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https://www.readbyqxmd.com/read/28432716/deciphering-tacrolimus-induced-toxicity-in-pancreatic-%C3%AE-cells
#1
J Triñanes, A E Rodriguez-Rodriguez, Y Brito, A Wagner, A P J De Vries, G Cuesto, A Acebes, E Salido, A Torres, E Porrini
β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h...
April 22, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28416471/chemotherapy-resistant-human-acute-myeloid-leukemia-cells-are-not-enriched-for-leukemic-stem-cells-but-require-oxidative-metabolism
#2
Thomas Farge, Estelle Saland, Fabienne de Toni, Nesrine Aroua, Moshen Hosseini, Robin Perry, Claudie Bosc, Mayumi Sugita, Lucille Stuani, Marine Fraisse, Sarah Scotland, Clément Larrue, Héléna Boutzen, Virginie Féliu, Marie-Laure Nicolau-Travers, Stephanie Cassant-Sourdy, Nicolas Broin, Marion David, Nizar Serhan, Audrey Sarry, Suzanne Tavitian, Tony Kaoma, Laurent Vallar, Jason Iacovoni, Laetitia K Linares, Camille Montersino, Remy Castellano, Emmanuel Griessinger, Yves Collette, Olivier Duchamp, Yara Barreira, Pierre Hirsch, Tony Palama, Lara Gales, Francois Delhommeau, Barbara H Garmy-Susini, Jean-Charles Portais, Francois Vergez, Mary Selak, Gwenn Danet-Desnoyers, Martin Carroll, Christian Récher, Jean Emmanuel Sarry
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSCs). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenograft (PDX) with cytarabine. Cytarabine residual AML cells are enriched neither in immature, quiescent cells nor LSCs. Strikingly, cytarabine-resistant pre-existing and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status...
April 17, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28414888/models-of-human-adamantinomatous-craniopharyngioma-tissue-steps-toward-an-effective-adjuvant-treatment
#3
Annett Hölsken, Rolf Buslei
Even though ACP is a benign tumor, treatment is challenging because of the tumor's eloquent location. Today, with the exception of surgical intervention and irradiation, further treatment options are limited. However, ongoing molecular research in this field provides insights into the pathways involved in ACP pathogenesis and reveal a plethora of druggable targets. In the next step, appropriate models are essential to identify the most suitable and effective substances for clinical practice. Primary cell cultures in low passages provide a proper and rapid tool for initial drug potency testing...
May 2017: Brain Pathology
https://www.readbyqxmd.com/read/28405515/psca-and-muc1-in-non-small-cell-lung-cancer-as-targets-of-chimeric-antigen-receptor-t-cells
#4
Xinru Wei, Yunxin Lai, Jin Li, Le Qin, Youdi Xu, Ruocong Zhao, Baiheng Li, Simiao Lin, Suna Wang, Qiting Wu, Qiubin Liang, Muyun Peng, Fenglei Yu, Yangqiu Li, Xuchao Zhang, Yilong Wu, Pentao Liu, Duanqing Pei, Yao Yao, Peng Li
In recent years, immunotherapies, such as those involving chimeric antigen receptor (CAR) T cells, have become increasingly promising approaches to non-small-cell lung cancer (NSCLC) treatment. In this study, we explored the antitumor potential of prostate stem cell antigen (PSCA)-redirected CAR T and mucin 1 (MUC1)-redirected CAR T cells in tumor models of NSCLC. First, we generated patient-derived xenograft (PDX) mouse models of human NSCLC that maintained the antigenic profiles of primary tumors. Next, we demonstrated the expression of PSCA and MUC1 in NSCLC, followed by the generation and confirmation of the specificity and efficacy of PSCA- and MUC1-targeting CAR T cells against NSCLC cell lines in vitro...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28401888/advances-in-pancreatic-islet-monolayer-culture-on-glass-surfaces-enable-super-resolution-microscopy-and-insights-into-beta-cell-ciliogenesis-and-proliferation
#5
Edward A Phelps, Chiara Cianciaruso, Jaime Santo-Domingo, Miriella Pasquier, Gabriele Galliverti, Lorenzo Piemonti, Ekaterine Berishvili, Olivier Burri, Andreas Wiederkehr, Jeffrey A Hubbell, Steinunn Baekkeskov
A robust and reproducible method for culturing monolayers of adherent and well-spread primary islet cells on glass coverslips is required for detailed imaging studies by super-resolution and live-cell microscopy. Guided by an observation that dispersed islet cells spread and adhere well on glass surfaces in neuronal co-culture and form a monolayer of connected cells, we demonstrate that in the absence of neurons, well-defined surface coatings combined with components of neuronal culture media collectively support robust attachment and growth of primary human or rat islet cells as monolayers on glass surfaces...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28401005/chk1-inhibition-potentiates-the-therapeutic-efficacy-of-parp-inhibitor-bmn673-in-gastric-cancer
#6
Yuping Yin, Qian Shen, Peng Zhang, Ruikang Tao, Weilong Chang, Ruidong Li, Gengchen Xie, Weizhen Liu, Lihong Zhang, Prabodh Kapoor, Shumei Song, Jaffer Ajani, Gordon B Mills, Jianying Chen, Kaixiong Tao, Guang Peng
Globally, gastric cancer is the second leading cause of cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric cancer cell survival and growth, which serves as an effective therapeutic target in gastric cancer...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28396094/ym155-induces-apoptosis-through-proteasome-dependent-degradation-of-mcl-1-in-primary-effusion-lymphoma
#7
Yuki Kojima, Fumihiko Hayakawa, Takanobu Morishita, Keiki Sugimoto, Yuka Minamikawa, Mizuho Iwase, Hideyuki Yamamoto, Daiki Hirano, Naoto Imoto, Kazuyuki Shimada, Seiji Okada, Hitoshi Kiyoi
Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL...
