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Checkpoint kinase 1

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https://www.readbyqxmd.com/read/28330872/nadph-oxidase-1-supports-proliferation-of-colon-cancer-cells-by-modulating-reactive-oxygen-species-dependent-signal-transduction
#1
Agnes Juhasz, Susan Markel, Shikha Gaur, Han Liu, Jiamo Lu, Guojian Jiang, Xiwei Wu, Smitha Antony, Yongzhong Wu, Giovanni Melillo, Jennifer L Meitzler, Diana C Haines, Donna Butcher, Krishnendu Roy, James H Doroshow
Reactive oxygen species (ROS) play a critical role in cell signaling and proliferation. NADPH oxidase 1 (NOX1), a membrane-bound flavin dehydrogenase that generates superoxide, is highly expressed in colon cancer. To investigate the role that NOX1 plays in colon cancer growth, we used shRNA to decrease NOX1 expression stably in HT-29 human colon cancer cells. The 80-90% decrease in NOX1 expression achieved by RNAi produced a significant decline in ROS production and a G1/S block that translated into a 2-3-fold increase in tumor cell doubling time without increased apoptosis...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28315636/pembrolizumab-for-metastatic-melanoma-in-a-renal-allograft-recipient-with-subsequent-graft-rejection-and-treatment-response-failure-a-case-report
#2
Vineet Kwatra, Narayan V Karanth, Kelum Priyadarshana, Michail Charakidis
BACKGROUND: Transplant patients were excluded from the pivotal phase III trials of checkpoint inhibitors in metastatic melanoma. The efficacy and toxicity profiles of checkpoint inhibitors in this cohort of patients are not well described. To the best of our knowledge, this is the first case report of a renal transplant patient with stage IV melanoma treated with a programmed cell death protein 1 checkpoint inhibitor that led to both treatment failure and renal graft rejection. CASE PRESENTATION: We present a case of a 58-year-old white man with a long-standing cadaveric renal transplant who was diagnosed with a B-Raf Proto-Oncogene, Serine/Threonine Kinase wild-type metastatic melanoma...
March 19, 2017: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/28303169/diallyl-trisulfide-suppresses-oxidative-stress-induced-activation-of-hepatic-stellate-cells-through-production-of-hydrogen-sulfide
#3
Feng Zhang, Huanhuan Jin, Li Wu, Jiangjuan Shao, Xiaojing Zhu, Anping Chen, Shizhong Zheng
Accumulating data reveal that garlic has beneficial effects against chronic liver disease. We previously reported that diallyl trisulfide (DATS), the primary organosulfur compound in garlic, reduced fibrosis and attenuated oxidative stress in rat fibrotic liver. The present study was aimed at elucidating the underlying mechanisms. The primary rat hepatic stellate cells (HSCs) were cultured and stimulated with hydrogen peroxide (H2O2) for inducing HSC activation under oxidative stress. We examined the effects of DATS on the profibrogenic properties and oxidative stress in H2O2-treated HSCs...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28301259/novel-treatment-of-melanoma-combined-parasite-derived-peptide-gk-1-and-anti-programmed-death-ligand-1-therapy
#4
Jesus Vera-Aguilera, Armando Perez-Torres, Diego Beltran, Cynthia Villanueva-Ramos, Mitchell Wachtel, Eduardo Moreno-Aguilera, Carlos Vera-Aguilera, Gary Ventolini, Raul Martínez-Zaguilán, Souad R Sennoune
Recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase pathway inhibitors, anticytotoxic T lymphocyte-associated antigen-4, and programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) pathway-blocking antibodies, as well as combination strategies, all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with melanoma. One promising new treatment modality is based on the use of immunomodulatory monoclonal antibodies that enhance the function of components of the antitumor immune response such as T cells or block immunologic checkpoints that restrain effective antitumor immunity...
