28105368/clinical-and-immunologic-correlates-of-response-to-pd-1-blockade-in-a-patient-with-metastatic-renal-medullary-carcinoma
#1
Kathryn E Beckermann, Pradeep C Jolly, Ju Y Kim, Jennifer Bordeaux, Igor Puzanov, W Kimryn Rathmell, Douglas B Johnson
BACKGROUND: Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in adolescent and young adults, typically in association with sickle cell trait. RMC exhibits rapid disease progression, frequent metastases at diagnosis, and dismal clinical outcomes. Currently available therapies, including cisplatin-based combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies demonstrate either transient responses or minimal activity. Therefore, further molecular characterization and additional treatment strategies are urgently needed in this aggressive disease...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28105216/identification-of-potential-therapeutic-targets-for-colorectal-cancer-by-bioinformatics-analysis
#2
Ming Yan, Maomin Song, Rixing Bai, Shi Cheng, Wenmao Yan
The aim of the present study was to identify potential therapeutic targets for colorectal cancer (CRC). The gene expression profile GSE32323, containing 34 samples, including 17 specimens of CRC tissues and 17 of paired normal tissues from CRC patients, was downloaded from the Gene Expression Omnibus database. Following data preprocessing using the Affy and preprocessCore packages, the differentially-expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28092672/bpgap1-spatially-integrates-jnk-erk-signaling-crosstalk-in-oncogenesis
#3
T Jiang, C Q Pan, B C Low
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#4
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#5
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28062704/radiosensitization-by-the-atr-inhibitor-azd6738-through-generation-of-acentric-micronuclei
#6
Magnus T Dillon, Holly E Barker, Malin Pedersen, Hind Hafsi, Shreerang A Bhide, Kate L Newbold, Christopher M Nutting, Martin McLaughlin, Kevin J Harrington
AZD6738 is an orally active ATR inhibitor (ATRi) currently in phase I clinical trials. We found in vitro growth inhibitory activity of this ATRi in a panel of human cancer cell lines. We demonstrated radiosensitization by AZD6738 to single radiation fractions in multiple cancer cell lines independent of both p53 and BRCA2 status by the clonogenic assay. Radiosensitization by AZD6738 to clinically relevant doses of fractionated radiation was demonstrated in vitro using a 3D tumor spheroid model and, in vivo, AZD6738 radiosensitized by abrogating the radiation-induced G2 cell-cycle checkpoint and inhibiting homologous recombination...
January 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28049532/checkpoint-kinase-inhibitor-azd7762-strongly-sensitises-urothelial-carcinoma-cells-to-gemcitabine
#7
Makoto Isono, Michèle J Hoffmann, Maria Pinkerneil, Akinori Sato, Martin Michaelis, Jindrich Cinatl, Günter Niegisch, Wolfgang A Schulz
BACKGROUND: More effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer. METHODS: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762...
January 3, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28042876/the-chk1-inhibitor-mk-8776-increases-the-radiosensitivity-of-human-triple-negative-breast-cancer-by-inhibiting-autophagy
#8
Zhi-Rui Zhou, Zhao-Zhi Yang, Shao-Jia Wang, Li Zhang, Ju-Rui Luo, Yan Feng, Xiao-Li Yu, Xing-Xing Chen, Xiao-Mao Guo
MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51...
January 2, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28031719/potential-role-of-immunotherapy-in-advanced-non-small-cell-lung-cancer
#9
REVIEW
Ramon Andrade de Mello, Ana Flávia Veloso, Paulo Esrom Catarina, Sara Nadine, Georgios Antoniou
Immuno checkpoint inhibitors have ushered in a new era with respect to the treatment of advanced non-small-cell lung cancer. Many patients are not suitable for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (eg, gefitinib, erlotinib, and afatinib) or with anaplastic lymphoma kinase inhibitors (eg, crizotinib and ceritinib). As a result, anti-PD-1/PD-L1 and CTLA-4 inhibitors may play a novel role in the improvement of outcomes in a metastatic setting. The regulation of immune surveillance, immunoediting, and immunoescape mechanisms may play an interesting role in this regard either alone or in combination with current drugs...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28031537/activation-of-atr-chk1-pathway-facilitates-ebv-mediated-transformation-of-primary-tonsillar-b-cells
#10
Vanessa Mordasini, Seigo Ueda, Roberta Aslandogmus, Christoph Berger, Claudine Gysin, Daniela Hühn, Alessandro A Sartori, Michele Bernasconi, David Nadal
Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection...
