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https://www.readbyqxmd.com/read/28804556/anti-tumor-efficacy-evaluation-of-a-novel-monoclonal-antibody-targeting-neutral-amino-acid-transporter-asct2-using-patient-derived-xenograft-mouse-models-of-gastric-cancer
#1
Noriyuki Kasai, Aya Sasakawa, Kenta Hosomi, Tze Wei Poh, Bernadette Lynn Chua, Wei Peng Yong, Jimmy So, Shing Leng Chan, Richie Soong, Koji Kono, Toshihiko Ishii, Kazuya Yamano
ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient-derived xenograft (PDX) mouse models...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28797031/regulation-of-hypoxia-induced-autophagy-in-glioblastoma-involves-atg9a
#2
Siti Aminah Abdul Rahim, Anne Dirkse, Anais Oudin, Anne Schuster, Jill Bohler, Vanessa Barthelemy, Arnaud Muller, Laurent Vallar, Bassam Janji, Anna Golebiewska, Simone P Niclou
BACKGROUND: Hypoxia is negatively associated with glioblastoma (GBM) patient survival and contributes to tumour resistance. Anti-angiogenic therapy in GBM further increases hypoxia and activates survival pathways. The aim of this study was to determine the role of hypoxia-induced autophagy in GBM. METHODS: Pharmacological inhibition of autophagy was applied in combination with bevacizumab in GBM patient-derived xenografts (PDXs). Sensitivity towards inhibitors was further tested in vitro under normoxia and hypoxia, followed by transcriptomic analysis...
August 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28796244/bet-bromodomain-inhibitors-synergize-with-atr-inhibitors-in-melanoma-in-melanoma
#3
Somsundar Veppil Muralidharan, Berglind Osk Einarsdottir, Joydeep Bhadury, Mattias F Lindberg, Jin Wu, Eric Campeau, Roger Olofsson Bagge, Ulrika Stierner, Lars Ny, Lisa M Nilsson, Jonas A Nilsson
Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28791708/exosomal-dnmt1-mediates-cisplatin-resistance-in-ovarian-cancer
#4
Ya-Lei Cao, Ting Zhuang, Bao-Heng Xing, Na Li, Qin Li
Ovarian cancer is the most common malignancy in women. Owing to late syndromic presentation and lack of efficient early detection, most cases are diagnosed at advanced stages. Surgery and platinum-based chemotherapy are still the standard care currently. However, resistance invoked often compromises the clinical value of the latter. Expression of DNA methyltransferase 1 (DNMT1) was analysed by gene array. Protein was determined by immunoblotting. Exosome was isolated with commercial kit. Cell proliferation was measured by CCK8 method...
August 8, 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/28791312/synergistic-antitumour-properties-of-viscumtt-in-alveolar-rhabdomyosarcoma
#5
Rahel Mascha Stammer, Susann Kleinsimon, Jana Rolff, Sebastian Jäger, Angelika Eggert, Georg Seifert, Catharina I Delebinski
Aqueous mistletoe extracts from the European mistletoe (Viscum album) contain mainly mistletoe lectins and viscotoxins as cytotoxic compounds. Lipophilic triterpene acids, which do not occur in conventional mistletoe preparations, were solubilised with β-cyclodextrins. The combination of an aqueous extract (viscum) and a triterpene-containing extract (TT) recreated a whole mistletoe extract (viscumTT). These extracts were tested on rhabdomyosarcoma in vitro, ex vivo, and in vivo with regard to anticancer effects...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28790197/breast-tumors-educate-the-proteome-of-stromal-tissue-in-an-individualized-but-coordinated-manner
#6
Xuya Wang, Arshag D Mooradian, Petra Erdmann-Gilmore, Qiang Zhang, Rosa Viner, Sherri R Davies, Kuan-Lin Huang, Ryan Bomgarden, Brian A Van Tine, Jieya Shao, Li Ding, Shunqiang Li, Matthew J Ellis, John C Rogers, R Reid Townsend, David Fenyö, Jason M Held
Cancer forms specialized microenvironmental niches that promote local invasion and colonization. Engrafted patient-derived xenografts (PDXs) locally invade and colonize naïve stroma in mice while enabling unambiguous molecular discrimination of human proteins in the tumor from mouse proteins in the microenvironment. To characterize how patient breast tumors form a niche and educate naïve stroma, subcutaneous breast cancer PDXs were globally profiled by species-specific quantitative proteomics. Regulation of PDX stromal proteins by breast tumors was extensive, with 35% of the stromal proteome altered by tumors consistently across different animals and passages...
