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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/29301827/thy1-targeted-microbubbles-for-ultrasound-molecular-imaging-of-pancreatic-ductal-adenocarcinoma
#2
Lotfi Abou-Elkacem, Huaijun Wang, Sayan M Chowdhury, Richard H Kimura, Sunitha V Bachawal, Sanjiv S Gambhir, Lu Tian, Juergen K Willmann
PURPOSE: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble-enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN:  Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MB Thy1-scFv...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29229290/simple-detection-of-telomere-fusions-in-pancreatic-cancer-intraductal-papillary-mucinous-neoplasm-and-pancreatic-cyst-fluid
#3
Tatsuo Hata, Marco Dal Molin, Anne McGregor-Das, Tae Jun Song, Christopher Wolfgang, James R Eshleman, Ralph H Hruban, Michael Goggins
Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated...
December 6, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29157102/chk1-inhibitor-sch-900776-enhances-the-antitumor-activity-of-mln4924-on-pancreatic-cancer
#4
Jian-Ang Li, Chao Song, Yefei Rong, Tiantao Kuang, Dansong Wang, Xuefeng Xu, Jian Yuan, Kuntian Luo, Bo Qin, Somaira Nowsheen, Zhenkun Lou, Wenhui Lou
MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156810/psc-derived-galectin-1-inducing-epithelial-mesenchymal-transition-of-pancreatic-ductal-adenocarcinoma-cells-by-activating-the-nf-%C3%AE%C2%BAb-pathway
#5
Dong Tang, Jingqiu Zhang, Zhongxu Yuan, Hongpeng Zhang, Yang Chong, Yuqin Huang, Jie Wang, Qingquan Xiong, Sen Wang, Qi Wu, Ying Tian, Yongdie Lu, Xiao Ge, Wenjing Shen, Daorong Wang
Galectin-1 has previously been shown to be strongly expressed in activated pancreatic stellate cells (PSCs) and promote the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms by which Galectin-1 promotes the malignant behavior of pancreatic cancer cells remain unclear. In this study, we examined the effects of Galectin-1 knockdown or overexpression in PSCs co-cultured with pancreatic cancer (PANC-1) cells. Immunohistochemical analysis showed expression of epithelial-mesenchymal transition (EMT) markers and MMP9 were positively associated with the expression of Galectin-1 in 66 human PDAC tissues...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29143337/intraductal-papillary-mucinous-neoplasm-of-the-pancreas-rapidly-xenografts-in-chicken-eggs-and-predicts-aggressiveness
#6
Zhefu Zhao, Nathalie Bauer, Ewa Aleksandrowicz, Libo Yin, Jury Gladkich, Wolfgang Gross, Jörg Kaiser, Thilo Hackert, Oliver Strobel, Ingrid Herr
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has a high risk of progressing to invasive pancreatic ductal adenocarcinoma (PDA), but experimental models for IPMN are largely missing. New experimental systems for the molecular characterization of IPMN and for personalized prognosis and treatment options for IPMN are urgently needed. We analyzed the potential use of fertilized chicken eggs for the culture of freshly resected IPMN tissue. We transplanted 49 freshly resected IPMN tissues into eggs and compared the growth characteristics to IPMN tissues transplanted into mice; this was followed by an analysis of histology, morphology and marker expression...
November 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29073149/intrapancreatic-injection-of-human-bone-marrow-derived-mesenchymal-stem-stromal-cells-alleviates-hyperglycemia-and-modulates-the-macrophage-state-in-streptozotocin-induced-type-1-diabetic-mice
#7
Norimitsu Murai, Hirokazu Ohtaki, Jun Watanabe, Zhifang Xu, Shun Sasaki, Kazumichi Yagura, Seiji Shioda, Shoichiro Nagasaka, Kazuho Honda, Masahiko Izumizaki
Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model...
2017: PloS One
https://www.readbyqxmd.com/read/28977862/identification-and-causes-of-metabonomic-difference-between-orthotopic-and-subcutaneous-xenograft-of-pancreatic-cancer
#8
Bohan Zhan, Shi Wen, Jie Lu, Guiping Shen, Xianchao Lin, Jianghua Feng, Heguang Huang
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors. However, the methodological differences between orthotopic and subcutaneous xenograft (OX and SX) models will cause confusion in understanding its pathological mechanism and clinical relevance. In this study, SX and OX models were established by implanting Panc-1 and BxPC-3 cell strains under skin and on the pancreas of mice, respectively. The tumor tissue and serum samples were collected for(1)H NMR spectroscopy followed by univariate and multivariate statistical analyses...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28893801/galectin-3-a-druggable-vulnerability-for-kras-addicted-cancers
#9
Laetitia Seguin, Maria F Camargo, Hiromi I Wettersten, Shumei Kato, Jay S Desgrosellier, Tami von Schalscha, Kathryn C Elliott, Erika Cosset, Jacqueline Lesperance, Sara M Weis, David A Cheresh
Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance...
