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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/29669169/genetic-testing-for-hereditary-prostate-cancer-current-status-and-limitations
#1
REVIEW
Jun Tu Zhen, Jamil Syed, Kevin Anh Nguyen, Michael S Leapman, Neeraj Agarwal, Karina Brierley, Xavier Llor, Erin Hofstatter, Brian Shuch
A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM)...
April 18, 2018: Cancer
https://www.readbyqxmd.com/read/29658881/negative-regulation-of-g2-m-by-atr-mei-41-chk1-grapes-facilitates-tracheoblast-growth-and-tracheal-hypertrophy-in-drosophila
#2
Amrutha Kizhedathu, Archit V Bagul, Arjun Guha
Imaginal progenitors in Drosophila are known to arrest in G2 during larval stages and proliferate thereafter. Here we investigate the mechanism and implications of G2 arrest in progenitors of the adult thoracic tracheal epithelium (tracheoblasts). We report that tracheoblasts pause in G2 for ~48-56 h and grow in size over this period. Surprisingly, tracheoblasts arrested in G2 express drivers of G2-M like Cdc25/String (Stg). We find that mechanisms that prevent G2-M are also in place in this interval. Tracheoblasts activate Checkpoint Kinase 1/Grapes (Chk1/Grp) in an ATR/mei-41-dependent manner...
April 16, 2018: ELife
https://www.readbyqxmd.com/read/29656007/mir-195-potentiates-the-efficacy-of-microtubule-targeting-agents-in-non-small-cell-lung-cancer
#3
Xiaojie Yu, Yiqiang Zhang, Xiuye Ma, Alexander Pertsemlidis
Microtubule-targeting agents (MTAs) are widely used for the treatment of non-small cell lung cancer (NSCLC). The response rate is only ∼25%, mainly attributable to drug resistance. To identify determinants of resistance in NSCLC, we performed a high-throughput screen using a library of miRNA mimics. Here we report that miR-195 synergizes with MTAs to inhibit the growth of NSCLC cells in vitro, that increased expression of miR-195 sensitizes NSCLC cells to MTAs and that repression of miR-195 confers resistance to MTAs...
April 13, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29650809/-molecular-targeted-therapies-for-hereditary-cancer-syndrome
#4
Hideki Shimodaira
Development of molecular targeted drugs has achieved remarkable improvement of systemic cancer therapy. Recently, the several molecular targeted drugs have become available which associated with the status of responsible genes for hereditary cancer syndrome. These drugs would allow to establish specific strategy for hereditary cancer syndrome or sporadic cancers with similar biological phenotype with hereditary cancer. Genetic tests for the diagnosis of hereditary cancer syndrome will have the meaning of biomarker for predicting the efficacy of these molecular targeted drugs...
April 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/29643855/targeting-sphingosine-kinase-isoforms-effectively-reduces-growth-and-survival-of-neoplastic-mast-cells-with-d816v-kit
#5
Geethani Bandara, Rosa Muñoz-Cano, Araceli Tobío, Yuzhi Yin, Hirsh D Komarow, Avanti Desai, Dean D Metcalfe, Ana Olivera
Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29643063/evaluation-of-prexasertib-a-checkpoint-kinase-1-inhibitor-in-a-phase-ib-study-of-patients-with-squamous-cell-carcinoma
#6
David S Hong, Kathleen N Moore, Manish R Patel, Stefan C Grant, Howard A Burris, William N William, Suzanne Jones, Funda Meric-Bernstam, Jeffrey Infante, Lisa Golden, Wei Zhang, Ricardo Martinez, Sameera R Wijayawardana, Richard P Beckmann, Aimee Bence Lin, Cathy Eng, Johanna C Bendell
PURPOSE: Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a Phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. EXPERIMENTAL DESIGN: Patients were given prexasertib 105 mg/m2 as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed...
April 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29621769/checkpoint-kinase-1-is-overexpressed-during-hpv16-induced-cervical-carcinogenesis
#7
Wei Lin, Suxiu Chen
PURPOSE: Cervical cancer is one of the leading causes of cancer death among women worldwide. Checkpoint kinase 1 (Chk1) has a critical role in DNA damage response and cell cycle checkpoint control. Emerging evidence suggests that Chk1 promotes tumor growth. However, whether Chk1 is important for development of cervical cancer is largely unknown. METHODS: The levels of Chk1 mRNA expression were determined using quantitative real-time polymerase chain reaction in a panel of 90 cervical specimens, including 30 cervical cancer tissues, 30 CIN II-III, and 30 normal cervical tissues...
