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https://www.readbyqxmd.com/read/28432815/immunoassays-for-the-quantification-of-alk-and-phosphorylated-alk-support-the-evaluation-of-on-target-alk-inhibitors-in-neuroblastoma
#1
Elizabeth R Tucker, Jennifer R Tall, Laura S Danielson, Sharon Gowan, Yann Jamin, Simon P Robinson, Udai Banerji, Louis Chesler
Targeted inhibition of Anaplastic Lymphoma Kinase (ALK) is a successful approach for the treatment of many ALK-aberrant malignancies, however the presence of resistant mutations necessitates both the development of more potent compounds and pharmacodynamic methods with which to determine their efficacy. We describe immunoassays designed to quantitate phosphorylation of ALK, and their use in preclinical models of neuroblastoma, a pediatric malignancy in which gain-of-function ALK mutations predict a poor overall outcome to conventional treatment...
April 22, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28432595/what-animal-models-have-taught-us-about-the-safety-and-efficacy-of-bisphosphonates-in-chronic-kidney-disease
#2
REVIEW
Matthew R Allen, Mohammad W Aref
PURPOSE OF REVIEW: Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. RECENT FINDINGS: Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models...
April 21, 2017: Current Osteoporosis Reports
https://www.readbyqxmd.com/read/28432176/a-phase-i-study-of-the-cdk4-6-inhibitor-ribociclib-lee011-in-pediatric-patients-with-malignant-rhabdoid-tumors-neuroblastoma-and-other-solid-tumors
#3
Birgit Geoerger, Franck Bourdeaut, Steven G DuBois, Matthias Fischer, James I Geller, Nicholas G Gottardo, Aurélien Marabelle, Andrew D J Pearson, Shakeel Modak, Thomas Cash, Giles W Robinson, Marlyane Motta, Alessandro Matano, Suraj G Bhansali, Jason R Dobson, Sudha Parasuraman, Susan N Chi
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off)...
April 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28432122/dual-regulation-of-stat1-and-stat3-by-the-tumor-suppressor-protein-pml-contributes-to-ifn%C3%AE-mediated-inhibition-of-angiogenesis
#4
Kuo-Sheng Hsu, Xuan Zhao, Xiwen Cheng, Dongyin Guan, Ganapati H Mahabeleshwar, Yu Liu, Ernest Borden, Mukesh K Jain, Hung-Ying Kao
IFNs are effective in inhibiting angiogenesis in preclinical models and in treating several angio-proliferative disorders. However, the detailed mechanisms of IFNα-mediated anti-angiogenesis are not completely understood. Stat1/2/3 and PML are IFNα downstream effectors and are pivotal regulators of angiogenesis. Here, we investigated PML's role in the regulation of Stat1/2/3 activity. In Pml knockout (KO) mice, ablation of Pml largely reduces IFNα angiostatic ability in Matrixgel plug assays. This suggested an essential role for PML in IFNα's anti-angiogenic function...
April 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28431879/improvement-of-herg-romk-index-of-spirocyclic-romk-inhibitors-through-scaffold-optimization-and-incorporation-of-novel-pharmacophores
#5
Shuzhi Dong, Kelsey VanGelder, Zhi-Cai Shi, Yang Yu, Zhicai Wu, Ron Ferguson, Zack Zhiqiang Guo, Haifeng Tang, Jessica Frie, Qinghong Fu, Xin Gu, Birgit T Priest, Brande Thomas-Fowlkes, Adam Weinglass, Michael Margulis, Jessica Liu, Lee-Yuh Pai, Caryn Hampton, Robin E Haimbach, Karen Owens, Vincent Tong, Shiyao Xu, Mengwei Hu, Gloria J Zingaro, Pierre Morissette, Juliann Ehrhart, Sophie Roy, Kathleen Sullivan, Alexander Pasternak
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone...
