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patient derived xenografts

Yongjia Hao, Jiankun Lyu, Rong Qu, Yi Tong, Deheng Sun, Fang Feng, Linjiang Tong, Tingyuan Yang, Zhenjiang Zhao, Lili Zhu, Jian Ding, Yufang Xu, Hua Xie, Honglin Li
First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib have achieved initially marked clinical efficacy for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR...
June 15, 2018: Journal of Medicinal Chemistry
Catherine J Libby, Sixue Zhang, Gloria A Benavides, Sarah E Scott, Yanjie Li, Matthew Redmann, Anh Nhat Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Corinne Elizabeth Augelli-Szafran, Wei Zhang, Anita B Hjelmeland
Tumor heterogeneity has hampered the development of novel effective therapeutic options for aggressive cancers, including the deadly primary adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is partially attributed to the tumor initiating cell (TIC) subset that contains highly tumorigenic, stem-like cells. TICs display metabolic plasticity but can have a reliance on aerobic glycolysis. Elevated expression of GLUT1 and GLUT3 is present in many cancer types, with GLUT3 being preferentially expressed in brain TICs (BTICs) to increase survival in low nutrient tumor microenvironments, leading to tumor maintenance...
June 15, 2018: ACS Chemical Biology
Stephen Yiu Chuen Choi, Susan L Ettinger, Dong Lin, Hui Xue, Xinpei Ci, Noushin Nabavi, Robert H Bell, Fan Mo, Peter W Gout, Neil E Fleshner, Martin E Gleave, Colin C Collins, Yuzhuo Wang
Development of neuroendocrine prostate cancer (NEPC) is emerging as a major problem in clinical management of advanced prostate cancer (PCa). As increasingly potent androgen receptor (AR)-targeting antiandrogens are more widely used, PCa transdifferentiation into AR-independent NEPC as a mechanism of treatment resistance becomes more common and precarious, since NEPC is a lethal PCa subtype urgently requiring effective therapy. Reprogrammed glucose metabolism of cancers, that is elevated aerobic glycolysis involving increased lactic acid production/secretion, plays a key role in multiple cancer-promoting processes and has been implicated in therapeutics development...
June 14, 2018: Cancer Medicine
Matthew Dankner, Mathieu Lajoie, Dan Moldoveanu, Tan-Trieu Nguyen, Paul Savage, Shivshankari Rajkumar, Xiu Huang, Maria Lvova, Alexei Protopopov, Dana Vuzman, David Hogg, Morag Park, Marie-Christine Guiot, Kevin Petrecca, Catalin Mihalcioiu, Ian R Watson, Peter M Siegel, April A N Rose
PURPOSE: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. EXPERIMENTAL DESIGN: Tumors from patients with BRAF WT, V600E (class I) and L597S (class II) metastatic melanoma were used to generate patient-derived-xenografts (PDX)...
June 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
Z Kozovska, A Patsalias, V Bajzik, E Durinikova, L Demkova, S Jargasova, B Smolkova, J Plava, L Kucerova, M Matuskova
BACKGROUND: Recent evidence in cancer research, developed the notion that malignant tumors consist of different subpopulations of cells, one of them, known as cancer stem cells, being attributed many important properties such as enhanced tumorigenicity, proliferation potential and profound multidrug resistance to chemotherapy. Several key stem cells markers were identified in colon cancer. In our study we focused on the aldehyde dehydrogenase type 1 (ALDH1) expression in colon cancer-derived cell lines HT-29/eGFP, HCT-116/eGFP and LS-180/eGFP, and its role in the chemoresistance and tumorigenic potential...
June 15, 2018: BMC Cancer
Ha Thi Vu, Masahiko Kobayashi, Ahmed M Hegazy, Yuko Tadokoro, Masaya Ueno, Atsuko Kasahara, Yusuke Takase, Naho Nomura, Hui Peng, Chiaki Ito, Yasushi Ino, Tomoki Todo, Mitsutoshi Nakada, Atsushi Hirao
Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells' responses to chemotherapeutics remains controversial. To investigate the roles of autophagy in malignant gliomas, we used CRISPR/CAS9 to knock out the ATG5 gene, which is essential for autophagosome formation, in tumor cells derived from glioblastoma patients. While ATG5 disruption inhibited autophagy, it did not change the phenotypes of glioma cells and did not alter their sensitivity to temozolomide, an agent used for glioblastoma patient therapy...