April 5, 2018: Gynecologic and Obstetric Investigation
https://www.readbyqxmd.com/read/29618387/deregulation-of-the-spindle-assembly-checkpoint-is-associated-with-paclitaxel-resistance-in-ovarian-cancer
#8
Taryne Chong, Amila Sarac, Cindy Q Yao, Linda Liao, Nicola Lyttle, Paul C Boutros, John M S Bartlett, Melanie Spears
BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients. RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays...
April 4, 2018: Journal of Ovarian Research
https://www.readbyqxmd.com/read/29616094/suv4-20h1-promotes-g1-to-s-phase-transition-by-downregulating-p21-waf1-cip1-expression-in-chronic-myeloid-leukemia-k562-cells
#9
Yupeng Wu, Yadong Wang, Ming Liu, Min Nie, Ying Wang, Yexuan Deng, Bing Yao, Tao Gui, Xinyu Li, Lingling Ma, Chan Guo, Chi Ma, Junyi Ju, Quan Zhao
Methylation of histone H4 lysine 20 (H4K20) has been associated with cancer. However, the functions of the histone methyltransferases that trigger histone H4K20 methylation in cancers, including suppressor of variegation 4-20 homolog 1 (Suv4-20h1), remain elusive. In the present study, it was demonstrated that the knockdown of the histone H4K20 methyltransferase Suv4-20h1 resulted in growth inhibition in chronic myeloid leukemia K562 cells. Disruption of Suv4-20h1 expression induced G1 arrest in the cell cycle and increased expression levels of cyclin dependent kinase inhibitor 1A (p21WAF1/CIP1 ), an essential cell cycle protein involved in checkpoint regulation...
May 2018: Oncology Letters
https://www.readbyqxmd.com/read/29563914/exhaustion-of-the-cd8-t-cell-compartment-in-patients-with-mutations-in-phosphoinositide-3-kinase-delta
#10
Marjolein W J Wentink, Yvonne M Mueller, Virgil A S H Dalm, Gertjan J Driessen, P Martin van Hagen, Joris M van Montfrans, Mirjam van der Burg, Peter D Katsikis
Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29545095/durvalumab-as-third-line-or-later-treatment-for-advanced-non-small-cell-lung-cancer-atlantic-an-open-label-single-arm-phase-2-study
#11
Marina Chiara Garassino, Byoung-Chul Cho, Joo-Hang Kim, Julien Mazières, Johan Vansteenkiste, Hervé Lena, Jesus Corral Jaime, Jhanelle E Gray, John Powderly, Christos Chouaid, Paolo Bidoli, Paul Wheatley-Price, Keunchil Park, Ross A Soo, Yifan Huang, Catherine Wadsworth, Phillip A Dennis, Naiyer A Rizvi
BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1...
March 12, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29531161/activation-of-the-receptor-tyrosine-kinase-axl-regulates-the-immune-microenvironment-in-glioblastoma
#12
Hirokazu Sadahiro, Kyung-Don Kang, Justin T Gibson, Mutsuko Minata, Hai Yu, Junfeng Shi, Rishi Raj Chhipa, Zhihong Chen, Songjia Lu, Yannick Simoni, Takuya Furuta, Hemragul Sabit, Suojun Zhang, Soniya Bastola, Shinobu Yamaguchi, Heba Allah Alsheikh, Svetlana Komarova, Jun Wang, Sung-Hak Kim, Dolores Hambardzumyan, Xinghua Lu, Evan W Newell, Biplab Dasgupta, Mitsutoshi Nakada, Ly James Lee, Louis B Nabors, Lyse A Norian, Ichiro Nakano
Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC...
March 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29527128/crosstalk-between-vegfr-and-other-receptor-tyrosine-kinases-for-tki-therapy-of-metastatic-renal-cell-carcinoma
#13
REVIEW
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29522917/dna-damage-response-following-x-irradiation-in-oral-cancer-cell-lines-hsc3-and-hsc4
#14
Sirimanas Jiaranuchart, Atsushi Kaida, Yusuke Onozato, Hiroyuki Harada, Masahiko Miura
OBJECTIVE: The objective of this study was to characterize the DNA damage response in two human oral cancer cell lines following X-irradiation. DESIGN: To visualize radiation-induced cell cycle alterations, two human oral cancer cell lines, HSC3 and HSC4, expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were established in this study. G2 arrest kinetics following irradiation were obtained from two-color flow cytometric analysis and pedigrees of Fucci fluorescence...