March 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#6
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28430664/identification-of-a-novel-pd-l1-positive-solid-tumor-transplantable-in-hla-a-0201-drb1-0101-transgenic-mice
#7
Laurie Rangan, Jeanne Galaine, Romain Boidot, Mohamad Hamieh, Magalie Dosset, Julie Francoual, Laurent Beziaud, Jean-René Pallandre, Elodie Lauret Marie Joseph, Afag Asgarova, Christophe Borg, Talal Al Saati, Yann Godet, Jean Baptiste Latouche, Séverine Valmary-Degano, Olivier Adotévi
HLA-A*0201/DRB1*0101 transgenic mice (A2/DR1 mice) have been developed to study the immunogenicity of tumor antigen-derived T cell epitopes. To extend the use and application of this mouse model in the field of antitumor immunotherapy, we described a tumor cell line generated from a naturally occurring tumor in A2/DR1 mouse named SARC-L1. Histological and genes signature analysis supported the sarcoma origin of this cell line. While SARC-L1 tumor cells lack HLA-DRB1*0101 expression, a very low expression of HLA-A*0201 molecules was found on these cells...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430642/immunocompetent-mouse-allograft-models-for-development-of-therapies-to-target-breast-cancer-metastasis
#8
Yuan Yang, Howard H Yang, Ying Hu, Peter H Watson, Huaitian Liu, Thomas R Geiger, Miriam R Anver, Diana C Haines, Philip Martin, Jeffrey E Green, Maxwell P Lee, Kent W Hunter, Lalage M Wakefield
Effective drug development to combat metastatic disease in breast cancer would be aided by the availability of well-characterized preclinical animal models that (a) metastasize with high efficiency, (b) metastasize in a reasonable time-frame, (c) have an intact immune system, and (d) capture some of the heterogeneity of the human disease. To address these issues, we have assembled a panel of twelve mouse mammary cancer cell lines that can metastasize efficiently on implantation into syngeneic immunocompetent hosts...
February 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429760/corrigendum-selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#9
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
No abstract text is available yet for this article.
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28429751/preclinical-study-of-raav2-strail-pharmaceutical-efficacy-biodistribution-and-safety-in-animals
#10
Q Ru, W Li, X Wang, S Zhang, L Chen, Y Zhang, Y Ge, Y Zu, Y Liu, D Zheng
The recombinant sTRAIL has been in clinical trial for various human malignancies. However, the half-life time of sTRAIL is very short, which might be an important factor influencing its clinical efficacy for cancer therapy. We previously reported the recombinant adeno-associated virus (AAV)-encoding sTRAIL95-281-mediated sTRAIL expression in vivo up to 8 months and suppressed tumor growth markedly in mouse xenografts. In the present study, we further evaluated the clinical potency for cancer gene therapy and the safety in mouse and non-human primates...
April 21, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28429453/tolcapone-induces-oxidative-stress-leading-to-apoptosis-and-inhibition-of-tumor-growth-in-neuroblastoma
#11
Tyler Maser, Maria Rich, David Hayes, Ping Zhao, Abhinav B Nagulapally, Jeffrey Bond, Giselle Saulnier Sholler
Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis...
April 21, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28429185/high-content-assessment-of-cardiac-function-using-heart-on-a-chip-devices-as-drug-screening-model
#12
Genevieve Conant, Benjamin Fook Lun Lai, Rick Xing Ze Lu, Anastasia Korolj, Erika Yan Wang, Milica Radisic
Drug discovery and development continues to be a challenge to the pharmaceutical industry despite great advances in cell and molecular biology that allow for the design of better targeted therapeutics. Many potential drug compounds fail during the clinical trial due to inefficacy and toxicity that were not predicted during preclinical stages. The fundamental problem lies with the use of traditional drug screening models that still largely rely on the use of cell lines or animal cell monolayers, which leads to lack of predictive power of human tissue and organ response to the drug candidates...