June 14, 2018: Cancer Science
Eliza Li Shan Fong, Tan Boon Toh, Quy Xiao Xuan Lin, Zheng Liu, Lissa Hooi, Masturah Bte Mohd Abdul Rashid, Touati Benoukraf, Edward Kai-Hua Chow, The Hung Huynh, Hanry Yu
This data article presents datasets associated with the research article entitled "Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer" (Fong et al., 2018) [1]. A three-dimensional macroporous sponge system was used to generate in vitro counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines. This article describes the viability, proliferative capacity and molecular features (genomic and transcriptomic profiles) of the cultured HCC-PDX cells...
June 2018: Data in Brief
Guohui Qin, Jingyao Lian, Lan Huang, Qitai Zhao, Shasha Liu, Zhen Zhang, Xinfeng Chen, Dongli Yue, Lifeng Li, Feng Li, Lidong Wang, Viktor Umansky, Bin Zhang, Shengli Yang, Yi Zhang
Purpose : Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured...
2018: Oncoimmunology
Martin C Pearce, John T Gamble, Prasad R Kopparapu, Edmond F O'Donnell, Monica J Mueller, Hyo Sang Jang, Julie A Greenwood, Arnold C Satterthwait, Robert L Tanguay, Xiao-Kun Zhang, Siva Kumar Kolluri
Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance...
May 25, 2018: Oncotarget
Evangelia K Papachristou, Kamal Kishore, Andrew N Holding, Kate Harvey, Theodoros I Roumeliotis, Chandra Sekhar Reddy Chilamakuri, Soleilmane Omarjee, Kee Ming Chia, Alex Swarbrick, Elgene Lim, Florian Markowetz, Matthew Eldridge, Rasmus Siersbaek, Clive S D'Santos, Jason S Carroll
Understanding the dynamics of endogenous protein-protein interactions in complex networks is pivotal in deciphering disease mechanisms. To enable the in-depth analysis of protein interactions in chromatin-associated protein complexes, we have previously developed a method termed RIME (Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins). Here, we present a quantitative multiplexed method (qPLEX-RIME), which integrates RIME with isobaric labelling and tribrid mass spectrometry for the study of protein interactome dynamics in a quantitative fashion with increased sensitivity...
June 13, 2018: Nature Communications
Hongyue Zhang, Ying Liu, Lixin Yan, Min Zhang, Xiufeng Yu, Wei Du, Siqi Wang, Qiaozhi Li, He Chen, Yafeng Zhang, Hanliang Sun, Zhidong Tang, Daling Zhu
Many long noncoding RNAs (lncRNAs) have been identified as powerful regulators of lung adenocarcinoma (LAD). However, the role of HOXA-AS3, a novel lncRNA, in LAD is largely unknown. In this study, we showed that HOXA-AS3 was significantly upregulated in LAD tissues and A549 cells. After knockdown of HOXA-AS3, cell proliferation, migration, and invasion were inhibited. Xenografts derived from A549 cells transfected with shRNA/HOXA-AS3 had significantly lower tumor weights and smaller tumor volumes. We also demonstrated that HOXA-AS3 increased HOXA6 mRNA stability by forming an RNA duplex...
June 13, 2018: Cell Death & Disease
David S Hersh, Bryan G Harder, Alison Roos, Sen Peng, Jonathan E Heath, Teklu Legesse, Anthony J Kim, Graeme F Woodworth, Nhan L Tran, Jeffrey A Winkles
Background: Glioblastoma (GBM) is a difficult-to-treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy-resistant. Our prior work has demonstrated an important role for the TWEAK receptor Fn14 in GBM patho-biology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods: Fn14 mRNA expression levels in the non-neoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from the TCGA data portal...