March 6, 2018: Archives of Oral Biology
https://www.readbyqxmd.com/read/29512742/mangiferin-induces-islet-regeneration-in-aged-mice-through-regulating-p16ink4a
#15
Hailian Wang, Xia He, Tiantian Lei, Yilong Liu, Guoli Huai, Minghan Sun, Shaoping Deng, Hongji Yang, Rongsheng Tong, Yi Wang
Previous studies by our group on mangiferin demonstrated that it exerts an anti‑hyperglycemic effect through the regulation of cell cycle proteins in 3‑month‑old, partially pancreatectomized (PPx) mice. However, β‑cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain β‑cell regeneration capability in aged mice. In the present study, 12‑month‑old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days...
March 1, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29507695/inhibiting-checkpoint-kinase-1-protects-bone-from-bone-resorption-by-mammary-tumor-in-a-mouse-model
#16
Shengzhi Liu, Yang Liu, Kazumasa Minami, Andy Chen, Qiaoqiao Wan, Yukun Yin, Liangying Gan, Aihua Xu, Nariaki Matsuura, Masahiko Koizumi, Yunlong Liu, Sungsoo Na, Jiliang Li, Harikrishna Nakshatri, Bai-Yan Li, Hiroki Yokota
DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29502948/mps1-phosphorylates-its-n-terminal-extension-to-relieve-autoinhibition-and-activate-the-spindle-assembly-checkpoint
#17
Guillaume Combes, Helena Barysz, Chantal Garand, Luciano Gama Braga, Ibrahim Alharbi, Philippe Thebault, Luc Murakami, Dominic P Bryne, Stasa Stankovic, Patrick A Eyers, Victor M Bolanos-Garcia, William C Earnshaw, John Maciejowski, Prasad V Jallepalli, Sabine Elowe
Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC...
February 20, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29490989/a-genetic-polymorphism-in-ctla-4-is-associated-with-overall-survival-in-sunitinib-treated-patients-with-clear-cell-metastatic-renal-cell-carcinoma
#18
Xiaoyan Liu, Jesse J Swen, Meta H M Diekstra, Epie Boven, Daniel Castellano, Hans Gelderblom, Ron Hj Mathijssen, Sita H Vermeulen, Egbert Oosterwijk, Kerstin Junker, Max Roessler, Kristin Alexiusdottir, Asgerdur Sverrisdottir, Marius T Radu, Valentin Ambert, Timothy Eisen, Anne Y Warren, Cristina Rodríguez-Antona, Jesus García-Donás, Karel K M Koudijs, Stefan Böhringer, Lambertus A Kiemeney, Brian Rini, Henk-Jan Guchelaar
PURPOSE: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKIs). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. EXPERIMENTAL DESIGN: 27 single nucleotide polymorphisms (SNPs) in CD274 (PD-L1) , PDCD1 (PD-1) and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients...
February 28, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29487979/the-multi-receptor-inhibitor-axitinib-reverses-tumor-induced-immunosuppression-and-potentiates-treatment-with-immune-modulatory-antibodies-in-preclinical-murine-models
#19
Heinz Läubli, Philipp Müller, Lucia D'Amico, Mélanie Buchi, Abhishek S Kashyap, Alfred Zippelius
Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies...
February 27, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29484112/evidence-that-pp2a-activity-is-dispensable-for-spindle-assembly-checkpoint-dependent-control-of-cdk1
#20
Nando Cervone, Rosa Della Monica, Angela Flavia Serpico, Cinzia Vetrei, Mario Scaraglio, Roberta Visconti, Domenico Grieco
Progression through mitosis, the cell cycle phase deputed to segregate replicated chromosomes, is granted by a protein phosphorylation wave that follows an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1, the major mitosis-promoting enzyme. To ensure correct chromosome segregation, the safeguard mechanism spindle assembly checkpoint (SAC) delays Cdk1 inactivation by preventing cyclin B degradation until mitotic spindle assembly. At the end of mitosis, reversal of bulk mitotic protein phosphorylation, downstream Cdk1 inactivation, is required to complete mitosis and crucially relies on the activity of major protein phosphatases like PP2A...
January 26, 2018: Oncotarget
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