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https://www.readbyqxmd.com/read/28515232/the-nuclear-export-factor-crm1-controls-juxta-nuclear-microtubule-dependent-virus-transport
#1
I-Hsuan Wang, Christoph J Burckhardt, Artur Yakimovich, Matthias K Morf, Urs F Greber
Transport of large cargo through the cytoplasm requires motor proteins and polarized filaments. Viruses that replicate in the nucleus of post-mitotic cells use microtubules and the dynein/dynactin motor to traffic to the nuclear membrane, and deliver their genome through nuclear pore complexes (NPCs) into the nucleus. How virus particles (virions) or cellular cargo are transferred from microtubules to the NPC is unknown. Here, we analyzed trafficking of incoming cytoplasmic adenoviruses by single particle tracking and super-resolution microscopy...
May 17, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28468797/selective-inhibition-of-nuclear-export-with-selinexor-in-patients-with-non-hodgkin-s-lymphoma
#2
John Kuruvilla, Michael Savona, Rachid Baz, Morten Mau-Sorensen, Nashat Gabrail, Ramiro Garzon, Richard Stone, Michael Wang, Lynn Savoie, Peter Martin, Ian Flinn, Meagan Jacoby, T J Unger, Jean R Saint-Martin, Tami Rashal, Sharon Friedlander, Robert Carlson, Michael Kauffman, Sharon Shacham, Martin Gutierrez
Patients with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B cell lymphoma (DLBCL), Richter's transformation, mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) were enrolled...
May 3, 2017: Blood
https://www.readbyqxmd.com/read/28399885/next-generation-sequencing-and-fish-studies-reveal-the-appearance-of-gene-mutations-and-chromosomal-abnormalities-in-hematopoietic-progenitors-in-chronic-lymphocytic-leukemia
#3
Miguel Quijada-Álamo, María Hernández-Sánchez, Cristina Robledo, Jesús-María Hernández-Sánchez, Rocío Benito, Adrián Montaño, Ana E Rodríguez-Vicente, Dalia Quwaider, Ana-África Martín, María García-Álvarez, María Jesús Vidal-Manceñido, Gonzalo Ferrer-Garrido, María-Pilar Delgado-Beltrán, Josefina Galende, Juan-Nicolás Rodríguez, Guillermo Martín-Núñez, José-María Alonso, Alfonso García de Coca, José A Queizán, Magdalena Sierra, Carlos Aguilar, Alexander Kohlmann, José-Ángel Hernández, Marcos González, Jesús-María Hernández-Rivas
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. METHODS: Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes...
April 11, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28392395/function-of-nup98-subtypes-and-their-fusion-proteins-nup98-topii%C3%AE-and-nup98-setbp1-in-nuclear-cytoplasmic-transport
#4
Shoko Saito, Takafumi Yokokawa, Gemmei Iizuka, Sadik Cigdem, Mitsuru Okuwaki, Kyosuke Nagata
Nup98 is a component of the nuclear pore complex. The nup98-fusion genes derived by chromosome translocations are involved in hematopoietic malignancies. Here, we investigated the functions of Nup98 isoforms and two unexamined Nup98-fusion proteins, Nup98-TopIIβ and Nup98-SETBP1. We first demonstrated that two Nup98 isoforms are expressed in various mouse tissues and similarly localized in the nucleus and the nuclear envelope. We also showed that Nup98-TopIIβ and Nup98-SETBP1 are localized in the nucleus and partially co-localized with full-length Nup98 and a nuclear export receptor XPO1...