April 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28389883/high-throughput-high-volume-nuclear-imaging-for-preclinical-in-vivo-compound-screening-%C3%A2
#8
Sven Macholl, Ciara M Finucane, Jacob Hesterman, Stephen J Mather, Rachel Pauplis, Deirdre Scully, Jane K Sosabowski, Erwan Jouannot
BACKGROUND: Preclinical single-photon emission computed tomography (SPECT)/CT imaging studies are hampered by low throughput, hence are found typically within small volume feasibility studies. Here, imaging and image analysis procedures are presented that allow profiling of a large volume of radiolabelled compounds within a reasonably short total study time. Particular emphasis was put on quality control (QC) and on fast and unbiased image analysis. METHODS: 2-3 His-tagged proteins were simultaneously radiolabelled by (99m)Tc-tricarbonyl methodology and injected intravenously (20 nmol/kg; 100 MBq; n = 3) into patient-derived xenograft (PDX) mouse models...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28379424/combination-therapy-with-potent-pi3k-and-mapk-inhibitors-overcomes-adaptive-kinome-resistance-to-single-agents-in-preclinical-models-of-glioblastoma
#9
Robert S McNeill, Demitra A Canoutas, Timothy J Stuhlmiller, Harshil D Dhruv, David M Irvin, Ryan E Bash, Steven P Angus, Laura E Herring, Jeremy M Simon, Kasey R Skinner, Juanita C Limas, Xin Chen, Ralf S Schmid, Marni B Siegel, Amanda E D Van Swearingen, Michael J Hadler, Erik P Sulman, Jann N Sarkaria, Carey K Anders, Lee M Graves, Michael E Berens, Gary L Johnson, C Ryan Miller
Background.: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates. Methods.: We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes...
March 30, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28376221/efficacy-of-nedd8-pathway-inhibition-in-preclinical-models-of-poorly-differentiated-clinically-aggressive-colorectal-cancer
#10
Gabriele Picco, Consalvo Petti, Francesco Sassi, Katia Grillone, Giorgia Migliardi, Teresa Rossi, Claudio Isella, Federica Di Nicolantonio, Ivana Sarotto, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico
Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing. Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry...
February 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28376176/tumor-sequencing-and-patient-derived-xenografts-in-the-neoadjuvant-treatment-of-breast-cancer
#11
Matthew P Goetz, Krishna R Kalari, Vera J Suman, Ann M Moyer, Jia Yu, Daniel W Visscher, Travis J Dockter, Peter T Vedell, Jason P Sinnwell, Xiaojia Tang, Kevin J Thompson, Sarah A McLaughlin, Alvaro Moreno-Aspitia, John A Copland, Donald W Northfelt, Richard J Gray, Katie Hunt, Amy Conners, Richard Weinshilboum, Liewei Wang, Judy C Boughey
Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown. Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies...
July 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28375738/sirt3-deficiency-increased-the-vulnerability-of-pancreatic-beta-cells-to-oxidative-stress-induced-dysfunction
#12
Yu Zhou, Arthur C K Chung, Rongrong Fan, Heung Man Lee, Gang Xu, Brian Tomlinson, Juliana C N Chan, Alice P S Kong
AIMS: Hyperlipidemia-induced oxidative stress is considered to be one of the main pathogenic factors that contribute to pancreatic beta cell dysfunction in the development of type 2 diabetes (T2D). Sirtuin 3 (Sirt3) is abundantly expressed in the mitochondria as an NAD(+)-dependent deacetylase and regulates mitochondrial adaptive responses to oxidative stress. We examined the antioxidant defense mechanism of Sirt3 in pancreatic beta cells in the context of hyperlipidemia. RESULTS: Chronic high-fat diet (HFD) feeding caused elevated oxidative stress accompanied by reduced Sirt3 expression in the pancreatic beta cells of wild-type mice...