April 20, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/28428790/nanoparticle-interactions-with-the-immune-system-clinical-implications-for-liposome-based-cancer-chemotherapy
#13
Ninh M La-Beck, Alberto A Gabizon
The development of stable and long-circulating liposomes provides protection of the drug cargo from degradation and increases tumor drug delivery, leading to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many liposomal as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval. The question that arises is whether we have missed key liposome-host interactions that can account for the gap between the major pharmacologic advantages in preclinical studies and the modest impact of the clinical effects in humans...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28428785/interferon-gamma-induces-changes-in-natural-killer-nk-cell-ligand-expression-and-alters-nk-cell-mediated-lysis-of-pediatric-cancer-cell-lines
#14
Arianexys Aquino-López, Vladimir V Senyukov, Zlatko Vlasic, Eugenie S Kleinerman, Dean A Lee
Natural killer (NK) cells have therapeutic potential for cancer due to their capacity for targeting tumor cells without prior sensitization. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion that secret 20 times the amount of interferon gamma (IFNγ) than resting NK cells. IFNγ can upregulate major histocompatibility complex (MHC)-class I, an inhibitory ligand for NK cells, but can also upregulate intercellular adhesion molecule 1 (ICAM-1) which promotes NK:target cell interaction for an efficient lysis...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28428443/mechanisms-of-pinometostat-epz-5676-treatment-emergent-resistance-in-mll-rearranged-leukemia
#15
Carly T Campbell, Jessica N Haladyna, David A Drubin, Ty M Thomson, Michael J Maria, Taylor Yamauchi, Nigel J Waters, Edward J Olhava, Roy M Pollock, Jesse J Smith, Robert A Copeland, Stephen J Blakemore, Kathrin M Bernt, Scott R Daigle
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well characterized leukemic genes.  Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment emergent resistance (TER) in cell lines confirmed to have MLL-r...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28428279/interaction-between-tumor-cell-surface-receptor-rage-and-proteinase-3-mediates-prostate-cancer-metastasis-to-bone
#16
Mikhail G Kolonin, Anna Sergeeva, Daniela I Staquicini, Tracey L Smith, Christy A Tarleton, Jeffrey J Molldrem, Richard L Sidman, Serena Marchiò, Renata Pasqualini, Wadih Arap
Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428272/hur-small-molecule-inhibitor-elicits-differential-effects-in-adenomatosis-polyposis-and-colorectal-carcinogenesis
#17
Michaela Lang, David Berry, Katharina Passecker, Ildiko Mesteri, Sabin Bhuju, Florian Ebner, Vitaly Sedlyarov, Rayko Evstatiev, Kyle Dammann, Alexander Loy, Orest Kuzyk, Pavel Kovarik, Vineeta Khare, Martin Beibel, Guglielmo Roma, Nicole Meisner-Kober, Christoph Gasche
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia...
February 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428049/stem-cells-for-retinal-disease-a-perspective-on-the-promise-and-perils
#18
Rajesh C Rao, Vaidehi S Dedania, Mark W Johnson
PURPOSE: To summarize key concepts, and early safety and efficacy signals from clinical trials for stem/progenitor cell-based interventions for retinal disease. DESIGN: Interpretive essay. METHODS: Review and synthesis of selected recent reports of stem/progenitor cell-based approaches for retinal disease, with interpretation and perspective. RESULTS: Stem/progenitor cell-based interventions represent a novel class of potential therapies for retinal diseases, such as age-related macular degeneration, inherited retinal dystrophies, and others...
April 17, 2017: American Journal of Ophthalmology
https://www.readbyqxmd.com/read/28427583/improving-atrial-fibrillation-therapy-is-there-a-gene-for-that
#19
REVIEW
William J Hucker, Alan Hanley, Patrick T Ellinor
Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment...
April 25, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28427564/inflammation-in-epileptic-encephalopathies
#20
Oleksii Shandra, Solomon L Moshé, Aristea S Galanopoulou
West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12%-15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS...
2017: Advances in Protein Chemistry and Structural Biology
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