April 20, 2018: Neuro-oncology
Jeff Hirst, Harsh B Pathak, Stephen Hyter, Ziyan Y Pessetto, Thuc Ly, Stefan Graw, Devin C Koestler, Adam J Krieg, Katherine F Roby, Andrew K Godwin
Drug development for front-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anti-cancer drugs...
June 11, 2018: Cancer Research
Kshitij Verma, Nehal Gupta, Tianzhu Zang, Phumvadee Wangtrakuldee, Sanjay K Srivastava, Trevor M Penning, Paul C Trippier
Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17 β-hydroxysteroid dehydrogenase is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy...
June 11, 2018: Molecular Cancer Therapeutics
Tina T Thomas, Sahiti Chukkapalli, Raelene A Van Noord, Melanie Krook, Mark J Hoenerhoff, Jonathan R Dillman, Elizabeth R Lawlor, Valerie P Opipari, Erika A Newman
Preclinical testing of anticancer therapies relies on relevant xenograft models that mimic the innate tendencies of cancer. Advantages of standard subcutaneous flank models include procedural ease and the ability to monitor tumor progression and response without invasive imaging. Such models are often inconsistent in translational clinical trials and have limited biologically relevant characteristics with low proclivity to produce metastasis, as there is a lack of a native microenvironment. In comparison, orthotopic xenograft models at native tumor sites have been shown to mimic the tumor microenvironment and replicate important disease characteristics such as distant metastatic spread...
May 25, 2018: Journal of Visualized Experiments: JoVE
Tobias Sivlér, Petter Sivlér, Mårten Skog, Luca Conti, Daniel Aili
OBJECTIVE: Wound dressings that use biosynthetic cellulose may be a good alternative to dressings currently used to treat chronic and acute ulcers because their nanostructure is similar to collagen. The objective of this study was to evaluate a wound dressing created with a new material that is composed of a fibrillary network of biosynthetic cellulose. METHODS: A case series of 8 patients in primary healthcare centers in Östergötland county council, Sweden, with chronic and acute lower limb wounds were treated with a wound dressing based on eiratex (S2Medical AB, Linköping, Sweden)...
June 7, 2018: Advances in Skin & Wound Care
Xin Fu, Lulu Yu, Yanshu Li, Yu Zhang, Xiaoping Xiao, Jinsheng Zhang, Ting Shu, Cai Jing, Qun Tang
Magnetic nanoparticles are emerging as promising candidates for next-generation of imaging contrast agents and its performance was largely dependent on physico-chemistry properties. In this paper, A new type of "top down" fabrication technique was developed to synthesize ultrasmall magnetic nanoparticle as contrast enhancer. In detailed, home-made oxygen plasma generator fragments larger KMnF3 nanoparticle (22 nm) into smaller (<5 nm) particle with enhanced hydrophilicity, as massive activated oxygen species produced during plasma could severally etch the nanoparticle, and VUV light irradiated it heavily as well, leaving it weak crystallinity, even splitting into ultrafine particle, also its surface transformed from hydrophobic to hydrophilic by oxidizing the passivated ligand, evidenced from the spectroscopy and microscopy...
June 11, 2018: Nanotechnology
Cailing Jiang, Shumin Li, Yanjing Li, Yuxian Bai
Despite recent advances in chemotherapy and surgical resection, the 5-year survival rate of esophageal cancer still remains at the low level. Therefore, it is very important to discover a new agent to improve the life expectancy of patients with esophageal cancer. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has recently exhibited promising anticancer activity against various cancer cells. But so far, the specific mechanism remains unclear. We have previously demonstrated that DHA reduced viability of esophageal cancer cells in a dose-dependent manner in vitro and induced cell cycle arrest and apoptosis...
2018: Analytical Cellular Pathology (Amsterdam)
Olivia M Yu, Jorge A Benitez, Steven W Plouffe, Daniel Ryback, Andrea Klein, Jeff Smith, Jason Greenbaum, Benjamin Delatte, Anjana Rao, Kun-Liang Guan, Frank B Furnari, Olga Meiri Chaim, Shigeki Miyamoto, Joan Heller Brown
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation...
June 11, 2018: Oncogene
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