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https://www.readbyqxmd.com/read/28331002/personalized-in-vitro-and-in-vivo-cancer-models-to-guide-precision-medicine
#1
Chantal Pauli, Benjamin D Hopkins, Davide Prandi, Reid Shaw, Tarcisio Fedrizzi, Andrea Sboner, Verena Sailer, Michael Augello, Loredana Puca, Rachele Rosati, Terra J McNary, Yelena Churakova, Cynthia Cheung, Joanna Triscott, David Pisapia, Rema Rao, Juan Miguel Mosquera, Brian Robinson, Bishoy M Faltas, Brooke E Emerling, Vijayakrishna K Gadi, Brady Bernard, Olivier Elemento, Himisha Beltran, Francesca Demichelis, Christopher J Kemp, Carla Grandori, Lewis C Cantley, Mark A Rubin
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial...
March 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28330821/beyond-precision-surgery-molecularly-motivated-precision-care-for-gastric-cancer
#2
REVIEW
Y Y Choi, J-H Cheong
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Despite the high disease prevalence, gastric cancer research has not gained much attention. Recently, genome-scale technology has made it possible to explore the characteristics of gastric cancer at the molecular level. Accordingly, gastric cancer can be classified into molecular subtypes that convey more detailed information of tumor than histopathological characteristics, and these subtypes are associated with clinical outcomes...
March 1, 2017: European Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28330676/stromal-gene-expression-is-predictive-for-metastatic-primary-prostate-cancer
#3
Fan Mo, Dong Lin, Mandeep Takhar, Varune Rohan Ramnarine, Xin Dong, Robert H Bell, Stanislav V Volik, Kendric Wang, Hui Xue, Yuwei Wang, Anne Haegert, Shawn Anderson, Sonal Brahmbhatt, Nicholas Erho, Xinya Wang, Peter W Gout, James Morris, R Jeffrey Karnes, Robert B Den, Eric A Klein, Edward M Schaeffer, Ashley Ross, Shancheng Ren, S Cenk Sahinalp, Yingrui Li, Xun Xu, Jun Wang, Jian Wang, Martin E Gleave, Elai Davicioni, Yinghao Sun, Yuzhuo Wang, Colin C Collins
BACKGROUND: Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for identification of biomarkers that can more accurately stratify patients with primary PCa. OBJECTIVE: To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes...
March 19, 2017: European Urology
https://www.readbyqxmd.com/read/28325666/development-of-novel-patient-derived-preclinical-models-from-malignant-effusions-in-patients-with-tyrosine-kinase-inhibitor-resistant-clear-cell-renal-cell-carcinoma
#4
Jiryeon Jang, Oliver Rath, Julia Schueler, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han-Yong Choi, Ghee-Young Kwon, Woong Yang Park, Jeeyun Lee, Se Hoon Park
PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen...
March 15, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28325293/a-pirna-like-small-rna-induces-chemoresistance-to-cisplatin-based-therapy-by-inhibiting-apoptosis-in-lung-squamous-cell-carcinoma
#5
Yuyan Wang, Tyler Gable, Mark Z Ma, David Clark, Jun Zhao, Yi Zhang, Wei Liu, Li Mao, Yuping Mei
Lung cancer is the leading cause of cancer-related death worldwide. Although advanced drugs have benefitted patients, therapeutic success has largely been hampered because of rapid development of resistance. Here we report that PIWI-interacting RNA likes (piR-Ls), a novel type of functional sncRNAs, play key roles in chemoresistance to cisplatin (CDDP)-based chemotherapy in lung squamous cell carcinoma (LSCC). piR-L-138 was upregulated upon CDDP-based chemotherapy both in LSCC cells and in patient-derived xenograft (PDX) LSCC models...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28315646/procedure-for-horizontal-transfer-of-patient-derived-xenograft-tumors-to-eliminate-corynebacterium-bovis
#6
Christopher A Manuel, Stacey M Bagby, Julie A Reisinger, Umarani Pugazhenthi, Todd M Pitts, Stephen B Keysar, John J Arcaroli, Jori K Leszczynski
Human patient-derived xenograft (PDX) tumors, propagated in immunodeficient mice, are rapidly growing in use as a model for cancer research. Horizontal transfer between mice, without in vitro cell culture, allows these tumors to retain many of their unique characteristics from their individual patient of origin. However, the immunodeficient mouse strains used to grow these tumors are susceptible to numerous opportunistic pathogens, including Corynebacterium bovis. At our institution, 2 in vivo tumor banks of PDX tumors had been maintained within nude mouse colonies enzootically infected with C...
