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https://www.readbyqxmd.com/read/29334371/cooperative-targeting-of-melanoma-heterogeneity-with-an-axl-antibody-drug-conjugate-and-braf-mek-inhibitors
#1
Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29334307/regorafenib-regresses-an-imatinib-resistant-recurrent-gastrointestinal-stromal-tumor-gist-with-a-mutation-in-exons-11-and-17-in-a-patient-derived-orthotopic-xenograft-pdox-nude-mouse-model
#2
Kentaro Miyake, Kei Kawaguchi, Tasuku Kiyuna, Masuyo Miyake, Kentaro Igarashi, Zhiying Zhang, Takashi Murakami, Yunfeng Li, Scott D Nelson, Irmina Elliott, Tara Russell, Arun Singh, Yukihiko Hiroshima, Masashi Momiyama, Ryusei Matsuyama, Takashi Chisima, Itaru Endo, Fritz C Eilber, Robert M Hoffman
Gastrointestinal stromal tumor (GIST) is a rare type of sarcoma. The aim of this study was to determine drug sensitivity for a regionally-recurrent case of GIST using a patient-derived orthotopic xenograft (PDOX) model. The PDOX model was established in the anterior wall of the stomach. GIST PDOX models were randomized into 5 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration (p.o.), daily, for 3 weeks); G3, sunitinib group (p.o., daily, for 3 weeks); G4, regorafenib (p...
January 15, 2018: Cell Cycle
https://www.readbyqxmd.com/read/29333924/dynamic-mr-imaging-for-functional-vascularization-depends-on-tissue-factor-signaling-in-glioblastoma
#3
Xiao Chen, Tian Xie, Jingqin Fang, Wei Xue, Houyi Kang, Haipeng Tong, Yu Guo, Bo Zhang, Sumei Wang, Yizeng Yang, Weiguo Zhang
Glomeruloid vascular proliferation (GVP) is a diagnostic hallmark and links to aggressive behavior, therapy resistance and poor prognosis in glioblastoma (GBM). It lacks clinical approaches to predict and monitor its formation and dynamic change. Yet the mechanism of GVPs also remains largely unknown. Using an in situ GBM xenograft mouse model, combined clinical MRI images of pre-surgery tumor and pathological investigation, we demonstrated that the inhibition of tissue factor (TF) decreased GVPs in Mouse GBM xenograft model...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29332537/azd9291-increases-sensitivity-to-radiation-in-pc-9-ir-cells-by-delaying-dna-damage-repair-after-irradiation-and-inducing-apoptosis
#4
Shenghai Wu, Lucheng Zhu, Linglan Tu, Sumei Chen, Haixiu Huang, Jingjing Zhang, Shenglin Ma, Shirong Zhang
AZD9291 is a novel, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which is administered orally. It has been proven effective in non-small cell lung cancer (NSCLC) patients, with both EGFR-sensitizing and EGFR T790M mutations in preclinical models. However, the potential therapeutic effects of AZD9291 combined with other modalities, including ionizing radiation, are not well understood. The presence of AZD9291 significantly increases the cell-killing effects of radiation in PC-9-IR cells with a secondary EGFR mutation (T790M), which was developed from NSCLC PC-9 cells (human lung adenocarcinoma cell with EGFR 19 exon 15 bp deletion) after chronic exposure to increasing doses of gefitinib, and in H1975 cells (human lung adenocarcinoma cell with EGFR exon 20 T790M mutation de novo), but not in PC-9 cells or in H460 cells (human lung adenocarcinoma cell with wild-type EGFR)...
January 13, 2018: Radiation Research
https://www.readbyqxmd.com/read/29332125/icg-001-exerts-potent-anticancer-activity-against-uveal-melanoma-cells
#5
Salma Kaochar, Jianrong Dong, Marie Torres, Kimal Rajapakshe, Fotis Nikolos, Christel M Davis, Erik A Ehli, Cristian Coarfa, Nicholas Mitsiades, Vasiliki Poulaki
Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program. Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29331886/anti-cancer-effects-of-hnha-and-lenvatinib-by-the-suppression-of-emt-mediated-drug-resistance-in-cancer-stem-cells
#6
Yong Sang Lee, Seok-Mo Kim, Bup-Woo Kim, Ho Jin Chang, Soo Young Kim, Cheong Soo Park, Ki Cheong Park, Hang-Seok Chang
Anaplastic thyroid cancer (ATC) constitutes less than 2% of total thyroid cancers but accounts for 20-40% of thyroid cancer-related deaths. Cancer stem cell drug resistance represents a primary factor hindering treatment. This study aimed to develop targeted agents against thyroid malignancy, focusing on individual and synergistic effects of HNHA (histone deacetylase), lenvatinib (FGFR), and sorafenib (tyrosine kinase) inhibitors. Patients with biochemically and histologically proven papillary thyroid cancer (PTC) and ATC were included...
