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https://www.readbyqxmd.com/read/29290973/human-oncoprotein-musashi-2-n-terminal-rna-recognition-motif-backbone-assignment-and-identification-of-rna-binding-pocket
#1
Lan Lan, Minli Xing, Justin T Douglas, Philip Gao, Robert P Hanzlik, Liang Xu
RNA-binding protein Musashi-2 (MSI2) is a key regulator in stem cells, it is over-expressed in a variety of cancers and its higher expression is associated with poor prognosis. Like Musashi-1, it contains two N-terminal RRMs (RNA-recognition Motifs, also called RBDs (RNA-binding Domains)), RRM1 and RRM2, which mediate the binding to their target mRNAs. Previous studies have obtained the three-dimensional structures of the RBDs of Musashi-1 and the RBD1:RNA complex. Here we show the binding of MSI2-RRM1 to a 15nt Numb RNA in Fluorescence Polarization assay and time resolved Fluorescence Resonance Energy Transfer assay...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29286153/chk1-inhibition-sensitizes-pancreatic-cancer-cells-to-gemcitabine-via-promoting-cdk-dependent-dna-damage-and-ribonucleotide-reductase-downregulation
#2
Min Liang, Tiangang Zhao, Linfeng Ma, Yingjie Guo
Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0...
December 20, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29279008/comparative-analysis-of-thermal-unfolding-simulations-of-rna-recognition-motifs-rrms-of-tar-dna-binding-protein-43-tdp-43
#3
Amresh Prakash, Vijay Kumar, Naveen Kumar Meena, Md Imtaiyaz Hassan, Andrew M Lynn
TAR DNA-binding protein 43 (TDP-43) inclusions have been found in Amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases. Many studies suggest the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy. To elucidate the structural stability and the unfolding dynamics of RRMs, we have carried out atomistic molecular dynamics simulations at two different temperatures (300 K and 500 K). The simulations results indicate that there are distinct structural differences in the unfolding pathway between the two domains and RRM1 unfolds faster than RRM2 in accordance with the lower thermal stability found experimentally...
December 26, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29214667/effect-of-ribonucleotide-reductase-m1-expression-on-overall-survival-in-patients-with-pancreatic-cancer-receiving-gemcitabine-chemotherapy-a-literature-based-meta-analysis
#4
REVIEW
Q L Han, Y H Zhou, Y Lyu, H Yan, G H Dai
WHAT IS KNOWN AND OBJECTIVE: The prognostic value of ribonucleotide reductase M1 (RRM1) in patients with pancreatic cancer receiving gemcitabine chemotherapy has been evaluated in several studies. However, the conclusions remain controversial. METHODS: By searching the PubMed and Embase databases, we conducted a meta-analysis to evaluate the prognostic significance of RRM1 expression in patients with pancreatic cancer receiving gemcitabine chemotherapy. Studies were pooled, and the hazard ratio (HR) and its corresponding 95% confidence interval (CI) were calculated...
December 6, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/29191829/st6gal-i-sialyltransferase-promotes-chemoresistance-in-pancreatic-ductal-adenocarcinoma-by-abrogating-gemcitabine-mediated-dna-damage
#5
Asmi Chakraborty, Kaitlyn A Dorsett, Hoa Q Trummell, Eddy S Yang, Patsy G Oliver, James A Bonner, Donald J Buchsbaum, Susan L Bellis
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Gemcitabine, as a single agent or in combination therapy, remains the frontline chemotherapy despite its limited efficacy due to de novo or acquired chemoresistance. There is an acute need to decipher mechanisms underlying chemoresistance and identify new targets to improve patient outcomes. Here we report a novel role for the ST6Gal-I sialyltransferase in gemcitabine resistance. Utilizing MiaPaCa-2 and BxPC-3 PDAC cells, we find that knockdown (KD) of ST6Gal-I expression, as well as removal of surface α2-6 sialic acids by neuraminidase, enhances gemcitabine-mediated cell death assessed via colonogenic assays and cleaved caspase 3 expression...
November 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29186204/mocetinostat-combined-with-gemcitabine-for-the-treatment-of-leiomyosarcoma-preclinical-correlates
#6
Gonzalo Lopez, Danielle Braggio, Abeba Zewdu, Lucia Casadei, Kara Batte, Hemant Kumar Bid, David Koller, Peter Yu, Obiajulu Hans Iwenofu, Anne Strohecker, Edwin Choy, Dina Lev, Raphael Pollock
Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of mocetinostat alone and in combination with gemcitabine in LMS. Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies...
