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Patient derived xenograft and methylation

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https://www.readbyqxmd.com/read/28228601/loss-of-tumor-suppressor-kdm6a-amplifies-prc2-regulated-transcriptional-repression-in-bladder-cancer-and-can-be-targeted-through-inhibition-of-ezh2
#1
Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G Rozen, Patrick Tan, Caretha L Creasy, See-Tong Pang, Michael T McCabe, Song Ling Poon, Bin Tean Teh
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type...
February 22, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28159862/temozolomide-in-the-era-of-precision-medicine
#2
REVIEW
Anish Thomas, Mamoru Tanaka, Jane Trepel, William C Reinhold, Vinodh N Rajapakse, Yves Pommier
In the January 1, 2017, issue of Cancer Research, Nagel and colleagues demonstrate the value of assays that determine the DNA repair capacity of cancers in predicting response to temozolomide. Using a fluorescence-based multiplex flow cytometric host cell reactivation assay that provides simultaneous readout of DNA repair capacity across multiple pathways, they show that the multivariate drug response models derived from cell line data were applicable to patient-derived xenograft models of glioblastoma. In this commentary, we first outline the mechanism of activity and current clinical application of temozolomide, which, until now, has been largely limited to glioblastoma...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28093071/spag6-and-l1td1-are-transcriptionally-regulated-by-dna-methylation-in-non-small-cell-lung-cancers
#3
Corinna Altenberger, Gerwin Heller, Barbara Ziegler, Erwin Tomasich, Maximilian Marhold, Thais Topakian, Leonhard Müllauer, Petra Heffeter, György Lang, Adelheid End-Pfützenreuter, Balazs Döme, Britt-Madeleine Arns, Walter Klepetko, Christoph C Zielinski, Sabine Zöchbauer-Müller
BACKGROUND: DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs...
January 5, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28040796/role-of-rpl39-in-metaplastic-breast-cancer
#4
Bhuvanesh Dave, Daniel D Gonzalez, Zhi-Bin Liu, Xiaoxian Li, Helen Wong, Sergio Granados, Nadeer E Ezzedine, Douglas H Sieglaff, Joe E Ensor, Kathy D Miller, Milan Radovich, Agda KarinaEtrovic, Steven S Gross, Olivier Elemento, Gordon B Mills, Michael Z Gilcrease, Jenny C Chang
BACKGROUND: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown...
June 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27872496/inactivation-of-klf4-promotes-t-cell-acute-lymphoblastic-leukemia-and-activates-the-map2k7-pathway
#5
Y Shen, C S Park, K Suppipat, T-A Mistretta, M Puppi, T M Horton, K Rabin, N S Gray, J P P Meijerink, H D Lacorazza
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL. In mice, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL by enhancing the G1-to-S transition in leukemic cells and promoting the expansion of leukemia-initiating cells...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27837553/biobanking-an-important-resource-for-precision-medicine-in-glioblastoma
#6
Si Yan Melanie Tan, Edwin Sandanaraj, Carol Tang, Beng Ti Christopher Ang
The Cancer Genome Atlas effort has generated significant interest in a new paradigm shift in tumor tissue analysis, patient diagnosis and subsequent treatment decision. Findings have highlighted the limitation of sole reliance on histology, which can be confounded by inter-observer variability. Such studies demonstrate that histologically similar grade IV brain tumors can be divided into four molecular subtypes based on gene expression, with each subtype demonstrating unique genomic aberrations and clinical outcome...
2016: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27765857/assessment-of-tryptophan-uptake-and-kinetics-using-1-2-18f-fluoroethyl-l-tryptophan-and-%C3%AE-11c-methyl-l-tryptophan-pet-imaging-in-mice-implanted-with-patient-derived-brain-tumor-xenografts
#7
Sharon K Michelhaugh, Otto Muzik, Anthony R Guastella, Neil V Klinger, Lisa A Polin, Hancheng Cai, Yanchun Xin, Thomas J Mangner, Shaohui Zhang, Csaba Juhasz, Sandeep Mittal
Abnormal tryptophan metabolism via the kynurenine pathway (KP) is involved in the pathophysiology of a variety of human diseases including cancers. α-[(11)C]-methyl-L-tryptophan ((11)C-AMT) positron emission tomography (PET) imaging demonstrated increased tryptophan uptake and trapping in epileptic foci and brain tumors, but the short half-life of (11)C limits its widespread clinical application. Recent in vitro studies suggested that the novel radiotracer 1-(2-[(18)F]fluoroethyl)-L-tryptophan ((18)F-FETrp) may be useful to assess tryptophan metabolism via the KP...