January 11, 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29331421/hyperglycaemia-induced-mir-301a-promotes-cell-proliferation-by-repressing-p21-and-smad4-in-prostate-cancer
#7
Xiaojuan Li, Jun Li, Yi Cai, Shubin Peng, Jun Wang, Zhaoming Xiao, Yu Wang, Yiran Tao, Jun Li, Qu Leng, Dinglan Wu, Shaodong Yang, Ziliang Ji, Yuefu Han, Liren Li, Xin Gao, Chunxian Zeng, Xingqiao Wen
Hyperglycaemia promotes the development of Prostate cancer (PCa). However, the roles of miRNAs in this disease process and the underlying mechanisms are largely unknown. In this study, we recruited 391 PCa patients in China and found that PCa patients with high level blood glucose (≥100 mg/dL) trended to have high Gleason score (GS≥7). miRNA-301a levels were significantly higher in prostate cancer than that in normal prostate tissues. Hyperglycaemia or high glucose treatment induced miR-301a expression in prostate tissues or PCa cell lines...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29331413/eef-2-kinase-targeted-mir-449b-confers-radiation-sensitivity-to-cancer-cells
#8
Cheng Ji, QiongHua Xu, LingChuan Guo, XiaoHui Wang, YiJie Ren, HongHan Zhang, WeiDong Zhu, ZhiJun Ming, YunSheng Yuan, XingCong Ren, JianXun Song, Yan Cheng, JinMing Yang, Yi Zhang
The roles of microRNA in regulation of various biological processes and in modulation of therapeutic effects have been widely appreciated. In this study, we found a positive correlation between miR-449 b expression and radiation sensitivity in cancer cells and in tumor specimens from patients. We showed that eEF-2 kinase, a negative regulator of global protein synthesis, is a target of miR-449 b. Introducing a miR-449 b mimic into cancer cells led to suppression of eEF-2 kinase expression, leading to increases of protein synthesis and depletion of cellular ATP...
January 10, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29330552/dosimetry-prediction-for-clinical-translation-of-64cu-pembrolizumab-immunopet-targeting-human-pd-1-expression
#9
Arutselvan Natarajan, Chirag B Patel, Frezghi Habte, Sanjiv S Gambhir
The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64Cu-pembrolizumab radiotracer and evaluated human dosimetry...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330466/target-engagement-imaging-of-parp-inhibitors-in-small-cell-lung-cancer
#10
Brandon Carney, Susanne Kossatz, Benjamin H Lok, Valentina Schneeberger, Kishore K Gangangari, Naga Vara Kishore Pillarsetty, Wolfgang A Weber, Charles M Rudin, John T Poirier, Thomas Reiner
Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo...
January 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29330447/human-placental-derived-adherent-stromal-cells-co-induced-with-tnf-%C3%AE-and-ifn-%C3%AE-inhibit-triple-negative-breast-cancer-in-nude-mouse-xenograft-models
#11
Hoshea Allen, Niva Shraga-Heled, Michal Blumenfeld, Tamar Dego-Ashto, Dana Fuchs-Telem, Ariel Gilert, Zami Aberman, Racheli Ofir
Culturing 3D-expanded human placental-derived adherent stromal cells (ASCs) in the presence of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) transiently upregulated the secretion of numerous anti-proliferative, anti-angiogenic and pro-inflammatory cytokines. In a 3D-spheroid screening assay, conditioned medium from these induced-ASCs inhibited proliferation of cancer cell lines, including triple-negative breast cancer (TNBC) lines. In vitro co-culture studies of induced-ASCs with MDA-MB-231 human breast carcinoma cells, a model representing TNBC, supports a mechanism involving immunomodulation and angiogenesis inhibition...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330297/characterization-and-evidence-of-the-mir-888-cluster-as-a-novel-cancer-network-in-prostate
#12
Tsuyoshi Hasegawa, Garrison Glavich, Mary Pahuski, Aleena M Short, Oliver John Semmes, Lifang Yang, Vitold Galkin, Richard R Drake, Aurora Esquela-Kerscher
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of ~22 nucleotide non-coding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients but the mechanism of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330294/establishment-of-the-first-well-differentiated-human-pancreatic-neuroendocrine-tumor-model
#13
Daniel Benten, Yasmin Behrang, Ludmilla Unrau, Victoria Weissmann, Gerrit Wolters-Eisfeld, Susanne Burdak-Rothkamm, Felix R Stahl, Martin Anlauf, Patricia Grabowski, Markus Möbs, Jan Dieckhoff, Bence Sipos, Martina Fahl, Corinna Eggers, Daniel Perez, Maximilian Bockhorn, Jakob R Izbicki, Ansgar W Lohse, Joerg Schrader
Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative in vitro and in vivo model systems. So far, the unavailability of a human model with a well-differentiated phenotype and typical growth characteristics has impaired pre-clinical research in NET. Herein, we establish and characterize a lymph node-derived cell line (NT-3) from a male patient with well-differentiated pancreatic NET. Neuroendocrine differentiation and tumor biology was compared to existing NET cell lines BON and QGP-1...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330291/keap1-inhibits-metastatic-properties-of-nsclc-cells-by-stabilizing-architectures-of-f-actin-and-focal-adhesions