2017: PloS One
https://www.readbyqxmd.com/read/29163710/combination-of-histoculture-drug-response-assay-and-qpcr-as-an-effective-method-to-screen-biomarkers-for-personalized-chemotherapy-in-esophageal-cancer
#7
Bin Wei, Jiru Wang, Xiaohui Zhang, Zhaoye Qian, Jingjing Wu, Yuan Sun, Qin Han, Li Wan, Jing Zhu, Yong Gao, Xiaofei Chen
Personalized chemotherapy with the use of biomarkers helps to maximize clinical efficiency. Therefore, the present study aimed to identify a potential method for identifying biomarkers in esophageal cancer. A total of 49 freshly resected tumor tissues and 72 paraffin-embedded specimens from patients with esophageal cancer were obtained. mRNA expression levels of ERCC1, BRCA1, TUBB3, FBW7, RRM1, MDM2, TS and TOP1 were measured quantitative reverse transcription polymerase chain reaction (RT-qPCR). In vitro chemosensitivity to cisplatin, docetaxel, gemcitabine, etoposide, fluorouracil and irinotecan were tested using histoculture drug response assay (HDRA)...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29158875/a-gene-module-based-eqtl-analysis-prioritizing-disease-genes-and-pathways-in-kidney-cancer
#8
Mary Qu Yang, Dan Li, William Yang, Yifan Zhang, Jun Liu, Weida Tong
Clear cell renal cell carcinoma (ccRCC) is the most common and most aggressive form of renal cell cancer (RCC). The incidence of RCC has increased steadily in recent years. The pathogenesis of renal cell cancer remains poorly understood. Many of the tumor suppressor genes, oncogenes, and dysregulated pathways in ccRCC need to be revealed for improvement of the overall clinical outlook of the disease. Here, we developed a systems biology approach to prioritize the somatic mutated genes that lead to dysregulation of pathways in ccRCC...
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/29152060/inhibition-of-chk1-sensitizes-ewing-sarcoma-cells-to-the-ribonucleotide-reductase-inhibitor-gemcitabine
#9
Kelli L Goss, Stacia L Koppenhafer, Kathryn M Harmoney, William W Terry, David J Gordon
Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29141648/polymorphisms-at-microrna-binding-sites-of-ara-c-and-anthracyclines-metabolic-pathway-genes-are-associated-with-outcome-of-acute-myeloid-leukemia-patients
#10
Hai-Xia Cao, Chao-Feng Miao, Liang Yan, Ping Tang, Li-Rong Zhang, Ling Sun
BACKGROUND: Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy. METHODS: A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system...
November 15, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29113399/dck-expression-a-potential-predictive-biomarker-in-the-adjuvant-gemcitabine-chemotherapy-for-biliary-tract-cancer-after-surgical-resection-results-from-a-phase-ii-study
#11
Sang Myung Woo, Kyong-Ah Yoon, Eun Kyung Hong, Weon Seo Park, Sung-Sik Han, Sang-Jae Park, Jungnam Joo, Eun Young Park, Ju Hee Lee, Yun-Hee Kim, Tae Hyun Kim, Woo Jin Lee
The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29098031/astaxanthin-inhibits-gemcitabine-resistant-human-pancreatic-cancer-progression-through-emt-inhibition-and-gemcitabine-resensitization
#12
Tao Yan, Hai-Ying Li, Jian-Song Wu, Qiang Niu, Wei-Hong Duan, Qing-Zeng Han, Wang-Ming Ji, Tao Zhang, Wei Lv
Pancreatic cancer rapidly acquires resistance to chemotherapy resulting in its being difficult to treat. Gemcitabine is the current clinical chemotherapy strategy; however, owing to gemcitabine resistance, it is only able to prolong the life of patients with pancreatic cancer for a limited number of months. Understanding the underlying molecular mechanisms of gemcitabine resistance and selecting a suitable combination of agents for the treatment of pancreatic cancer is required. Astaxanthin (ASX) is able to resensitize gemcitabine-resistant human pancreatic cancer cells (GR-HPCCs) to gemcitabine...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29092062/gemcitabine-based-chemotherapy-in-adrenocortical-carcinoma-a-multicenter-study-of-efficacy-and-predictive-factors
#13
Judith E K Henning, Timo Deutschbein, Barbara Altieri, Sonja Steinhauer, Stefan Kircher, Silviu Sbiera, Vanessa Wild, Wiebke Schlötelburg, Matthias Kroiss, Paola Perotti, Andreas Rosenwald, Alfredo Berruti, Martin Fassnacht, Cristina L Ronchi
Context: Adrenocortical carcinoma (ACC) is rare and confers an unfavorable prognosis in advanced stages. Other than combination chemotherapy with cisplatin, etoposide, doxorubicin, and mitotane, the second- and third-line regimens are not well-established. Gemcitabine (GEM)-based chemotherapy was suggested in a phase 2 clinical trial with 28 patients. In other solid tumors, human equilibrative nucleoside transporter type 1 (hENT1) and/or ribonucleotide reductase catalytic subunit M1 (RRM1) expression have been associated with resistance to GEM...
