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Moritz von Fallois, Reinhard Depping
No abstract text is available yet for this article.
October 18, 2016: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
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
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...
October 4, 2016: Oncotarget
Hani Bagheri, Chansonette Badduke, Ying Qiao, Rita Colnaghi, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Jiadi Wen, Robert S Wildin, Malgorzata J M Nowaczyk, Jennifer Eichmeyer, Anna Lehman, Bruno Maranda, Sally Martell, Xianghong Shan, Suzanne M E Lewis, Mark O'Driscoll, Cheryl Y Gregory-Evans, Evica Rajcan-Separovic
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome...
March 17, 2016: JCI Insight
Irfana Muqbil, Amro Aboukameel, Sivan Elloul, Robert Carlson, William Senapedis, Erkan Baloglu, Michael Kauffman, Sharon Shacham, Divaya Bhutani, Jeffrey Zonder, Asfar S Azmi, Ramzi M Mohammad
In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL...
September 28, 2016: Cancer Letters
Jimi Kim, Elizabeth McMillan, Hyun Seok Kim, Niranjan Venkateswaran, Gurbani Makkar, Jaime Rodriguez-Canales, Pamela Villalobos, Jasper Edgar Neggers, Saurabh Mendiratta, Shuguang Wei, Yosef Landesman, William Senapedis, Erkan Baloglu, Chi-Wan B Chow, Robin E Frink, Boning Gao, Michael Roth, John D Minna, Dirk Daelemans, Ignacio I Wistuba, Bruce A Posner, Pier Paolo Scaglioni, Michael A White
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies...
September 28, 2016: Nature
John A Martignetti, Ying Chen, Catalina Camacho, Thomas R Silvers, Albiruni R A Razak, Nashat Y Gabrail, John F Gerecitano, Eva Kalir, Elena Pereira, Brad R Evans, Susan J Ramus, Fei Huang, Nolan Priedigkeit, Estefania Rodriguez, Michael Donovan, Faisal M Khan, Tamara Kalir, Robert P Sebra, Andrew Uzilov, Rong Chen, Rileen Sinha, Richard Halpert, Jean-Noel Billaud, Sharon Shacham, Dilara McCauley, Yosef Landesman, Tami Rashal, Michael Kauffman, Mansoor R Mirza, Morten Mau-Sørensen, Peter Dottino
PURPOSE: Ovarian cancer's (OvCa) high fatality-to-case ratio is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum sensitive and resistant OvCa. EXPERIMENTAL DESIGN: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO data sets and tissue microarrays (TMAs)...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jasper Edgar Neggers, Els Vanstreels, Erkan Baloglu, Sharon Shacham, Yosef Landesman, Dirk Daelemans
Exportin-1 (CRM1/XPO1) is a crucial nuclear export protein that transports a wide variety of proteins from the nucleus to the cytoplasm. These cargo proteins include tumor suppressors and growth-regulatory factors and as such XPO1 is considered a potential anti-cancer target. From this perspective, inhibition of the XPO1-mediated nuclear export by selective inhibitor of nuclear export (SINE) compounds has shown broad-spectrum anti-cancer activity. Furthermore, the clinical candidate SINE, selinexor, is currently in multiple phase I/II/IIb trials for treatment of cancer...
September 13, 2016: Oncotarget
Joel G Turner, Jana L Dawson, Steven Grant, Kenneth H Shain, William S Dalton, Yun Dai, Mark Meads, Rachid Baz, Michael Kauffman, Sharon Shacham, Daniel M Sullivan
BACKGROUND: Acquired drug resistance is the greatest obstacle to the successful treatment of multiple myeloma (MM). Despite recent advanced treatment options such as liposomal formulations, proteasome inhibitors, immunomodulatory drugs, myeloma-targeted antibodies, and histone deacetylase inhibitors, MM is still considered an incurable disease. METHODS: We investigated whether the clinical exportin 1 (XPO1) inhibitor selinexor (KPT-330), when combined with pegylated liposomal doxorubicin (PLD) or doxorubicin hydrochloride, could overcome acquired drug resistance in multidrug-resistant human MM xenograft tumors, four different multidrug-resistant MM cell lines, or ex vivo MM biopsies from relapsed/refractory patients...
2016: Journal of Hematology & Oncology
Cheryl Taylor-Kashton, Daniel Lichtensztejn, Erkan Baloglu, William Senapedis, Sharon Shacham, Michael G Kauffman, Rami Kotb, Sabine Mai
Cover: The cover image, by Sabine Mai et al., is based on the Research Article XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells, DOI: 10.1002/jcp.25378.
December 2016: Journal of Cellular Physiology
Kinga Wrobel, Yiru Chen Zhao, Eylem Kulkoyluoglu, Karen Lee Ann Chen, Kadriye Hieronymi, Jamie Holloway, Sarah Li, Tania Ray, Partha Sarathi Ray, Yosef Landesman, Alexander Edward Lipka, Rebecca Lee Smith, Zeynep Madak-Erdogan
Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies...