#14
Bo Wu, Shu Yang, Haimei Sun, Tingyi Sun, Fengqing Ji, Yurong Wang, Lie Xu, Deshan Zhou
Low expression of the tumor suppressor, Kelch-like ECH-associated protein 1 (KEAP1) in non-small cell lung cancer (NSCLC) often results in higher malignant biological behavior and poor prognosis; however, the underlying mechanism remains unclear. The present study demonstrates that overexpression of Keap1 significantly suppresses migration and invasion of three different lung cancer cells (A549, H460, and H1299). Highly-expressed Keap1, compared to the control, promotes formation of multiple stress fibers with larger mature focal adhesion complexes in the cytoplasm where only fine focal adhesions were observed in the membrane under control conditions...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330290/dual-inhibition-of-cdk4-and-cdk2-via-targeting-p27-tyrosine-phosphorylation-induces-a-potent-and-durable-response-in-breast-cancer-cells
#15
Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
Cyclin-dependent kinase 4/6 (CDK4/6) specific inhibitors, such as Palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue Palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330284/novel-intergenically-spliced-chimera-nfatc3-pla2g15-is-associated-with-aggressive-t-all-biology-and-outcome
#16
Jonathan Bond, Christine Tran Quang, Guillaume Hypolite, Mohamed Belhocine, Aurélie Bergon, Gaëlle Cordonnier, Jacques Ghysdael, Elizabeth Macintyre, Nicolas Boissel, Salvatore Spicuglia, Vahid Asnafi
Leukemias are frequently characterized by the expression of oncogenic fusion chimeras that normally arise due to chromosomal rearrangements. Intergenically-spliced chimeric RNAs (ISCs) are transcribed in the absence of structural genomic changes, and aberrant ISC expression is now recognized as a potential driver of cancer. To better understand these potential oncogenic drivers, high-throughput RNA-sequencing (RNA-seq) was performed on T-acute lymphoblastic leukemia (T-ALL) patient specimens (n=24) and candidate T-ALL-related ISCs were identified (n=55; a median of 4 per patient)...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29330203/personalized-rna-medicine-for-pancreatic-cancer
#17
Maud-Emmanuelle Gilles, Liangliang Hao, Ling Huang, Rajesha Rupaimoole, Pedro P Lopez-Casas, Emilia Pulver, Jong Cheol Jeong, Senthil K Muthuswamy, Manuel Hidalgo, Sangeeta N Bhatia, Frank J Slack
PURPOSE: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.  Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330146/demethylation-induced-overexpression-of-shc3-drives-c-raf-independent-activation-of-mek-erk-in-hcc
#18
Yun Liu, Xinran Zhang, Baicai Yang, Hao Zhuang, Hua Guo, Wen Wei, Yuan Li, Ruibing Chen, Yongmei Li, Ning Zhang
Invasion and intrahepatic metastasis are major factors of poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we show that increased Src homolog and collagen homolog 3 (Shc3) expression in malignant HCC cell lines associate with HCC invasion and metastasis. Shc3 was significantly upregulated in tumors of 33 HCC patient samples as compared to adjacent normal tissues. Further analysis of 52 HCC patient samples showed that Shc3 expression correlated with microvascular invasion, cancer staging, and poor prognosis...
January 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29329543/stat3-induced-lncrna-haglros-overexpression-contributes-to-the-malignant-progression-of-gastric-cancer-cells-via-mtor-signal-mediated-inhibition-of-autophagy
#19
Jin-Fei Chen, Peng Wu, Rui Xia, Jian Yang, Xin-Ying Huo, Dong-Ying Gu, Cui-Ju Tang, Wei De, Fen Yang
BACKGROUND: Long noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression...
January 12, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29329364/downregulation-of-drp1-a-fission-regulator-is-associated-with-human-lung-and-colon-cancers
#20
Young Yeon Kim, Seong-Hoon Yun, Jeanho Yun
Dynamin-related protein 1 (Drp1), a dynamin-related GTPase, is a key regulator of mitochondrial fission. Although recent studies have shown that Drp1 plays important roles in various important cellular processes, such as maintaining proper mitochondrial function, apoptosis and necrosis, the potential involvement of Drp1 in cancer development has not been fully addressed. To explore the role of Drp1 in cancer, we examined Drp1 levels in various human cancer tissues. Tissue array analysis showed that the level of Drp1 was decreased significantly in malignant colon and lung cancer tissues, whereas no change in Drp1 was observed in breast and prostate tumors...
January 10, 2018: Acta Biochimica et Biophysica Sinica
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