March 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-a-growth-of-hepatocellular-carcinoma-cells-via-accumulated-chromosomal-instability
#5
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer, but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
March 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28293123/pembrolizumab-in-the-treatment-of-metastatic-non-small-cell-lung-cancer-patient-selection-and-perspectives
#6
REVIEW
Ashwin Somasundaram, Timothy F Burns
Lung cancer is the leading killer of both men and women in the US, and the 5-year survival remains poor. However, the approval of checkpoint blockade immunotherapy has shifted the treatment paradigm and provides hope for improved survival. The ability of non-small-cell lung cancer (NSCLC) to evade the host immune system can be overcome by agents such as pembrolizumab (MK-3475/lambrolizumab), which is a monoclonal antibody targeting the programmed death 1 (PD-1) receptor. In early studies, treatment with pembrolizumab led to dramatic and durable responses in select patients (PD-L1+ tumors)...
2017: Lung Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28289089/molecular-pathways-oncologic-pathways-and-their-role-in-t-cell-exclusion-and-immune-evasion-a-new-role-for-the-axl-receptor-tyrosine-kinase
#7
Todd A Aguilera, Amato J Giaccia
With the clinical impact of CTLA-4 and PD-1/PD-L1 immune checkpoint therapies, widespread interest in cancer immunotherapy has been ignited. However, the rate and extent of clinical responses to approved therapies are limited and often non-existent in many solid tumors. This is partially because immune checkpoint therapies are most effective against T-cell inflamed tumors, and non-T-cell inflamed or T-cell excluded tumors remain a significant barrier. New strategies are needed to overcome immune resistance mechanisms that arise during tumor development which result in T-cell exclusion...
March 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28287848/immunomodulating-and-immunoresistance-properties-of-cancer-initiating-cells-implications-for-the-clinical-success-of-immunotherapy
#8
Cristina Maccalli, Giorgio Parmiani, Soldano Ferrone
Cancer-initiating cells (CICs) represent a relatively rare subpopulation of cells endowed with self-renewal, stemness properties, tumorigenicity in immunodeficient mice, and resistance to standard therapies as well as to immunotherapy. Here, we review the biological and immunological characteristics of CICs with special focus on the immunomodulating mechanisms they utilize to escape from immunosurveillance. The recently developed immunotherapeutic strategies have yielded remarkable clinical results in many types of tumors, indicating that indeed a patient's immune system can mount an immune response, which is effective in controlling tumor growth...
March 13, 2017: Immunological Investigations
https://www.readbyqxmd.com/read/28276898/association-of-ribosomal-protein-s6-kinase-1-with-cellular-radiosensitivity-of-non-small-lung-cancer
#9
Ye Wang, Hong Mei, Qiang Shao, Jian Wang, Zhenyu Lin
PURPOSE: Ribosomal S6 kinase 1 (S6K1) plays an important role in cell proliferation, protein translation and cell survival. This study investigated the possibility of using S6K1 as a new target in the radiotherapy of non-small cell lung cancer (NSCLC) and its potential mechanism. MATERIALS AND METHODS: shRNA interference technology was applied to silence the expression of S6K1 in A549 and H460, and clonogenic assay was performed to measure the radiosensitizing effects...
March 2, 2017: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/28275910/mechanisms-of-drug-resistance-in-melanoma
#10
Matthew Winder, Amaya Virós
Metastatic melanoma is associated with poor outcome and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand1(PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28270606/functional-characterization-of-cfi-402257-a-potent-and-selective-mps1-ttk-kinase-inhibitor-for-the-treatment-of-cancer
#11
Jacqueline M Mason, Xin Wei, Graham C Fletcher, Reza Kiarash, Richard Brokx, Richard Hodgson, Irina Beletskaya, Mark R Bray, Tak W Mak
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28270495/the-checkpoint-kinase-1-inhibitor-prexasertib-induces-regression-of-preclinical-models-of-human-neuroblastoma
#12
Caitlin D Lowery, Alle B VanWye, Michele Dowless, Wayne Blosser, Beverly L Falcon, Julie Stewart, Jennifer Stephens, Richard P Beckmann, Aimee Bence Lin, Louis F Stancato
PURPOSE: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2/M cell cycle checkpoints. We evaluated prexasertib (LY2606368), a small molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on preclinical models of neuroblastoma...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28259529/novel-pyrrolopyrimidines-as-mps1-ttk-kinase-inhibitors-for-breast-cancer
#13
Yasuro Sugimoto, Dwitiya B Sawant, Harold A Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V Darby, Robert W Brueggemeier
New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions...
