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https://www.readbyqxmd.com/read/28722661/dck-expression-a-potential-predictive-biomarker-in-the-adjuvant-gemcitabine-chemotherapy-for-biliary-tract-cancer-after-surgical-resection-results-from-a-phase-ii-study
#1
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...
July 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28687003/inhibition-of-chk1-sensitizes-ewing-sarcoma-cells-to-the-ribonucleotide-reductase-inhibitor-gemcitabine
#2
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...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28650318/tandem-hnrnp-a1-rna-recognition-motifs-act-in-concert-to-repress-the-splicing-of-survival-motor-neuron-exon-7
#3
Irene Beusch, Pierre Barraud, Ahmed Moursy, Antoine Cléry, Frédéric Hai-Trieu Allain
HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function...
June 26, 2017: ELife
https://www.readbyqxmd.com/read/28597542/the-efficacy-and-safety-of-gemcitabine-cisplatin-prednisone-thalidomide-versus-chop-in-patients-with-newly-diagnosed-peripheral-t-cell-lymphoma-with-analysis-of-biomarkers
#4
Ling Li, Wenjing Duan, Lei Zhang, Xin Li, Xiaorui Fu, Xinhua Wang, Jingjing Wu, Zhenchang Sun, Xudong Zhang, Yu Chang, Feifei Nan, Jiaqin Yan, Zhaoming Li, Ken H Young, Mingzhi Zhang
We compared the efficacy and safety of gemcitabine, cisplatin, prednisone and thalidomide (GDPT) with standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with newly diagnosed peripheral T-cell lymphoma (PTCL) in a prospective randomized controlled and open-label clinical trial. Between July 2010 and June 2016, 103 patients were randomly allocated into two groups, of whom 52 were treated with GDPT therapy and 51 with CHOP therapy. The 2-year progression-free survival (PFS) and overall survival (OS) rates were better in the GDPT group than in the CHOP group (57% vs...
June 9, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28576472/redirecting-sr-protein-nuclear-trafficking-through-an-allosteric-platform
#5
Brandon E Aubol, Kendra L Hailey, Laurent Fattet, Patricia A Jennings, Joseph A Adams
Although phosphorylation directs serine-arginine (SR) proteins from nuclear storage speckles to the nucleoplasm for splicing function, dephosphorylation paradoxically induces similar movement, raising the question of how such chemical modifications are balanced in these essential splicing factors. In this new study, we investigated the interaction of protein phosphatase 1 (PP1) with the SR protein splicing factor (SRSF1) to understand the foundation of these opposing effects in the nucleus. We found that RNA recognition motif 1 (RRM1) in SRSF1 binds PP1 and represses its catalytic function through an allosteric mechanism...
July 7, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28573946/influence-of-cytarabine-metabolic-pathway-polymorphisms-in-acute-myeloid-leukemia-induction-treatment
#6
Juan Eduardo Megías-Vericat, Pau Montesinos, María José Herrero, Federico Moscardó, Virginia Bosó, David Martínez-Cuadrón, Luis Rojas, Rebeca Rodríguez-Veiga, Blanca Boluda, Luis Sendra, José Cervera, José Luis Poveda, Miguel Ángel Sanz, Salvador F Aliño
Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, ...
June 2, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28556593/comparative-molecular-profiling-of-hpv-induced-squamous-cell-carcinomas
#7
Robert F Koncar, Rebecca Feldman, El Mustapha Bahassi, Nooshin Hashemi Sadraei
Approximately 5% of all cancer incidences result from human papillomavirus (HPV) infection. HPV infection most commonly leads to cancers of the anogenital region or oropharynx. It is unknown whether different HPV-mediated cancers collectively share a molecular signature and it is important to determine if there are targetable alterations common to different types of HPV-positive tumors. We analyzed 743 p53 wild-type samples of anal, cervical, oropharyngeal, and vulvar squamous cell carcinomas which underwent multiplatform testing at a commercial molecular profiling service...
July 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28556483/drug-sensitivity-and-resistance-testing-identifies-plk1-inhibitors-and-gemcitabine-as-potent-drugs-for-malignant-peripheral-nerve-sheath-tumors-mpnst
#8
Matthias Kolberg, Jarle Bruun, Astrid Murumägi, John P Mpindi, Christian H Bergsland, Maren Høland, Ina A Eilertsen, Stine A Danielsen, Olli Kallioniemi, Ragnhild A Lothe
Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity and apoptosis...
May 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28542332/non-canonical-binding-interactions-of-the-rna-recognition-motif-rrm-domains-of-p34-protein-modulate-binding-within-the-5s-ribonucleoprotein-particle-5s-rnp
#9
Anyango D Kamina, Noreen Williams
RNA binding proteins are involved in many aspects of RNA metabolism. In Trypanosoma brucei, our laboratory has identified two trypanosome-specific RNA binding proteins P34 and P37 that are involved in the maturation of the 60S subunit during ribosome biogenesis. These proteins are part of the T. brucei 5S ribonucleoprotein particle (5S RNP) and P34 binds to 5S ribosomal RNA (rRNA) and ribosomal protein L5 through its N-terminus and its RNA recognition motif (RRM) domains. We generated truncated P34 proteins to determine these domains' interactions with 5S rRNA and L5...
2017: PloS One
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
#10
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
#11
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
#12
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...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28469953/microrna-1468-5p-inhibits-glioma-cell-proliferation-and-induces-cell-cycle-arrest-by-targeting-rrm1
#13
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-catalytic-subunit-m1-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#14
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 biological and clinical significance of ribonucleotide reductase (RR) in multiple myeloma.Experimental Design: We assessed the impact of RR expression on patient outcome in multiple myeloma. We then characterized the effect of genetic and pharmacologic inhibition of ribonucleotide reductase catalytic subunit M1 (RRM1) on multiple myeloma growth and survival using siRNA and clofarabine, respectively, in both in vitro and in vivo mouse xenograft models.Results: Newly diagnosed multiple myeloma 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
#15
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
#16
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
#17
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, 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 up-regulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage...
June 2, 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
#18
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
#19
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
#20
Anne-Marie M van Roon, Chris Oubridge, Eiji Obayashi, Benedetta Sposito, Andrew J Newman, Bertrand Séraphin, 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...
June 2017: RNA
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