December 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/28030830/ikaros-regulation-of-the-bcl6-bach2-axis-and-its-clinical-relevance-in-acute-lymphoblastic-leukemia
#11
Zheng Ge, Xilian Zhou, Yan Gu, Qi Han, Jianyong Li, Baoan Chen, Qinyu Ge, Elanora Dovat, Jonathon L Payne, Tianyu Sun, Chunhua Song, Sinisa Dovat
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/28030784/dutch-melanoma-treatment-registry-quality-assurance-in-the-care-of-patients-with-metastatic-melanoma-in-the-netherlands
#12
Anouk Jochems, Maartje G Schouwenburg, Brenda Leeneman, Margreet G Franken, Alfons J M van den Eertwegh, John B A G Haanen, Hans Gelderblom, Carin A Uyl-de Groot, Maureen J B Aarts, Franchette W P J van den Berkmortel, Willeke A M Blokx, Mathilde C Cardous-Ubbink, Gerard Groenewegen, Jan Willem B de Groot, Geke A P Hospers, Ellen Kapiteijn, Rutger H Koornstra, Wim H Kruit, Marieke W Louwman, Djura Piersma, Rozemarijn S van Rijn, Albert J Ten Tije, Gerard Vreugdenhil, Michel W J M Wouters, Jacobus J M van der Hoeven
BACKGROUND: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. METHODS: The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma...
December 25, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/28025997/a-novel-chk1-binding-peptide-that-enhances-genotoxic-sensitivity-through-the-cellular-redistribution-of-nuclear-chk1
#13
Kwang Seok Kim, Kyu Jin Choi, Sangwoo Bae
Since checkpoint kinase 1 (Chk1) is an essential factor for cell viability following DNA damage, the inhibition of Chk1 has been a major focus of pharmaceutical development to enhance the sensitivity of tumor cells to chemo- and radiotherapy that damage DNA. However, due to the off-target effects of conventional Chk1-targeting strategies and the toxicity of Chk1 inhibitors, alternative strategies are required to target Chk1. To facilitate such efforts, in this study, we identified a specific Chk1-binding 12-mer peptide from the screening of a phage display library and characterized the peptide in terms of cellular cytotoxicity, and in terms of its effect on Chk1 activity and sensitivity to genotoxic agents...
November 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28025497/mechanisms-governing-ddk-regulation-of-the-initiation-of-dna-replication
#14
REVIEW
Larasati, Bernard P Duncker
The budding yeast Dbf4-dependent kinase (DDK) complex-comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)-is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites...
December 22, 2016: Genes
https://www.readbyqxmd.com/read/28018344/adjunct-strategies-for-tuberculosis-vaccines-modulating-key-immune-cell-regulatory-mechanisms-to-potentiate-vaccination
#15
REVIEW
Lakshmi Jayashankar, Richard Hafner
Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette-Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/28017606/generation-of-a-spindle-checkpoint-arrest-from-synthetic-signaling-assemblies
#16
Ivan Yuan, Ioanna Leontiou, Priya Amin, Karen M May, Sadhbh Soper Ní Chafraidh, Eliška Zlámalová, Kevin G Hardwick
The spindle checkpoint acts as a mitotic surveillance system, monitoring interactions between kinetochores and spindle microtubules and ensuring high-fidelity chromosome segregation [1-3]. The checkpoint is activated by unattached kinetochores, and Mps1 kinase phosphorylates KNL1 on conserved MELT motifs to generate a binding site for the Bub3-Bub1 complex [4-7]. This leads to dynamic kinetochore recruitment of Mad proteins [8, 9], a conformational change in Mad2 [10-12], and formation of the mitotic checkpoint complex (MCC: Cdc20-Mad3-Mad2 [13-15])...