September 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28858862/pancreas-cancer-precision-treatment-using-avatar-mice-from-a-bioinformatics-perspective
#10
Javier Perales-Patón, Elena Piñeiro-Yañez, Héctor Tejero, Pedro P López-Casas, Manuel Hidalgo, Gonzalo Gómez-López, Fátima Al-Shahrour
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death among solid malignancies. Unfortunately, PDAC lethality has not substantially decreased over the past 20 years. This aggressiveness is related to the genomic complexity and heterogeneity of PDAC, but also to the absence of an effective screening for the detection of early-stage tumors and a lack of efficient therapeutic options. Therefore, there is an urgent need to improve the arsenal of anti-PDAC drugs for an effective treatment of these patients...
2017: Public Health Genomics
https://www.readbyqxmd.com/read/28793277/o-2-18-f-fluoroethyl-l-tyrosine-18-f-fet-uptake-in-insulinoma-first-results-from-a-xenograft-mouse-model-and-from-human
#11
Alessio Imperiale, Frédéric Boisson, Guillaume Kreutter, Bernard Goichot, Izzie Jacques Namer, Philippe Bachellier, Patrice Laquerriere, Laurence Kessler, Patrice Marchand, David Brasse
INTRODUCTION: Herein we have evaluated the uptake of O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) in insulinoma in comparison with those of 6-(18)F-fluoro-3,4-dihydroxy-l-phenylalanine ((18)F-FDOPA) providing first data from both murine xenograft model and one patient with proved endogenous hyperinsulinemic hypoglycemia. METHODS: Dynamic (18)F-FET and carbidopa-assisted (18)F-FDOPA PET were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F murine beta cells and on a 30-year-old man with type-1 multiple endocrine neoplasia and hyperinsulinemic hypoglycemia defined by a positive fasting test...
July 12, 2017: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/28761381/nmda-receptors-are-important-regulators-of-pancreatic-cancer-and-are-potential-targets-for-treatment
#12
William G North, Fuli Liu, Liz Z Lin, Ruiyang Tian, Bonnie Akerman
Pancreatic cancer, particularly adenocarcinoma of the pancreas, is a common disease with a poor prognosis. In this study, the importance of N-methyl-D-aspartate (NMDA) receptors for the growth and survival of pancreatic cancer was investigated. Immunohistochemistry performed with antibodies against GluN1 and GluN2B revealed that all invasive adenocarcinoma and neuroendocrine pancreatic tumors likely express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel-blocker antagonist and GluN2B antagonist significantly reduced cell viability in vitro...
2017: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/28748183/neodymium-140-dota-lm3-evaluation-of-an-in-vivo-generator-for-pet-with-a-non-internalizing-vector
#13
Gregory W Severin, Lotte K Kristensen, Carsten H Nielsen, Jesper Fonslet, Andreas I Jensen, Anders F Frellsen, K M Jensen, Dennis R Elema, Helmut Maecke, Andreas Kjær, Karl Johnston, Ulli Köster
(140)Nd (t1/2 = 3.4 days), owing to its short-lived positron emitting daughter (140)Pr (t1/2 = 3.4 min), has promise as an in vivo generator for positron emission tomography (PET). However, the electron capture decay of (140)Nd is chemically disruptive to macrocycle-based radiolabeling, meaning that an in vivo redistribution of the daughter (140)Pr is expected before positron emission. The purpose of this study was to determine how the delayed positron from the de-labeled (140)Pr affects preclinical imaging with (140)Nd...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28736522/gliotoxin-targets-nuclear-notch2-in-human-solid-tumor-derived-cell-lines-in-vitro-and-inhibits-melanoma-growth-in-xenograft-mouse-model
#14
Rainer Hubmann, Wolfgang Sieghart, Susanne Schnabl, Mohammad Araghi, Martin Hilgarth, Marlies Reiter, Dita Demirtas, Peter Valent, Christoph Zielinski, Ulrich Jäger, Medhat Shehata
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28650393/orthotopic-patient-derived-pancreatic-cancer-xenografts-engraft-into-the-pancreatic-parenchyma-metastasize-and-induce-muscle-wasting-to-recapitulate-the-human-disease
#15
Kristina L Go, Daniel Delitto, Sarah M Judge, Michael H Gerber, Thomas J George, Kevin E Behrns, Steven J Hughes, Andrew R Judge, Jose G Trevino
OBJECTIVE: Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model...
