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N O Elander, K Aughton, P Ghaneh, J P Neoptolemos, D H Palmer, T F Cox, F Campbell, E Costello, C M Halloran, J R Mackey, A G Scarfe, J W Valle, A C McDonald, R Carter, N C Tebbutt, D Goldstein, J Shannon, C Dervenis, B Glimelius, M Deakin, R M Charnley, A Anthoney, M M Lerch, J Mayerle, A Oláh, M W Büchler, W Greenhalf
BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups...
March 9, 2018: British Journal of Cancer
M Carolina Gallego Iradi, Judy C Triplett, James D Thomas, Rachel Davila, Anthony M Crown, Hilda Brown, Jada Lewis, Maurice S Swanson, Guilian Xu, Edgardo Rodriguez-Lebron, David R Borchelt
To understand how mutations in Matrin 3 (MATR3) cause amyotrophic lateral sclerosis (ALS) and distal myopathy, we used transcriptome and interactome analysis, coupled with microscopy. Over-expression of wild-type (WT) or F115C mutant MATR3 had little impact on gene expression in neuroglia cells. Only 23 genes, expressed at levels of >100 transcripts showed ≥1.6-fold changes in expression by transfection with WT or mutant MATR3:YFP vectors. We identified ~123 proteins that bound MATR3, with proteins associated with stress granules and RNA processing/splicing being prominent...
March 6, 2018: Scientific Reports
Sherise D Ferguson, Shouhao Zhou, Joanne Xiu, Yuuri Hashimoto, Nader Sanai, Lyndon Kim, Santosh Kesari, John de Groot, David Spetzler, Amy B Heimberger
Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance. Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance...
January 30, 2018: Oncotarget
K Tryfonidis, C Papadaki, S Assele, E Lagoudaki, J Menis, A Koutsopoulos, M Trypaki, E Tsakalaki, M Sfakianaki, B Hasan, E Stathopoulos, V Georgoulias, J Souglakos
Differences in gene expression levels between the primary tumors (PTs) and matched regional lymph nodal metastases (LNs) in patients with totally excised non-small cell lung cancer (NSCLC) were explored. Microdissected formalin-fixed paraffin-embedded (FFPE) samples from (PT) and their matched infiltrated LNs, from 239 patients [183 (with matched PT and LNs samples)-case and 56 PT only samples-control cohorts] were analyzed for BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression by quantitative real-time polymerase-chain reaction (PCR)...
February 22, 2018: Pharmacogenomics Journal
Pedro Serrano, John A Hammond, Michael Geralt, Kurt Wüthrich
Splicing factor RBM10 and its close homologues RBM5 and RBM6 govern the splicing of oncogenes such as Fas, NUMB, and Bcl-X. The molecular architecture of these proteins includes zinc fingers (ZnFs) and RNA recognition motifs (RRMs). Three of these domains in RBM10 that constitute the RNA binding part of this splicing factor were found to individually bind RNAs with micromolar affinities. It was thus of interest to further investigate the structural basis of the well-documented high-affinity RNA recognition by RMB10...
February 16, 2018: Biochemistry
Baixing Wu, Shichen Su, Deepak P Patil, Hehua Liu, Jianhua Gan, Samie R Jaffrey, Jinbiao Ma
Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A "reader." hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively...
January 29, 2018: Nature Communications
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
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
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
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...
April 2018: Journal of Clinical Pharmacy and Therapeutics
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 found 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 clonogenic assays and cleaved caspase 3 expression...
January 19, 2018: Journal of Biological Chemistry
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
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
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
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
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
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
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
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
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 cell surface death receptor and mammalian target of rapamycin 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...
December 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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