February 16, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28253714/microarray-expression-analysis-of-mycn-amplified-neuroblastoma-cells-after-inhibition-of-cdk2
#14
H Song, F Wu, S Li, Z Wang, X Liu, Y Cui, C Lin
The study was aimed to explore the underlying molecular mechanisms of CDK2 inhibition in neuroblastoma by bioinformatics analysis. Gene expression profile GSE16480 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were identified from IMR32 between each time point and average expression of all time points. Gene significance was calculated using dSVDsig algorithm of dnet package. Protein-protein interaction (PPI) network was built. Then, integrated with gene significance, a core PPI network was detected by dNetPipeline algorithm in dnet package...
March 3, 2017: Neoplasma
https://www.readbyqxmd.com/read/28236980/significance-of-immune-checkpoint-proteins-in-egfr-mutant-non-small-cell-lung-cancer
#15
Ross A Soo, Hye Ryun Kim, Bernadette Reyna Asuncion, Zul Fazreen, Mohamed Feroz Mohd Omar, Maria Cynthia Herrera, Joey Sze Yun Lim, Grace Sia, Richie Soong, Byoung-Chul Cho
OBJECTIVES: To characterize the expression of PD-L1, PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Samples from 90 patients with newly diagnosed advanced stage NSCLC harboring EGFR mutations and treated with first line EGFR tyrosine kinase inhibitors (TKI) within 3 months of diagnosis were stained for CTLA-4, PD-L1, PD-1, TIM-3 and CD3 expression by immunohistochemistry...
March 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28229253/the-biology-of-uveal-melanoma
#16
Adriana Amaro, Rosaria Gangemi, Francesca Piaggio, Giovanna Angelini, Gaia Barisione, Silvano Ferrini, Ulrich Pfeffer
Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11...
February 22, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28224235/oral-mucosal-changes-induced-by-anticancer-targeted-therapies-and-immune-checkpoint-inhibitors
#17
REVIEW
Emmanuelle Vigarios, Joel B Epstein, Vincent Sibaud
Development of biological targeted therapies and immune checkpoint inhibitors has redefined the treatment for many cancers; however, the increasing use of new protocols has led to physicians observing a new spectrum of toxicities. To date, oral adverse events induced by these new anticancer therapies have been mainly reported using nonspecific terminology ("stomatitis," "mucosal inflammation," "mucositis") and remain poorly characterized, with the exception of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis...
February 22, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28202004/a-phase-ii-study-to-evaluate-ly2603618-in-combination-with-gemcitabine-in-pancreatic-cancer-patients
#18
Berta Laquente, Jose Lopez-Martin, Donald Richards, Gerald Illerhaus, David Z Chang, George Kim, Philip Stella, Dirk Richel, Cezary Szcylik, Stefano Cascinu, G L Frassineti, Tudor Ciuleanu, Karla Hurt, Scott Hynes, Ji Lin, Aimee Bence Lin, Daniel Von Hoff, Emiliano Calvo
BACKGROUND: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer. METHODS: Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m(2) gemcitabine combined or 1000 mg/m(2) gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference...
February 15, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28197389/adaptive-resistance-to-anti-pd1-therapy-by-tim-3-upregulation-is-mediated-by-the-pi3k-akt-pathway-in-head-and-neck-cancer
#19
Gulidanna Shayan, Raghvendra Srivastava, Jing Li, Nicole Schmitt, Lawrence P Kane, Robert L Ferris
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28188673/socs-potential-immune-checkpoint-molecules-for-cancer-immunotherapy
#20
REVIEW
Shunsuke Chikuma, Mitsuhiro Kanamori, Setsuko Mise-Omata, Akihiko Yoshimura
Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals, respectively. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine Interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway...
February 11, 2017: Cancer Science
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