August 8, 2017: Science Signaling
https://www.readbyqxmd.com/read/28783171/the-pdgfr%C3%AE-laminin-b1-keratin-19-cascade-drives-tumor-progression-at-the-invasive-front-of-human-hepatocellular-carcinoma
#7
O Govaere, M Petz, J Wouters, Y-P Vandewynckel, E J Scott, B Topal, F Nevens, C Verslype, Q M Anstee, H Van Vlierberghe, W Mikulits, T Roskams
Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28783167/toosendanin-demonstrates-promising-antitumor-efficacy-in-osteosarcoma-by-targeting-stat3
#8
T Zhang, J Li, F Yin, B Lin, Z Wang, J Xu, H Wang, D Zuo, G Wang, Y Hua, Z Cai
Signal transducer and activator of transcription 3(STAT3) is an emerging target for cancer therapy. In this study, we identify Toosendanin (TSN) is an effective inhibitor of STAT3, leading to the impediment of various oncogenic processes in osteosarcoma. TSN selectively inactivates phospho-STAT3 (Tyr-705); subsequent molecular docking and in vitro SPR analysis uncover TSN directly binds to the SH2 domain of STAT3. Consequently, TSN blocks STAT3 dimerization and impairs the complex formation of STAT3 and epidermal growth factor receptor (EGFR)...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28782139/low-doses-of-curcuma-longa-modulates-cell-migration-and-cell-cell-adhesion
#9
Paloma Santos de Campos, Bibiana Franzen Matte, Leonardo Francisco Diel, Luciano Henrique Jesus, Lisiane Bernardi, Alessandro Menna Alves, Pantelis Varvaki Rados, Marcelo Lazzaron Lamers
Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC...
August 7, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28778085/investigation-of-factors-affecting-the-efficacy-of-3c23k-a-human-monoclonal-antibody-targeting-misiir
#10
Sarah E Gill, Qing Zhang, Gary L Keeney, William A Cliby, S John Weroha
MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#11
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28768804/synergistic-action-of-the-mcl-1-inhibitor-s63845-with-current-therapies-in-preclinical-models-of-triple-negative-and-her2-amplified-breast-cancer
#12
Delphine Merino, James R Whittle, François Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maïa Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Gräsel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David C S Huang, Gordon K Smyth, Olivier Geneste, Guillaume Lessene, Jane E Visvader, Geoffrey J Lindeman
The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28768734/human-tissue-models-in-cancer-research-looking-beyond-the-mouse
#13
EDITORIAL
Samuel J Jackson, Gareth J Thomas
Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of 'non-animal human tissue' models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28766870/extracellular-hyaluronic-acid-influences-the-efficacy-of-egfr-tyrosine-kinase-inhibitors-in-a-biomaterial-model-of-glioblastoma
#14
Sara Pedron, Jacob S Hanselman, Mark A Schroeder, Jann N Sarkaria, Brendan A C Harley
3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients...