October 2016: Molecular Endocrinology
Thomas B Alexander, Norman J Lacayo, John K Choi, Raul C Ribeiro, Ching-Hon Pui, Jeffrey E Rubnitz
PURPOSE: To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. PATIENTS AND METHODS: Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561)...
August 9, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
François Bertucci, Pascal Finetti, Daniel Birnbaum
No abstract text is available yet for this article.
2016: Oncoscience
Vincent Camus, Aspasia Stamatoullas, Sylvain Mareschal, Pierre-Julien Viailly, Nasrin Sarafan-Vasseur, Elodie Bohers, Sydney Dubois, Jean Michel Picquenot, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, Marie Cornic, Valérie Tallon-Simon, Stéphanie Becker, Liana Veresezan, Thierry Frebourg, Pierre Vera, Christian Bastard, Hervé Tilly, Fabrice Jardin
Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study...
September 2016: Haematologica
S Barrio, T D Shanafelt, J Ojha, K G Chaffee, C Secreto, K M Kortüm, S Pathangey, D L Van-Dyke, S L Slager, R Fonseca, N E Kay, E Braggio
High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution...
July 29, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Alberto Marini, Anna Maria Lena, Emanuele Panatta, Cristina Ivan, Leng Han, Han Liang, Margherita Annicchiarico-Petruzzelli, Nicola Di Daniele, George A Calin, Eleonora Candi, Gerry Melino
Transcribed-ultraconserved regions (T-UCRs) are long non-coding RNAs (lncRNA) encoded by a subset of long ultraconserved stretches in the human genome. Recent studies revealed that the expression of several T-UCRs is altered in cancer and growing evidences underline the importance of T-UCRs in oncogenesis, offering also potential new strategies for diagnosis and prognosis. We found that overexpression of one specific T-UCRs named uc.63 is associated with bad outcome in luminal A subtype of breast cancer patients...
July 13, 2016: Oncotarget
Parvathi Ranganathan, Trinayan Kashyap, Xueyan Yu, Xiaomei Meng, Tzung-Huei Lai, Betina McNeil, Bhavana Bhatnagar, Sharon Shacham, Michael Kauffman, Adrienne M Dorrance, William Blum, Deepa Sampath, Yosef Landesman, Ramiro Garzon
PURPOSE: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore we asked whether adding already established effective drugs such as Topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. EXPERIMENTAL DESIGN: The efficacy of combinatorial drug treatment using Topo II inhibitors (Idarubicin, Daunorubicin, Mitoxantrone, Etoposide) and selinexor was evaluated in established cellular and animal models of AML...
June 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Andrew L Hong, Yuen-Yi Tseng, Glenn S Cowley, Oliver Jonas, Jaime H Cheah, Bryan D Kynnap, Mihir B Doshi, Coyin Oh, Stephanie C Meyer, Alanna J Church, Shubhroz Gill, Craig M Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V Kryukov, Paul A Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D Crompton, Alykhan F Shamji, Carlos Rodriguez-Galindo, Katherine A Janeway, Charles W M Roberts, Kimberly Stegmaier, Paul van Hummelen, Michael J Cima, Robert S Langer, Levi A Garraway, Stuart L Schreiber, David E Root, William C Hahn, Jesse S Boehm
Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets...
2016: Nature Communications
Z A Hing, H Y J Fung, P Ranganathan, S Mitchell, D El-Gamal, J A Woyach, K Williams, V M Goettl, J Smith, X Yu, X Meng, Q Sun, T Cagatay, A M Lehman, D M Lucas, E Baloglu, S Shacham, M G Kauffman, J C Byrd, Y M Chook, R Garzon, R Lapalombella
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care...
June 21, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Fabrice Jardin, Anais Pujals, Laura Pelletier, Elodie Bohers, Vincent Camus, Sylvain Mareschal, Sydney Dubois, Brigitte Sola, Marlène Ochmann, François Lemonnier, Pierre-Julien Viailly, Philippe Bertrand, Catherine Maingonnat, Alexandra Traverse-Glehen, Philippe Gaulard, Diane Damotte, Richard Delarue, Corinne Haioun, Christian Argueta, Yosef Landesman, Gilles Salles, Jean-Philippe Jais, Martin Figeac, Christiane Copie-Bergman, Thierry Jo Molina, Jean Michel Picquenot, Marie Cornic, Thierry Fest, Noel Milpied, Emilie Lemasle, Aspasia Stamatoullas, Peter Moeller, Martin J S Dyer, Christer Sundstrom, Christian Bastard, Hervé Tilly, Karen Leroy
Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics...
September 2016: American Journal of Hematology
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