March 1, 2017: Journal of the American Association for Laboratory Animal Science: JAALAS
https://www.readbyqxmd.com/read/28315377/patient-derived-xenografts-a-platform-for-accelerating-translational-research-in-prostate-cancer
#7
Alastair H Davies, Yuzhuo Wang, Amina Zoubeidi
Recently, there has been renewed interest in the development and characterization of patient-derived tumour xenograft (PDX) models. Numerous PDX models have been established for prostate cancer and, importantly, retain the principal molecular, genetic, and histological characteristics of the donor tumour. As such, these models provide significant improvements over standard cell line xenograft models for biological studies, preclinical drug development, and personalized medicine strategies. This review summarizes the current state of the art in this field, illustrating the opportunities and limitations of PDX models in translational prostate cancer research...
March 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28314386/veliparib-in-combination-with-radiotherapy-for-the-treatment-of-mgmt-unmethylated-glioblastoma
#8
Toni Rose Jue, Kyoko Nozue, Ashleigh J Lester, Swapna Joshi, Lisette B W Schroder, Shane P Whittaker, Sheri Nixdorf, Robert W Rapkins, Mustafa Khasraw, Kerrie L McDonald
BACKGROUND: The O (6) -methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM. METHODS: The inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors...
March 17, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28295723/suzuki-miyaura-cross-coupling-reactions-of-highly-fluorinated-arylboronic-esters-catalytic-studies-and-stoichiometric-model-reactions-on-the-transmetallation-step
#9
Thomas Braun, Johannes Kohlmann, Reik Laubenstein, Roy Herrmann
Fluorinated 4-aryl phenylalanine amino acid derivatives (aryl = 2-C5NF4, 4-C6H4SF5, 2-C6H4SCF3, C6F5) were obtained in Suzuki-Miyaura cross-coupling reactions of phenylalanine precursors with highly fluorinated aryl boronic acid and esters in the presence of CsF. Pd(II) complexes bearing phenyl alanine derived ligands such as trans-[PdBr{4-C6H4CH2CH{NHC(O)CH3}CO2Et}-(PiPr3)2] were used as catalysts. Stoichiometric model reactions indicate the intermediate generation of the boronate Cs[BF(2-C5NF4)(pin)] (pin = pinacolato = O2C2Me4)...
March 14, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28292941/preclinical-anti-tumor-efficacy-of-bay-1129980-a-novel-auristatin-based-anti-c4-4a-lypd3-antibody-drug-conjugate-for-the-treatment-of-non-small-cell-lung-cancer
#10
Jörg Willuda, Lars Linden, Hans-Georg Lerchen, Charlotte Kopitz, Beatrix Stelte-Ludwig, Carol Pena, Claudia Lange, Sven Golfier, Christoph Kneip, Patricia E Carrigan, Kirk Mclean, Joachim Schuhmacher, Oliver von Ahsen, Jörg Müller, Frank Dittmer, Rudolf Beier, Sherif El-Sheikh, Jan Tebbe, Gabriele Leder, Heiner Apeler, Rolf Jautelat, Karl Ziegelbauer, Bertolt Kreft
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28292264/establishment-of-patient-derived-gastric-cancer-xenografts-a-useful-tool-for-preclinical-evaluation-of-targeted-therapies-involving-alterations-in-her-2-met-and-fgfr2-signaling-pathways
#11
Haiyong Wang, Jun Lu, Jian Tang, Shitu Chen, Kuifeng He, Xiaoxia Jiang, Weiqin Jiang, Lisong Teng
BACKGROUND: Targeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients. METHODS: GC tissues from 32 patients were collected and implanted into immuno-deficient mice...
March 14, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28290700/metabolic-response-to-everolimus-in-patient-derived-triple-negative-breast-cancer-xenografts
#12
Leslie R Euceda, Deborah K Hill, Endre Stokke, Rana Hatem, Rania El Botty, Ivan Bièche, Elisabetta Marangoni, Tone F Bathen, Siver A Moestue
Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals)...