August 2, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28765324/glesatinib-exhibits-antitumor-activity-in-lung-cancer-models-and-patients-harboring-met-exon-14-mutations-and-overcomes-mutation-mediated-resistance-to-type-i-met-inhibitors-in-nonclinical-models
#15
Lars Engstrom, Ruth Aranda, Matthew Lee, Elizabeth A Tovar, Curt Essenburg, Zachary B Madaj, Harrah Chiang, David Briere, Jill Hallin, Pedro P Lopez-Casas, Natalia Banos, Camino Menéndez, Manuel Hidalgo, Vanessa Tassell, Richard Chao, Darya I Chudova, Richard B Lanman, Peter Olson, Lyudmila Bazhenova, Sandip P Patel, Carrie R Graveel, Mizuki Nishino, Geoffrey I Shapiro, Nir Peled, Mark M Awad, Pasi A Janne, James G Christensen
MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations.  We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28762582/detection-of-homozygous-deletions-in-tumor-suppressor-genes-ranging-from-dozen-to-hundreds-nucleotides-in-cancer-models
#16
Lun-Ching Chang, Suleyman Vural, Dmitriy Sonkin
Tumor suppressor genes can be inactivated by several mechanisms and, in a majority of cases, both alleles need to be affected. One of the mechanisms of inactivation is due to deletions ranging from dozen to hundreds of nucleotides; such deletions are often missed by variant callers. HomDelDetect is a method to detect such homozygous deletions in cancer models, such as cancer cell lines and potentially patient tumor derived xenografts. This method can be applied to partial exome, whole exome, whole genome sequencing, and RNA-seq data...
August 1, 2017: Human Mutation
https://www.readbyqxmd.com/read/28760449/tumor-microenvironment-determines-response-to-a-heat-activated-thermosensitive-liposome-formulation-of-cisplatin-in-cervical-carcinoma
#17
Yannan N Dou, Naz Chaudary, Martin C Chang, Michael Dunne, Huang Huang, David A Jaffray, Michael Milosevic, Christine Allen
Significant heterogeneity in the tumor microenvironment of human cervical cancer patients is known to challenge treatment outcomes in this population. The current standard of care for cervical cancer patients is radiation therapy and concurrent cisplatin (CDDP) chemotherapy. Yet this treatment strategy fails to control loco-regional disease in 10-30% of patients. In order to improve the loco-regional control rate, a thermosensitive liposome formulation of CDDP (HTLC) was developed to increase local concentrations of drug in response to mild hyperthermia (HT)...
July 29, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28756008/efficacy-of-the-cdk-inhibitor-dinaciclib-in%C3%A2-vitro-and-in%C3%A2-vivo-in-t-cell-acute-lymphoblastic-leukemia
#18
Sausan A Moharram, Kinjal Shah, Fatima Khanum, Alissa Marhäll, Mohiuddin Gazi, Julhash U Kazi
T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL...
July 26, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28754817/multifaceted-role-of-btla-in-the-control-of-cd8-t-cell-fate-after-antigen-encounter
#19
Krit Ritthipichai, Cara Haymaker, Melisa Martinez-Paniagua, Andrew Aschenbrenner, Xiaohui Yi, Minying Zhang, Charuta Kale, Yared Hailemichael, Willem W Overwijk, Luis Vence, Jason Roszik, Navin Varadarajan, Roza Nurieva, Laszlo G Radvanyi, Patrick Hwu, Chantale Bernatchez
Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8(+) TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8(+)BTLA(+)TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation...
July 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28754668/transglutaminase-2-inhibition-reverses-mesenchymal-transdifferentiation-of-glioma-stem-cells-by-regulating-c-ebp%C3%AE-signaling
#20
Jinlong Yin, Young Taek Oh, Jeong-Yub Kim, Sung Soo Kim, Eunji Choi, Tae Hoon Kim, Jun Hee Hong, Nakho Chang, Hee Jin Cho, Jason Kyungha Sa, Jeong Cheol Kim, Hyung Joon Kwon, Saewhan Park, Weiwei Lin, Ichiro Nakano, Ho-Shin Gwak, Heon Yoo, Seung-Hoon Lee, Jeongwu Lee, Jong Heon Kim, Soo-Youl Kim, Do-Hyun Nam, Myung-Jin Park, Jong Bae Park
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NFκB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome...
July 28, 2017: Cancer Research
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