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https://www.readbyqxmd.com/read/28521448/clinical-implications-of-ribonucleotide-reductase-subunit-m1-in-patients-with-pancreatic-cancer-who-undergo-curative-resection-followed-by-adjuvant-chemotherapy-with-gemcitabine
#1
Toru Aoyama, Yohei Miyagi, Masaaki Murakawa, Koichiro Yamaoku, Yosuke Atsumi, Manabu Shiozawa, Makoto Ueno, Manabu Morimoto, Takashi Oshima, Norio Yukawa, Takaki Yoshikawa, Yasushi Rino, Munetaka Masuda, Soichiro Morinaga
To the best of our knowledge, the clinical implications of using ribonucleoside reductase subunit M1 (RRM1) in patients who undergo curative resection and adjuvant chemotherapy have not been established. In the present study, the clinical data from 101 consecutive patients who underwent macroscopically curative resection, and who received adjuvant gemcitabine chemotherapy for pancreatic cancer at the Kanagawa Cancer Centre (Yokohama, Kanagawa, Japan) between April 2005 and December 2014 were retrospectively analyzed...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28520216/evaluation-of-prediction-of-polymorphisms-of-dna-repair-genes-on-the-efficacy-of-platinum-based-chemotherapy-in-patients-with-non-small-cell-lung-cancer-a-network-meta-analysis
#2
Bao-Hong Fu, Xiao-Lin Yu, Qiang Zhang, Xin-Long Huo, Li-Jie Liu, Xin Li, Li-Xin Dong
This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in 8 DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820) and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation...
May 18, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28507282/p53-suppresses-ribonucleotide-reductase-via-inhibiting-mtorc1
#3
Zhengfu He, Xing Hu, Weijin Liu, Adrienne Dorrance, Ramiro Garzon, Peter J Houghton, Changxian Shen
Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme for the production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide reductase subunit 1 (RRM1) and 2 (RRM2) via inhibiting mammalian target of rapamycin complex 1 (mTORC1). In vitro, cancer cell lines and mouse embryonic fibroblast cells were treated with different concentrations of pharmacological inhibitors for different times. In vivo, rhabdomyosarcoma Rh30 cell tumor-bearing mice were treated with rapamycin or AZD8055...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28469953/microrna-1468-5p-inhibits-glioma-cell-proliferation-and-induces-cell-cycle-arrest-by-targeting-rrm1
#4
Kuan Jiang, Tongle Zhi, Wenhui Xu, Xiupeng Xu, Weining Wu, Tianfu Yu, Er Nie, Xu Zhou, Zhongyuan Bao, Xin Jin, Junxia Zhang, Yingyi Wang, Ning Liu
MicroRNAs are associated with different types of cancers. In this study, we found that miR-1468-5p could inhibit growth and cell cycle progression in glioma by targeting ribonucleotide reductase large subunit M1 (RRM1). First, we analyzed miR-1468-5p expression in different glioma grades and the prognostic significance of its expression in glioblastoma multiform patients from the Chinese Glioma Genome Atlas. Then, we expressed miR-1468-5p in U87 and U251 cells and assessed the effects on proliferation and cell cycle progression using cell counting kit-8, colony formation, EdU and flow cytometry assays...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28442502/ribonucleotide-reductase-large-subunit-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#5
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K Samur, Yu-Tzu Tai, Nikhil C Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C Anderson
Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28422153/clinical-pharmacogenetic-models-for-personalized-cancer-treatment-application-to-malignant-mesothelioma
#6
Katja Goričar, Viljem Kovač, Vita Dolžan
Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28416140/ribonucleotide-reductase-requires-subunit-switching-in-hypoxia-to-maintain-dna-replication
#7
Iosifina P Foskolou, Christian Jorgensen, Katarzyna B Leszczynska, Monica M Olcina, Hanna Tarhonskaya, Bauke Haisma, Vincenzo D'Angiolella, William K Myers, Carmen Domene, Emily Flashman, Ester M Hammond
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage...
April 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28411237/physical-interaction-between-human-ribonucleotide-reductase-large-subunit-and-thioredoxin-increases-colorectal-cancer-malignancy
#8
Meng Lou, Qian Liu, Guoping Ren, Jiling Zeng, Xueping Xiang, Yongfeng Ding, Qinghui Lin, Tingting Zhong, Xia Liu, Lijun Zhu, Hongyan Qi, Jing Shen, Haoran Li, Jimin Shao
Ribonucleotide reductase (RR) is the rate-limiting enzyme in DNA synthesis by catalyzing the reduction of ribonucleotides to deoxyribonucleotides. During each enzymatic turnover, reduction of the active site disulfide in the catalytic large subunit is performed by a pair of shuttle cysteine residues in its C-terminal tail. Thioredoxin (Trx) and Glutaredoxin (Grx) are ubiquitous redox proteins, catalyzing thiol-disulfide exchange reactions. Here, immunohistochemical examination of clinical colorectal cancer (CRC) specimens revealed that human thioredoxin1 (hTrx1), but not human glutaredoxin1 (hGrx1), was upregulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage...