October 20, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/27765068/genome-wide-methylation-profiling-of-ovarian-cancer-patient-derived-xenografts-treated-with-the-demethylating-agent-decitabine-identifies-novel-epigenetically-regulated-genes-and-pathways
#8
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27750381/molecular-heterogeneity-of-non-small-cell-lung-carcinoma-patient-derived-xenografts-closely-reflect-their-primary-tumors
#9
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
February 1, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27742014/kdm4c-a-h3k9me3-histone-demethylase-is-involved-in-the-maintenance-of-human-escc-initiating-cells-by-epigenetically-enhancing-sox2-expression
#10
Xiang Yuan, Jinyu Kong, Zhikun Ma, Na Li, Ruinuo Jia, Yiwen Liu, Fuyou Zhou, Qimin Zhan, Gang Liu, Shegan Gao
Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDH(bri+) phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDH(bri+) subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDH(bri+) TICs population in vitro and specifically targeted the TICs in ALDH(bri+)-derived xenograft, retarding engraftment...
October 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27614696/in-vivo-anti-tumor-activity-of-the-parp-inhibitor-niraparib-in-homologous-recombination-deficient-and-proficient-ovarian-carcinoma
#11
Mariam M AlHilli, Marc A Becker, S John Weroha, Karen S Flatten, Rachel M Hurley, Maria I Harrell, Ann L Oberg, Matt J Maurer, Kieran M Hawthorne, Xiaonan Hou, Sean C Harrington, Sarah McKinstry, X Wei Meng, Keith M Wilcoxen, Kimberly R Kalli, Elizabeth M Swisher, Scott H Kaufmann, Paul Haluska
OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo...
November 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27582487/essential-role-of-dna-methyltransferase-1-mediated-transcription-of-insulin-like-growth-factor-2-in-resistance-to-histone-deacetylase-inhibitors
#12
Hye-Young Min, Su-Chan Lee, Jong Kyu Woo, Hyun Jin Jung, Kwan Hee Park, Hae Min Jeong, Seung Yeob Hyun, Jaebeom Cho, Wooin Lee, Ji Eun Park, So Jung Kwon, Hyo-Jong Lee, Xiao Ni, Young Kee Shin, Faye M Johnson, Madeleine Duvic, Ho-Young Lee
Purpose: Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.Experimental Design: The methylation status of CCCTC-binding factor (CTCF)-binding sites in the IGF2/H19 imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing...
March 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27496707/cancer-associated-fibroblasts-in-pancreatic-cancer-are-reprogrammed-by-tumor-induced-alterations-in-genomic-dna-methylation
#13
Qian Xiao, Donger Zhou, Agnieszka A Rucki, Jamila Williams, Jiaojiao Zhou, Guanglan Mo, Adrian Murphy, Kenji Fujiwara, Jennifer Kleponis, Bulent Salman, Christopher L Wolfgang, Robert A Anders, Shu Zheng, Elizabeth M Jaffee, Lei Zheng
Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27399418/139%C3%A2-clinically-applicable-and-biologically-validated-mri-radiomic-test-method-predicts-glioblastoma-genomic-landscape-and-survival
#14
Pascal O Zinn, Sanjay K Singh, Aikaterini Kotrotsou, Faramak Zandi, Ginu Thomas, Masumeh Hatami, Markus M Luedi, Ahmed Elakkad, Islam Hassan, Joy Gumin, Erik P Sulman, Frederick F Lang, Rivka R Colen
INTRODUCTION: Imaging is the modality of choice for noninvasive characterization of biological tissue and organ systems; imaging serves as early diagnostic tool for most disease processes and is rapidly evolving, thus transforming the way we diagnose and follow patients over time. A vast number of cancer imaging characteristics have been correlated to underlying genomics; however, none have established causality. Therefore, our objectives were to test if there is a causal relationship between imaging and genomic information; and to develop a clinically relevant radiomic pipeline for glioblastoma molecular characterization...
August 2016: Neurosurgery
https://www.readbyqxmd.com/read/27381626/mechanisms-of-therapy-resistance-in-patient-derived-xenograft-models-of-brca1-deficient-breast-cancer
#15
Petra Ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jóźwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen, Jelle Wesseling, Jos Jonkers
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined...