January 9, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/27996348/involvement-of-the-activation-of-nrf2-ho-1-p38-mapk-signaling-pathways-and-endoplasmic-reticulum-stress-in-furazolidone-induced-cytotoxicity-and-s-phase-arrest-in-human-hepatocyte-l02-cells-modulation-of-curcumin
#17
Chongshan Dai, Lei Lei, Bin Li, Yang Lin, Xilong Xiao, Shusheng Tang
Furazolidone (FZD) is extensively used as the antiprotozoal and antibacterial drug in clinic. The previous study has shown that curcumin pretreatment could improve FZD induced cytotoxicity by inhibiting oxidative stress and mitochondrial apoptotic pathway. The current study aimed to investigate the potential roles of endoplasmic reticulum (ER) stress, p38 mitogen-activated protein kinases (p38 MAPK) signaling pathway in curcumin against FZD cytotoxicity by using human hepatocyte L02 cells. The results showed that curcumin could markedly attenuate FZD induced cytotoxicity...
December 20, 2016: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/27979966/insulin-like-growth-factor-1-receptor-signaling-is-required-for-optimal-atr-chk1-kinase-signaling-in-uvb-irradiated-human-keratinocytes
#18
Michael G Kemp, Dan F Spandau, Richard Simman, Jeffrey B Travers
Ultraviolet B (UVB) wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB-irradiated cells also activate a checkpoint signaling cascade mediated by the ATR (ataxia telangiectasia-mutated and rad3-related) and CHK1 (checkpoint kinase 1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor-1 receptor (IGF-1) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation...
December 15, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27974384/brca-testing-by-single-molecule-molecular-inversion-probes
#19
Kornelia Neveling, Arjen R Mensenkamp, Ronny Derks, Michael Kwint, Hicham Ouchene, Marloes Steehouwer, Bart van Lier, Ermanno Bosgoed, Alwin Rikken, Marloes Tychon, Dimitra Zafeiropoulou, Steven Castelein, Jayne Hehir-Kwa, Djie Tjwan Thung, Tom Hofste, Stefan H Lelieveld, Stijn M M Bertens, Ivo B J F Adan, Astrid Eijkelenboom, Bastiaan B Tops, Helger Yntema, Tomasz Stokowy, Per M Knappskog, Hildegunn Høberg-Vetti, Vidar M Steen, Evan Boyle, Beth Martin, Marjolijn J L Ligtenberg, Jay Shendure, Marcel R Nelen, Alexander Hoischen
BACKGROUND: Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements in terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential in the area of clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested single gene tests, those for breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2), and developed an automated work flow based on smMIPs...
December 14, 2016: Clinical Chemistry
https://www.readbyqxmd.com/read/27964702/minichromosome-maintenance-complex-is-required-for-checkpoint-kinase-2-chromatin-loading-and-its-phosphorylation-to-dna-damage-response-in-scc-4-cells
#20
Zhenglin Gong, Yi Feng, Bo Yu, Ruizhi Zhang, Ping Zhang, Menglong Cao, Haoliang Liu, Tiantian Yang, Rui Luo
Checkpoint kinase 2 (Chk2) is a significant mediator of diverse responses to DNA damage. The present study was aimed to identify possible interactive proteins of Chk2 and try to clarify the underlying mechanism regarding Chk2 chromatin loading and its phosphorylation to DNA damage response in oral squamous cell carcinoma (OSCC). Differently tagged Chk2 and minichromosome maintenance (MCM) complex (MCM2, MCM3, MCM5, and MCM6) were overexpressed into SCC-4 cells. After 48 h of transfection cell fractionation was performed to localize proteins...
December 12, 2016: Protein and Peptide Letters
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