March 14, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28290604/glucagon-like-peptide-1-receptor-agonist-ameliorates-the-insulin-resistance-function-of-islet-%C3%AE-cells-via-the-activation-of-pdx-1-jak-signaling-transduction-in-c57-bl6-mice-with-high-fat-diet-induced-diabetes
#13
Tao Hao, Hongtao Zhang, Sheyu Li, Haoming Tian
Long-term exposure to a high-fat diet (HFD) causes glucotoxicity and lipotoxicity in islet β cells and leads to the development of metabolic dysfunctions. Reductions in pancreatic and duodenal homeobox-1 (PDX-1) expression have been shown to induce type 2 diabetes mellitus by causing impairments to islet β cells. Glucagon-like peptide 1 (GLP-1) treatment reduces endogenous insulin resistance in HFD-induced type 2 diabetes mellitus. In the present study, the underlying mechanism by which GLP-1 exerts its function in type 2 diabetes mellitus was investigated...
March 7, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28286209/esophageal-adenocarcinoma-cells-and-xenograft-tumors-exposed-to-erb-b2-receptor-tyrosine-kinase-2-and-3-inhibitors-activate-transforming-growth-factor-beta-signaling-which-induces-epithelial-to-mesenchymal-transition
#14
Eva A Ebbing, Anne Steins, Evelyn Fessler, Phylicia Stathi, Willem Joost Lesterhuis, Kausilia K Krishnadath, Louis Vermeulen, Jan Paul Medema, Maarten F Bijlsma, Hanneke W M van Laarhoven
BACKGROUND & AIMS: Drugs that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) are the standard treatment of patients with different types of cancer, including HER2-overexpressing gastroesophageal tumors. Unfortunately, cancer cells become resistant to these drugs, so overall these drugs provide little benefit to patients with these tumors. We investigated mechanisms that mediate resistance of esophageal adenocarcinoma (EAC) cells and patient-derived xenograft (PDX) tumors to ERBB inhibitors...
March 9, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28273909/protectin-dx-increases-survival-in-a-mouse-model-of-sepsis-by-ameliorating-inflammation-and-modulating-macrophage-phenotype
#15
Haifa Xia, Lin Chen, Hong Liu, Zhipeng Sun, Wen Yang, Yiyi Yang, Shunan Cui, Shengnan Li, Yaxin Wang, Limin Song, Amro Fayez Abdelgawad, You Shang, Shanglong Yao
Recently, a serial of studies have demonstrated that lipid mediators derived from Omega-3 fatty acid docosahexaenoic acid have pro-resolving or anti-inflammatory effects in many inflammatory diseases. Here, we sought to evaluate whether Protectin DX (PDX, an isomer of Protecin D1), a newly identified lipid mediator, could protect mice against sepsis and explore the underling mechanism. Animal model of sepsis was established by cecum ligation and puncture (CLP). We found that PDX increased overall survival rate within eight days and attenuated multiple organ injury in septic mice...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28261303/stimulation-of-%C3%AE-adrenergic-receptors-plays-a-protective-role-via-increased-expression-of-raf-1-and-pdx-1-in-hyperglycemic-rat-pancreatic-islet-rin-m5f-cells
#16
Sher Zaman Safi, Rajes Qvist, Gracie Ong, Hamed Karimian, Muhammad Imran, Ikram Shah
INTRODUCTION: It is a widely held view that a progressive reduction of beta-cell mass occurs in the progression of diabetes. RAF-1 kinase and pancreas duodenal homeobox 1 (PDX-1) are major factors that promote survival of cells and maintain normal insulin functions. In this study we investigated the effect of a β-adrenergic receptor agonist and antagonist on RAF-1 and PDX-1, and their respective effects on apoptosis and insulin release in RIN-m5F cells. MATERIAL AND METHODS: RIN-m5F cells were cultured in normal (5 mM) and high (25 mM) glucose to mimic diabetic conditions, followed by treatment with 5 µM, 10 µM and 20 µM of isoproterenol and isoproterenol + propranolol for 6, 12 and 24 h...