April 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28396636/enhancing-drug-efficacy-and-therapeutic-index-through-cheminformatics-based-selection-of-small-molecule-binary-weapons-that-improve-transporter-mediated-targeting-a-cytotoxicity-system-based-on-gemcitabine
#9
Justine M Grixti, Steve O'Hagan, Philip J Day, Douglas B Kell
The transport of drug molecules is mainly determined by the distribution of influx and efflux transporters for which they are substrates. To enable tissue targeting, we sought to develop the idea that we might affect the transporter-mediated disposition of small-molecule drugs via the addition of a second small molecule that of itself had no inhibitory pharmacological effect but that influenced the expression of transporters for the primary drug. We refer to this as a "binary weapon" strategy. The experimental system tested the ability of a molecule that on its own had no cytotoxic effect to increase the toxicity of the nucleoside analog gemcitabine to Panc1 pancreatic cancer cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28379442/an-rrm-znf-rna-recognition-module-targets-rbm10-to-exonic-sequences-to-promote-exon-exclusion
#10
Katherine M Collins, Yaroslav A Kainov, Evangelos Christodolou, Debashish Ray, Quaid Morris, Timothy Hughes, Ian A Taylor, Eugene V Makeyev, Andres Ramos
RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein...
April 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28348170/crystal-structure-of-u2-snrnp-sf3b-components-hsh49p-in-complex-with-cus1p-binding-domain
#11
Anne-Marie A M van Roon, Chris Oubridge, Eiji Obayashi, Benedetta Sposito, Andrew James Newman, Bertrand Seraphin, Kiyoshi Nagai
Spliceosomal proteins Hsh49p and Cus1p are components of SF3b, which together with SF3a, Msl1p/Lea1p, Sm proteins and U2 snRNA, form U2 snRNP, which plays a crucial role in pre-mRNA splicing. Hsh49p, comprising two RRMs, forms a heterodimer with Cus1p. We determined the crystal structures of Saccharomyces cerevisiae full-length Hsh49p as well as its RRM1 in complex with a minimal binding region of Cus1p (residues 290-368). The structures show that the Cus1 fragment binds to the α-helical surface of Hsh49p RRM1, opposite the four-stranded β-sheet, leaving the canonical RNA binding surface available to bind RNA...
March 27, 2017: RNA
https://www.readbyqxmd.com/read/28284018/chemical-shift-assignments-of-the-first-and-second-rrms-of-nrd1-a-fission-yeast-mapk-target-rna-binding-protein
#12
Ayaho Kobayashi, Teppei Kanaba, Ryosuke Satoh, Yutaka Ito, Reiko Sugiura, Masaki Mishima
Negative regulator differentiation 1 (Nrd1), a fission yeast RNA binding protein, modulates cytokinesis and sexual development and contributes to stress granule formation in response to environmental stresses. Nrd1 comprises four RRM domains and binds and stabilizes Cdc4 mRNA that encodes the myosin II light chain. Nrd1 binds the Cpc2 fission-yeast RACK1 homolog, and the interaction promotes Nrd1 localization to stress granules. Interestingly, Pmk1 mitogen-activated protein kinase phosphorylates Thr40 in the unstructured N-terminal region and Thr126 in the first RRM domain of Nrd1...
March 11, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28280620/potential-actionable-targets-in-appendiceal-cancer-detected-by-immunohistochemistry-fluorescent-in-situ-hybridization-and-mutational-analysis
#13
Erkut Borazanci, Sherri Z Millis, Jeffery Kimbrough, Nancy Doll, Daniel Von Hoff, Ramesh K Ramanathan
BACKGROUND: Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. METHODS: Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55)...
February 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28263595/enhanced-binding-affinity-for-an-i-motif-dna-substrate-exhibited-by-a-protein-containing-nucleobase-amino-acids
#14
Xiaoguang Bai, Poulami Talukder, Sasha M Daskalova, Basab Roy, Shengxi Chen, Zhongxian Li, Larisa M Dedkova, Sidney M Hecht
Several variants of a nucleic acid binding motif (RRM1) of putative transcription factor hnRNP LL containing nucleobase amino acids at specific positions have been prepared and used to study binding affinity for the BCL2 i-motif DNA. Molecular modeling suggested a number of amino acids in RRM1 likely to be involved in interaction with the i-motif DNA, and His24 and Arg26 were chosen for modification based on their potential ability to interact with G14 of the i-motif DNA. Four nucleobase amino acids were introduced into RRM1 at one or both of positions 24 and 26...