November 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29045512/gemcitabine-plus-sirolimus-for-relapsed-and-progressing-osteosarcoma-patients-after-standard-chemotherapy-a-multicenter-single-arm-phase-ii-trial-of-spanish-group-for-research-on-sarcoma-geis
#14
J Martin-Broto, A Redondo, C Valverde, M A Vaz, J Mora, X Garcia Del Muro, A Gutierrez, C Tous, A Carnero, D Marcilla, A Carranza, P Sancho, J Martinez-Trufero, R Diaz-Beveridge, J Cruz, V Encinas, M Taron, D S Moura, P Luna, N Hindi, A Lopez-Pousa
Background: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. FAS and mTOR pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. Patients and Methods: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma (GEIS)...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28949378/expression-of-ercc1-rrm1-tubb3-in-correlation-with-apoptosis-repressor-arc-dna-mismatch-repair-proteins-and-p53-in-liver-metastasis-of-colorectal-cancer
#15
Csaba Tóth, Farkas Sükösd, Erzsébet Valicsek, Esther Herpel, Peter Schirmacher, Marcus Renner, Christoph Mader, László Tiszlavicz, Jörg Kriegsmann
Liver metastasis in colorectal cancer is common and the primary treatment is chemotherapy. To date, there is no routinely used test in clinical practice to predict the effectiveness of conventional chemotherapy. Therefore, biomarkers with predictive value for conventional chemotherapy would be of considerable benefit in treatment planning. We analysed three proteins [excision repair cross-complementing 1 (ERCC1), ribonucleoside-diphosphate reductase 1 (RRM1) and class III β-tubulin (TUBB3)] in colorectal cancer liver metastasis...
September 14, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28934484/regulation-of-hur-structure-and-function-by-dihydrotanshinone-i
#16
Preet Lal, Linda Cerofolini, Vito Giuseppe D'Agostino, Chiara Zucal, Carmelo Fuccio, Isabelle Bonomo, Erik Dassi, Stefano Giuntini, Danilo Di Maio, Vikalp Vishwakarma, Ranjan Preet, Sha Neisha Williams, Max S Fairlamb, Rachel Munk, Elin Lehrmann, Kotb Abdelmohsen, Saioa R Elezgarai, Claudio Luchinat, Ettore Novellino, Alessandro Quattrone, Emiliano Biasini, Leonardo Manzoni, Myriam Gorospe, Dan A Dixon, Pierfausto Seneci, Luciana Marinelli, Marco Fragai, Alessandro Provenzani
The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28887583/mir-608-regulating-the-expression-of-ribonucleotide-reductase-m1-and-cytidine-deaminase-is-repressed-through-induced-gemcitabine-chemoresistance-in-pancreatic-cancer-cells
#17
Azam Rajabpour, Ali Afgar, Habibollah Mahmoodzadeh, Jalal-E-Din Radfar, Farzad Rajaei, Ladan Teimoori-Toolabi
PURPOSE: Gemcitabine resistance is the main problem in pancreatic adenocarcinoma patients. Hence, we aimed to identify the correlation between expression of RRM1 and CDA as the resistance genes and their predicted targeting miR-608 in the resistant pancreatic cancer cell lines to gemcitabine. METHODS: Dual luciferase assay was performed to determine whether both RRM1 and CDA are targeted by miR-608 in 293T and pancreatic cancer cell lines. AsPC-1 and MIA PaCa-2 cell lines became gradually resistant to gemcitabine by exposing to the increasing doses of gemcitabine...
October 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28878380/an-in-silico-approach-to-predict-and-exploit-synthetic-lethality-in-cancer-metabolism
#18
Iñigo Apaolaza, Edurne San José-Eneriz, Luis Tobalina, Estíbaliz Miranda, Leire Garate, Xabier Agirre, Felipe Prósper, Francisco J Planes
Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28791697/the-association-of-genetic-variations-in-dna-repair-pathways-with-severe-toxicities-in-nsclc-patients-undergoing-platinum-based-chemotherapy
#19
Yi Zheng, Zheng Deng, Jiye Yin, Shiming Wang, Daru Lu, Xiaoke Wen, Xiangping Li, Di Xiao, Chengping Hu, Xiang Chen, Wei Zhang, Honghao Zhou, Zhaoqian Liu
Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy...
December 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28753842/molecular-and-genomic-profiling-to-identify-actionable-targets-in-chromophobe-renal-cell-cancer
#20
Philip Abbosh, Srinath Sundararajan, Sherri Z Millis, Adam Hauben, Sandeep Reddy, Daniel M Geynisman, Robert Uzzo
Metastatic chromophobe renal cell cancer (chRCC) is a rare subtype of RCC with no standard treatment. We performed molecular profiling of 12 chRCC cases to identify alterations predictive of response to therapy. Tests included immunohistochemistry assays, fluorescence in situ hybridization, and next-generation sequencing. Analysis identified c-KIT overexpression in 6/9 (67%) samples analyzed, and loss of protein expression of RRM1 and MGMT in 11/12 (92%) and of PTEN in 7/12 samples (58%). Mutations of TP53, PTEN, APC, and VHL genes were identified...
January 23, 2017: European Urology Focus
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