November 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27302921/a-comprehensively-characterized-cell-line-panel-highly-representative-of-clinical-ovarian-high-grade-serous-carcinomas
#16
Kelsie L Thu, Mahboubeh Papari-Zareei, Victor Stastny, Kai Song, Michael Peyton, Victor D Martinez, Yu-An Zhang, Isabel B Castro, Marileila Varella-Garcia, Hanquan Liang, Chao Xing, Ralf Kittler, Sara Milchgrub, Diego H Castrillon, Heather L Davidson, C Patrick Reynolds, Wan L Lam, Jayanthi Lea, Adi F Gazdar
Recent literature suggests that most widely used ovarian cancer (OVCA) cell models do not recapitulate the molecular features of clinical tumors. To address this limitation, we generated 18 cell lines and 3 corresponding patient-derived xenografts predominantly from high-grade serous carcinoma (HGSOC) peritoneal effusions. Comprehensive genomic characterization and comparison of each model to its parental tumor demonstrated a high degree of molecular similarity. Our characterization included whole exome-sequencing and copy number profiling for cell lines, xenografts, and matched non-malignant tissues, and DNA methylation, gene expression, and spectral karyotyping for a subset of specimens...
June 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27257787/cystathionine-beta-synthase-inhibition-for-colon-cancer-enhancement-of-the-efficacy-of-aminooxyacetic-acid-via-the-prodrug-approach
#17
Celia Chao, John R Zatarain, Ye Ding, Ciro Coletta, Amy A Mrazek, Nadiya Druzhyna, Paul Johnson, Haiying Chen, Judy L Hellmich, Antonia Asimakopoulou, Kazunori Yanagi, Gabor Olah, Petra Szoleczky, Gabor Törö, Fredrick J Bohanon, Minal Cheema, Rachel Lewis, David Eckelbarger, Akbar Ahmad, Katalin Módis, Ashley Untereiner, Bartosz Szczesny, Andreas Papapetropoulos, Jia Zhou, Mark R Hellmich, Csaba Szabo
Colon cancer cells contain high levels of cystathionine-beta-synthase (CBS). Its product, hydrogen sulfide (H2S) promotes the growth and proliferation of colorectal tumor cells. In order to improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171...
May 16, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27244881/conjugation-to-the-sigma-2-ligand-sv119-overcomes-uptake-blockade-and-converts-dm-erastin-into-a-potent-pancreatic-cancer-therapeutic
#18
Kerri A Ohman, Yassar M Hashim, Suwanna Vangveravong, Timothy M Nywening, Darren R Cullinan, S Peter Goedegebuure, Jingxia Liu, Brian A Van Tine, Herve Tiriac, David A Tuveson, David G DeNardo, Dirk Spitzer, Robert H Mach, William G Hawkins
Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic...
June 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27151136/tryptophan-pet-imaging-of-the-kynurenine-pathway-in-patient-derived-xenograft-models-of-glioblastoma
#19
Anthony R Guastella, Sharon K Michelhaugh, Neil V Klinger, William J Kupsky, Lisa A Polin, Otto Muzik, Csaba Juhász, Sandeep Mittal
Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM...
2016: Molecular Imaging
https://www.readbyqxmd.com/read/27129160/ppmp-a-novel-tubulin-depolymerizing-agent-against-esophageal-cancer-in-patient-derived-tumor-xenografts
#20
Yuqiao Sheng, Kangdong Liu, Qiong Wu, Naomi Oi, Hanyong Chen, Kanamata Reddy, Yanan Jiang, Ke Yao, Haitao Li, Wei Li, Yi Zhang, Mohammad Saleem, Wei-Ya Ma, Ann M Bode, Ziming Dong, Zigang Dong
Esophageal cancer is one of the least studied and deadliest cancers worldwide with a poor prognosis due to limited options for treatment. Chemotherapy agents such as the microtubule-targeting compounds are the mainstay of palliation for advanced esophageal cancer treatment. However, the toxicity and side effects of tubulin-binding agents (TBAs) have promoted the development of novel, more potent but less toxic TBAs. Herein, we identified 2-[4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-5-yl]-5-[(2-methylprop-2-en-1-yl)oxy] phenol (PPMP) as a novel TBA for esophageal cancer treatment...
May 24, 2016: Oncotarget
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