June 22, 2017: Pancreas
https://www.readbyqxmd.com/read/28609371/orthotopic-patient-derived-pancreatic-cancer-xenografts-engraft-into-the-pancreatic-parenchyma-metastasize-and-induce-muscle-wasting-to-recapitulate-the-human-disease
#16
Kristina L Go, Daniel Delitto, Sarah M Judge, Michael H Gerber, Thomas J George, Kevin E Behrns, Steven J Hughes, Andrew R Judge, Jose G Trevino
OBJECTIVE: Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model...
July 2017: Pancreas
https://www.readbyqxmd.com/read/28591747/identification-and-causes-of-metabonomic-difference-between-orthotopic-and-subcutaneous-xenograft-of-pancreatic-cancer
#17
Bohan Zhan, Shi Wen, Jie Lu, Guiping Shen, Xianchao Lin, Jianghua Feng, Heguang Huang
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors. However, the methodological differences between orthotopic and subcutaneous xenograft (OX and SX) models will cause confusion in understanding its pathological mechanism and clinical relevance. In this study, SX and OX models were established by implanting Panc-1 and BxPC-3 cell strains under skin and on the pancreas of mice, respectively. The tumor tissue and serum samples were collected for1H NMR spectroscopy followed by univariate and multivariate statistical analyses...
May 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28439784/practical-calculation-method-to-estimate-the-absolute-boron-concentration-in-tissues-using-18-f-fbpa-pet
#18
Tadashi Watabe, Kohei Hanaoka, Sadahiro Naka, Yasukazu Kanai, Hayato Ikeda, Masanao Aoki, Eku Shimosegawa, Mitsunori Kirihata, Jun Hatazawa
PURPOSE: The purpose of this study was to establish a practical method to estimate the absolute boron concentrations in the tissues based on the standardized uptake values (SUVs) after administration of 4-borono-phenylalanine (BPA) using 4-borono-2-(18)F-fluoro-phenylalanine ((18)F-FBPA) PET. METHODS: Rat xenograft models of C6 glioma (n = 7, body weight 241 ± 28.0 g) were used for the study. PET was performed 60 min after intravenous injection of (18)F-FBPA (30...
July 2017: Annals of Nuclear Medicine
https://www.readbyqxmd.com/read/28390868/small-nucleolar-noncoding-rna-snora23-up-regulated-in-human-pancreatic-ductal-adenocarcinoma-regulates-expression-of-spectrin-repeat-containing-nuclear-envelope-2-to-promote-growth-and-metastasis-of-xenograft-tumors-in-mice
#19
Lin Cui, Kenji Nakano, Sumalee Obchoei, Kiyoko Setoguchi, Masaki Matsumoto, Tsuyoshi Yamamoto, Satoshi Obika, Kazuaki Shimada, Nobuyoshi Hiraoka
BACKGROUND & AIMS: Small nucleolar noncoding RNAs (snoRNAs) regulate function of ribosomes, and specific snoRNAs are dysregulated in some cancer cells. We investigated dysregulation of snoRNAs in pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: We investigated snoRNA expression in PDAC cell lines by complementary DNA microarray and quantitative reverse transcription polymerase chain reaction. In PDAC (n = 133), intraductal papillary mucinous neoplasm (n = 16), mucinous cystic neoplasm-associated PDAC (n = 1), and non-tumor pancreas (n = 8) and liver (n = 3) tissues from subjects who underwent surgical resection, levels of snoRNA were measured by quantitative reverse transcription polymerase chain reaction and compared with clinicopathologic parameters and survival times determined by Kaplan-Meier analysis...
July 2017: Gastroenterology
https://www.readbyqxmd.com/read/28242812/crispr-knockout-of-the-hur-gene-causes-a-xenograft-lethal-phenotype
#20
Shruti Lal, Edwin C Cheung, Mahsa Zarei, Ranjan Preet, Saswati N Chand, Nicole C Mambelli-Lisboa, Carmella Romeo, Matthew C Stout, Eric Londin, Austin Goetz, Cinthya Y Lowder, Avinoam Nevler, Charles J Yeo, Paul M Campbell, Jordan M Winter, Dan A Dixon, Jonathan R Brody
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively...
June 2017: Molecular Cancer Research: MCR
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