April 4, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28361078/targeting-the-seeds-of-small-cell-lung-cancer
#13
EDITORIAL
Sylvia Mahara, Ron Firestein
The concept of antibody drug conjugates (ADCs), which includes the delivery of cytotoxic drugs to antigen-expressing tumor cells by harnessing the antigen-selectivity of a monoclonal antibody, has the potential to redefine the landscape of translational medicine. With the advent of patient derived xenograft (PDX) models and sophisticated genomic technologies, the identification of a selective antigen can be accurately validated within the appropriate tumor milieu. However, a major biological hurdle in cancer translational medicine is the inherent tumoral heterogeneity, underscoring the importance of targeting the 'right' sub-population of cancer cells...
March 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/28348404/proteogenomic-integration-reveals-therapeutic-targets-in-breast-cancer-xenografts
#14
Kuan-Lin Huang, Shunqiang Li, Philipp Mertins, Song Cao, Harsha P Gunawardena, Kelly V Ruggles, D R Mani, Karl R Clauser, Maki Tanioka, Jerry Usary, Shyam M Kavuri, Ling Xie, Christopher Yoon, Jana W Qiao, John Wrobel, Matthew A Wyczalkowski, Petra Erdmann-Gilmore, Jacqueline E Snider, Jeremy Hoog, Purba Singh, Beifung Niu, Zhanfang Guo, Sam Qiancheng Sun, Souzan Sanati, Emily Kawaler, Xuya Wang, Adam Scott, Kai Ye, Michael D McLellan, Michael C Wendl, Anna Malovannaya, Jason M Held, Michael A Gillette, David Fenyö, Christopher R Kinsinger, Mehdi Mesri, Henry Rodriguez, Sherri R Davies, Charles M Perou, Cynthia Ma, R Reid Townsend, Xian Chen, Steven A Carr, Matthew J Ellis, Li Ding
Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases...
March 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28348116/increased-vimentin-in-human-%C3%AE-and-%C3%AE-cells-in-type-2-diabetes
#15
Maaike Roefs, Françoise Carlotti, Katherine Jones, Hannah Wills, Alexander Hamilton, Michael Verschoor, Joanna Williams Durkin, Laura Garcia-Perez, Melissa Brereton, Laura McCulloch, Marten Engelse, Paul Johnson, Barbara Hansen, Kevin Docherty, Eelco de Koning, Anne Clark
Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with (T2DM, n=28) and without diabetes (ND, n=38), and in non-human primates at different stages of the diabetic syndrome; normoglycaemic (ND, n=4), obese, hyperinsulinaemic (HI, n=4) and hyperglycaemic (DM, n=8)...
March 27, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28348046/b-cell-lymphoma-patient-derived-xenograft-models-enable-drug-discovery-and-are-a-platform-for-personalized-therapy
#16
Liang Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan V Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Huifang Guo, Zhihong Chen, Wenjing Tao, Carrie Li, Jack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y Huang, Yiping Shao, Laura Lam, Qing Yi, Lynn Wang, Michael Wang
PURPOSE: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma PDX (patient-derived xenograft) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. EXPERIMENTAL DESIGN: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt's lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28342842/protectin-dx-suppresses-hepatic-gluconeogenesis-through-ampk-ho-1-mediated-inhibition-of-er-stress
#17
Tae Woo Jung, Hyung-Chun Kim, A M Abd El-Aty, Ji Hoon Jeong
Several studies have shown that protectins, which are ω-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6...
March 22, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28341665/an-anti-cd47-antibody-is-effective-in-pediatric-brain-tumor-models
#18
(no author information available yet)
The anti-CD47 antibody Hu5F9-G4 selectively kills tumor cells in pediatric brain tumor PDX models.
March 24, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28340497/p450-inhibitor-ketoconazole-increased-the-intratumor-drug-levels-and-antitumor-activity-of-fenretinide-in-human-neuroblastoma-xenograft-models
#19
Lluis Lopez-Barcons, Barry J Maurer, Min H Kang, C Patrick Reynolds
We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay...
March 24, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28331002/personalized-in-vitro-and-in-vivo-cancer-models-to-guide-precision-medicine
#20
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
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