March 1, 2017: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/28253305/chitosan-assisted-differentiation-of-porcine-adipose-tissue-derived-stem-cells-into-glucose-responsive-insulin-secreting-clusters
#17
Hui-Yu Liu, Chih-Chien Chen, Yuan-Yu Lin, Yu-Jen Chen, Bing-Hsien Liu, Shiu-Chung Wong, Cheng-Yu Wu, Yun-Tsui Chang, Han-Yi E Chou, Shih-Torng Ding
The unique advantage of easy access and abundance make the adipose-derived stem cells (ADSCs) a promising system of multipotent cells for transplantation and regenerative medicine. Among the available sources, porcine ADSCs (pADSCs) deserve especial attention due to the close resemblance of human and porcine physiology, as well as for the upcoming availability of humanized porcine models. Here, we report on the isolation and conversion of pADSCs into glucose-responsive insulin-secreting cells. We used the stromal-vascular fraction of the dorsal subcutaneous adipose from 9-day-old male piglets to isolate pADSCs, and subjected the cells to an induction scheme for differentiation on chitosan-coated plates...
2017: PloS One
https://www.readbyqxmd.com/read/28249646/chromosomal-abnormalities-and-molecular-landscape-of-metastasizing-mucinous-salivary-adenocarcinoma
#18
Alex Panaccione, Yi Zhang, Yanfang Mi, Yoshitsugu Mitani, Guo Yan, Manju L Prasad, W Hayes McDonald, Adel K El-Naggar, Wendell G Yarbrough, Sergey V Ivanov
BACKGROUND: Mucinous adenocarcinoma of the salivary gland (MAC) is a lethal cancer with unknown molecular etiology and a high propensity to lymph node metastasis. Mostly due to its orphan status, MAC remains one of the least explored cancers that lacks cell lines and mouse models that could help translational and pre-clinical studies. Surgery with or without radiation remains the only treatment modality but poor overall survival (10-year, 44%) underscores the urgent need for mechanism-based therapies...
March 2017: Oral Oncology
https://www.readbyqxmd.com/read/28248952/patient-derived-xenografts-as-in-vivo-models-for-research-in-urological-malignancies
#19
REVIEW
Takahiro Inoue, Naoki Terada, Takashi Kobayashi, Osamu Ogawa
Lack of appropriate models that recapitulate the complexity and heterogeneity of urological tumours precludes most of the preclinical reagents that target urological tumours from receiving regulatory approval. Patient-derived xenograft (PDX) models are characterized by direct engraftment of patient-derived tumour fragments into immunocompromised mice. PDXs can maintain the original histology, as well as the molecular and genetic characteristics of the source tumour. Thus, PDX models have various advantages over conventional cell-line-derived xenograft (CDX) and other models, which has resulted in an increase in the use of urological tumour PDXs in the analysis of tumour biology and, importantly, for drug development and treatment decisions in personalized medicine...
February 21, 2017: Nature Reviews. Urology
https://www.readbyqxmd.com/read/28212573/dynamic-variations-in-epithelial-to-mesenchymal-transition-emt-atm-and-slfn11-govern-response-to-parp-inhibitors-and-cisplatin-in-small-cell-lung-cancer
#20
C Allison Stewart, Pan Tong, Robert J Cardnell, Triparna Sen, Lerong Li, Carl M Gay, Fatemah Masrorpour, You Fan, Rasha O Bara, Ying Feng, Yuanbin Ru, Junya Fujimoto, Samrat T Kundu, Leonard E Post, Karen Yu, Yuqiao Shen, Bonnie S Glisson, Ignatio Wistuba, John V Heymach, Don L Gibbons, Jing Wang, Lauren Averett Byers
Small cell lung cancer (SCLC) is one of the most aggressive forms of cancer, with a 5-year survival <7%. A major barrier to progress is the absence of predictive biomarkers for chemotherapy and novel targeted agents such as PARP inhibitors. Using a high-throughput, integrated proteomic, transcriptomic, and genomic analysis of SCLC patient-derived xenografts (PDXs) and profiled cell lines, we identified biomarkers of drug sensitivity and determined their prevalence in patient tumors. In contrast to breast and ovarian cancer, PARP inhibitor response was not associated with mutations in homologous recombination (HR) genes (e...
February 15, 2017: Oncotarget
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