May 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28388555/targeting-mantle-cell-lymphoma-metabolism-and-survival-through-simultaneous-blockade-of-mtor-and-nuclear-transporter-exportin-1
#5
Kazumasa Sekihara, Kaori Saitoh, Lina Han, Stefan Ciurea, Shinichi Yamamoto, Mika Kikkawa, Saiko Kazuno, Hikari Taka, Naoko Kaga, Hajime Arai, Takashi Miida, Michael Andreeff, Marina Konopleva, Yoko Tabe
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, characterized by aberrant expression of growth-regulating and oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is associated with its pathogenesis. mTOR signaling, a central regulator of cell metabolism, is frequently activated in MCL and is also an important therapeutic target in this cancer. This study investigated the antitumor effects and molecular/metabolic changes induced by the combination of the small-molecule selective inhibitor XPO1 inhibitor KPT-185 and the dual mTORC1/2 kinase inhibitor AZD-2014 on MCL cells...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28344316/gain-in-the-short-arm-of-chromosome-2-2p-induces-gene-overexpression-and-drug-resistance-in-chronic-lymphocytic-leukemia-analysis-of-the-central-role-of-xpo1
#6
A Cosson, E Chapiro, N Bougacha, J Lambert, L Herbi, H-A Cung, C Algrin, B Keren, F Damm, C Gabillaud, M-N Brunelle-Navas, F Davi, H Merle-Béral, M Le Garff-Tavernier, D Roos-Weil, S Choquet, M Uzunov, V Morel, V Leblond, K Maloum, S Leprêtre, P Feugier, C Lesty, J Lejeune, L Sutton, Y Landesman, S A Susin, F Nguyen-Khac
Leukemia accepted article preview online, 27 March 2017. doi:10.1038/leu.2017.100.
March 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28336527/a-phase-i-clinical-trial-of-single-agent-selinexor-in-acute-myeloid-leukemia
#7
Ramiro Garzon, Michael Savona, Rachid Baz, Michael Andreeff, Nashat Gabrail, Martin Gutierrez, Lynn Savoie, Morten Mau-Sorensen, Nina Wagner-Johnston, Karen Yee, T J Unger, Jean Richard Saint-Martin, Robert Carlson, Tami Rashal, Trinayan Kashyap, Boris Klebanov, Sharon Shacham, Michael Kauffman, Richard Stone
Selinexor is a novel, first-in-class, Selective Inhibitor of Nuclear Export (SINE) compound, which blocks XPO1 function, leads to nuclear accumulation of tumor suppressor proteins (TSPs) and induces cancer cell death. A phase I dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8 or 10 doses of selinexor in 21- or 28-day cycle...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28325843/a-biochemical-framework-for-eif4e-dependent-mrna-export-and-nuclear-re-cycling-of-the-export-machinery
#8
Laurent Volpon, Biljana Culjkovic-Kraljacic, Hye Seon Sohn, Alexis Blanchett-Cohen, Michael J Osborne, Katherine L B Borden
The eukaryotic translation initiation factor eIF4E acts in the nuclear export and translation of a subset of mRNAs. Both of these functions contribute to its oncogenic potential. While the biochemical mechanisms that underlie translation are relatively well understood, the molecular basis for eIF4E's role in mRNA export remains largely unexplored. To date over 3000 transcripts, many encoding oncoproteins, were identified as potential nuclear eIF4E export targets. These target RNAs typically contain a ~50 nucleotide eIF4E sensitivity element (4ESE) in the 3' UTR and a 7-methylguanosine cap on the 5' end...
March 21, 2017: RNA
https://www.readbyqxmd.com/read/28314790/selinexor-kpt-330-induces-tumor-suppression-through-nuclear-sequestration-of-ikappab-and-down-regulation-of-survivin
#9
Jayasree S Nair, Elgilda Musi, Gary K Schwartz
PURPOSE: Selinexor, a small molecule that inhibits nuclear export protein XPO1 has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few and hence the need to identify novel targets and strategic therapies is of utmost importance. EXPERIMENTAL DESIGN: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28269752/a-80-gene-set-potentially-predicts-the-relapse-in-laryngeal-carcinoma-optimized-by-support-vector-machine
#10
Bo Yang, Qing Guo, Fei Wang, Kemin Cai, Xueli Bao, Jiusheng Chu
OBJECTIVE: The present study was performed to identify a gene set for predicting the relapse in laryngeal carcinoma using large data analysis methods. METHODS: Two gene expression profile data of laryngeal carcinoma (GSE27020 and GSE25727) were downloaded from public database. Genes associated with tumor relapse, namely informative genes, were identified by Cox regression analysis. Then the protein-protein interaction (PPI) network consisting of informative genes was constructed...