March 17, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28263231/appendix-derived-pseudomyxoma-peritonei-pmp-molecular-profiling-toward-treatment-of-a-rare-malignancy
#15
Elizabeth M Gleeson, Rebecca Feldman, Beth L Mapow, Lynn T Mackovick, Kristine M Ward, William F Morano, Rene R Rubin, Wilbur B Bowne
OBJECTIVES: Pseudomyxoma peritonei (PMP) is a rare malignancy originating from the appendix, characterized by disseminated mucinous tumor implants on peritoneal surfaces. We examined the role of multiplatform molecular profiling to study biomarker-guided treatment strategies for this rare malignancy. METHODS: A total of 54 patients with appendix-derived PMP were included in the study. Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing), protein expression (immunohistochemistry), and gene amplification (C/fluorescent in situ hybridization)...
March 3, 2017: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28259943/sclareolide-enhances-gemcitabine%C3%A2-induced-cell-death-through-mediating-the-nicd-and-gli1-pathways-in-gemcitabine%C3%A2-resistant-human-pancreatic-cancer
#16
Sheng Chen, Ye Wang, Wen-Long Zhang, Mao-Sheng Dong, Jian-Hua Zhang
Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc‑1 and ASPC‑1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine‑resistant cells (GR‑HPCCs)...
April 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28257838/als-causing-cleavages-of-tdp-43-abolish-its-rrm2-structure-and-unlock-ctd-for-enhanced-aggregation-and-toxicity
#17
Yuanyuan Wei, Liangzhong Lim, Lu Wang, Jianxing Song
Pathological TDP-43 is cleaved into various fragments. Two major groups of ∼35 and ∼25 kDa have enhanced aggregation and cytotoxicity but the underlying mechanisms remain elusive. While the ∼35-kDa fragments contain entire RRM1, RRM2 and C-terminal domain (CTD) with a middle hydrophobic segment flanked by two prion-like regions; the ∼25-kDa one cleaved at Arg208 only consists of the truncated RRM2 and CTD. Remarkably, the 25-kDa fragment was characterized to induce cell death by gain of cytotoxicity and recapitulate pathological features of TDP-43 proteinopathies...
April 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28196013/prognostic-implications-of-expression-profiling-for-gemcitabine-related-genes-hent1-dck-rrm1-rrm2-in-patients-with-resectable-pancreatic-adenocarcinoma-receiving-adjuvant-chemotherapy
#18
Marek Sierzega, Radosław Pach, Piotr Kulig, Janusz Legutko, Jan Kulig
OBJECTIVES: The aim of this study was to examine the relevance of expression profiling of 4 genes involved in the action of gemcitabine among patients with pancreatic ductal-cell adenocarcinoma (PDAC). METHODS: A group of 100 patients who underwent pancreatic resections for PDAC and received adjuvant chemotherapy with gemcitabine between 2007 and 2010 was identified. Expression of mRNAs for human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunits (RRM1, RRM2), and deoxycytidine kinase (dCK) was examined by quantitative real-time polymerase chain reaction, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and dichotomized into groups of low and moderate/high expression levels grouped by tertiles...
May 2017: Pancreas
https://www.readbyqxmd.com/read/28192940/analysis-of-tertiary-interactions-between-sart3-and-u6-small-nuclear-rna-using-modified-nanocapillaries
#19
Choongman Lee, Joon Kyu Park, Yeoan Youn, Joo Hyoung Kim, Kyo-Seok Lee, Nak-Kyoon Kim, Eunji Kim, Eunice Eunkyeong Kim, Kyung-Hwa Yoo
We employed modified glass nanocapillaries to investigate interactions between the RNA-binding protein, known as cell carcinoma antigen recognized by T cells-3 (SART3), and the noncoding spliceosome component, U6 small nuclear RNA (snRNA), at the single-molecule level. We functionalized the nanocapillaries with U6 snRNA fragments, which were hybridized to DNA molecules and then covalently attached to the nanocapillary surface. When transported through the modified nanocapillaries, two different SART3-derived constructs, HAT-RRM1-RRM2 and RRM1-RRM2, exhibited resistive ionic current pulses with different dwell times, which represented their different binding affinities to tethered U6 snRNAs...
February 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28176818/mechanisms-responsible-for-the-synergistic-antileukemic-interactions-between-atr-inhibition-and-cytarabine-in-acute-myeloid-leukemia-cells
#20
Jun Ma, Xinyu Li, Yongwei Su, Jianyun Zhao, Daniel A Luedtke, Valeria Epshteyn, Holly Edwards, Guan Wang, Zhihong Wang, Roland Chu, Jeffrey W Taub, Hai Lin, Yue Wang, Yubin Ge
Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2...
February 8, 2017: Scientific Reports
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