2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28196522/xpo1-in-b-cell-hematological-malignancies-from-recurrent-somatic-mutations-to-targeted-therapy
#11
REVIEW
Vincent Camus, Hadjer Miloudi, Antoine Taly, Brigitte Sola, Fabrice Jardin
Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies...
February 14, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27917343/a-new-bioinformatic-insight-into-the-associated-proteins-in-psychiatric-disorders
#12
Wenlong Zhao, Wenjing Yang, Shuanglin Zheng, Qiong Hu, Ping Qiu, Xinghua Huang, Xiaoqian Hong, Fenghua Lan
BACKGROUND: Psychiatric diseases severely affect the quality of patients' lives and bring huge economic pressure to their families. Also, the great phenotypic variability among these patients makes it difficult to investigate the pathogenesis. Nowadays, bioinformatics is hopeful to be used as an effective tool for the diagnosis of psychiatric disorders, which can identify sensitive biomarkers and explore associated signaling pathways. METHODS: In this study, we performed an integrated bioinformatic analysis on 1945 mental-associated proteins including 91 secreted proteins and 593 membrane proteins, which were screened from the Universal Protein Resource (Uniport) database...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27863053/caffeic-acid-phenethyl-ester-cape-revisited-covalent-modulation-of-xpo1-crm1-activities-and-implication-for-its-mechanism-of-action
#13
EDITORIAL
Sijin Wu, Keren Zhang, Hongqiang Qin, Mingshan Niu, Weijie Zhao, Mingliang Ye, Hanfa Zou, Yongliang Yang
Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anticarcinogenic, antioxidant, and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE...
May 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27825468/novel-therapeutic-targets-in-waldenstrom-macroglobulinemia
#14
REVIEW
Aneel Paulus, Sikander Ailawadhi, Asher Chanan-Khan
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27807105/xpo1-may-be-therapeutically-targetable-in-kras-mutant-nsclc
#15
(no author information available yet)
XPO1 inhibition selectively targets KRAS-mutant NSCLC cells by suppressing NFκB signaling.
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27806331/xpo1-inhibitor-combination-therapy-with-bortezomib-or-carfilzomib-induces-nuclear-localization-of-i%C3%AE%C2%BAb%C3%AE-and-overcomes-acquired-proteasome-inhibitor-resistance-in-human-multiple-myeloma
#16
Joel G Turner, Trinayan Kashyap, Jana L Dawson, Juan Gomez, Alexis A Bauer, Steven Grant, Yun Dai, Kenneth H Shain, Mark Meads, Yosef Landesman, Daniel M Sullivan
Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27780859/the-second-generation-exportin-1-inhibitor-kpt-8602-demonstrates-potent-activity-against-acute-lymphoblastic-leukemia
#17
Thomas Vercruysse, Jolien De Bie, Jasper E Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan L Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27757501/-radiation-response-enhanced-by-inhibition-of-xpo1-in-preclinical-rectal-cancer-models
#18
Moritz von Fallois, Reinhard Depping
No abstract text is available yet for this article.
December 2016: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/27733172/crm1-xpo1-is-associated-with-clinical-outcome-in-glioma-and-represents-a-therapeutic-target-by-perturbing-multiple-core-pathways
#19
Xuejiao Liu, Yulong Chong, Yiming Tu, Ning Liu, Chenglong Yue, Zhenglei Qi, Huize Liu, Yao Yao, Hongmei Liu, Shangfeng Gao, Mingshan Niu, Rutong Yu
BACKGROUND: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. METHODS: In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model...
October 12, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27713151/selinexor-a-selective-inhibitor-of-nuclear-export-sine-compound-acts-through-nf-%C3%AE%C2%BAb-deactivation-and-combines-with-proteasome-inhibitors-to-synergistically-induce-tumor-cell-death
#20
Trinayan Kashyap, Christian Argueta, Amro Aboukameel, Thaddeus John Unger, Boris Klebanov, Ramzi M Mohammad, Irfana Muqbil, Asfar S Azmi, Claire Drolen, William Senapedis, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells...
November 29, 2016: Oncotarget
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