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Preclinical models

Christine T Dinh, Olena Bracho, Christine Mei, Esperanza Bas, Cristina Fernandez-Valle, Fred Telischi, Xue-Zhong Liu
HYPOTHESIS: Microsurgical implantation of mouse merlin-deficient Schwann cells (MD-SC) into the cerebellopontine angle of immunodeficient rats will initiate tumor formation, hearing loss, and vestibular dysfunction. BACKGROUND: The progress in identifying effective drug therapies for treatment of Neurofibromatosis type II (NF2) is limited by the availability of animal models of VS that develop hearing loss and imbalance. METHODS: A microsurgical technique for implanting MD-SCs onto the cochleovestibular nerve of rats was developed...
March 19, 2018: Otology & Neurotology
Flora Pirozzi, Kai Ren, Alessandra Murabito, Alessandra Ghigo
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by irreversible chronic inflammation and airflow obstruction. It affects more than 64 million patients worldwide and it is predicted to become the third cause of death in the industrialized world by 2030. Current available therapies are not able to block disease progression and to reduce mortality, underlying the need of a better understanding of COPD pathophysiological mechanisms to identify new molecular therapeutic targets...
March 20, 2018: Current Medicinal Chemistry
Pilar Carranza-Rosales, Nancy Elena Guzmán-Delgado, Irma Edith Carranza-Torres, Ezequiel Viveros-Valdez, Javier Morán-Martínez
Breast cancer is the most common cancer type diagnosed in women, it represents a critical public health problem worldwide, with 1,671,149 estimated new cases and nearly 571,000 related deaths. Research on breast cancer has mainly been conducted using two-dimensional (2D) cell cultures and animal models. The usefulness of these models is reflected in the vast knowledge accumulated over the past decades. However, considering that animal models are three-dimensional (3D) in nature, the validity of the studies using 2D cell cultures has recently been questioned...
March 20, 2018: Current Topics in Microbiology and Immunology
Lisa A Santry, Thomas M McAusland, Leonardo Susta, Geoffrey A Wood, Pierre P Major, Jim J Petrik, Byram W Bridle, Sarah K Wootton
Newcastle disease virus (NDV) is a single-stranded, negative-sense RNA virus in the Paramyxoviridae family. Although primarily an avian pathogen, NDV is a potent oncolytic virus that has been shown to be safe and effective in a variety of preclinical cancer models and human clinical trials. To produce virus for oncolytic trials, NDV is commonly amplified in embryonated chicken eggs and purified from the allantoic fluid. Conventional methods for purifying virus from allantoic fluid often result in relatively low-titer preparations containing high levels of impurities, including immunogenic chicken host cell proteins from allantoic fluid...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Adam Vandergriff, Ke Huang, Deliang Shen, Shiqi Hu, Michael Taylor Hensley, Thomas G Caranasos, Li Qian, Ke Cheng
Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart. Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker...
2018: Theranostics
Yongming Pan, Jianqin Xu, Cheng Chen, Fangming Chen, Ping Jin, Keyan Zhu, Chenyue W Hu, Mengmeng You, Minli Chen, Fuliang Hu
Alzheimer's disease (AD) is the most common form of dementia characterized by aggregation of amyloid β (Aβ) and neuronal loss. One of the risk factors for AD is high cholesterol levels, which are known to promote Aβ deposition. Previous studies have shown that royal jelly (RJ), a product of worker bees, has potential neuroprotective effects and can attenuate Aβ toxicity. However, little is known about how RJ regulates Aβ formation and its effects on cholesterol levels and neuronal metabolic activities...
2018: Frontiers in Aging Neuroscience
Nagraj Mani, Andrew G Cole, Janet R Phelps, Andrzej Ardzinski, Kyle D Cobarrubias, Andrea Cuconati, Bruce D Dorsey, Ellen Evangelista, Kristi Fan, Fang Guo, Haitao Guo, Ju-Tao Guo, Troy O Harasym, Salam Kadhim, Steven G Kultgen, Amy C H Lee, Alice H L Li, Quanxin Long, Sara A Majeski, Richeng Mao, Kevin D McClintock, Stephen P Reid, Rene Rijnbrand, Nicholas M Snead, Holly M Micolochick Steuer, Kim Stever, Sunny Tang, Xiaohe Wang, Qiong Zhao, Michael J Sofia
AB-423 is a sulfamoylbenzamide (SBA) class of HBV capsid inhibitor in Phase 1 clinical trials. In cell culture models AB-423 showed potent inhibition of HBV replication (EC50 /EC90 = 0.08-0.27 μM/0.33-1.32 μM) with no significant cytotoxicity (CC50 >10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50 values. AB-423 inhibited HBV genotypes A through D and nucleos/tide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pgRNA and rcDNA indicating it is a class II capsid inhibitor...
March 19, 2018: Antimicrobial Agents and Chemotherapy
Tamer M Sakr, M H Sanad, Walaa H Abd-Alla, Dina H Salama, Gehan M Saleh
Challenges facing cardiovascular imaging necessitate innovation of better radiopharmaceuticals to augment or replace the existing ones. This research assesses the ability and competency of radioiodinated esmolol as a potential cardio selective imaging agent. Radioiodinated esmolol was synthesized with 97.3 ± 0.3% radiochemical yield and with high stability up to 48 h at room temperature as well as in rat serum. Molecular modeling study was performed to confirm the binding of iodinated esmolol to β1 -adrenergic receptor...
March 9, 2018: Applied Radiation and Isotopes
Rong Deng, Na Shen, Yang Yang, Hongliang Yu, Shuping Xu, Ying-Wei Yang, Shujun Liu, Kamel Meguellati, Fei Yan
Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML...
March 14, 2018: Biomaterials
Diego F Munoz, Cong Xu, Sylvia K Plevritis
We present a Monte Carlo simulation model that reproduces US invasive breast cancer incidence and mortality trends from 1975 to 2010 as a function of screening and adjuvant treatment. This model was developed for multiple purposes, including to quantify the impact of screening and adjuvant therapy on past and current trends, predict future trends, and evaluate potential outcomes under hypothetical screening and treatment interventions. The model first generates the life histories of individual breast cancer patients by determining the patient's age, tumor size, estrogen receptor (ER) status, human epidermal growth factor 2 (HER2) status, SEER (Surveillance, Epidemiology, and End Results) historic stage, detection mode at time of detection, preclinical tumor course, and death age and cause of death (breast cancer v...
April 2018: Medical Decision Making: An International Journal of the Society for Medical Decision Making
Ryan B Gil, Alberto Ortiz, Maria D Sanchez-Niño, Katerina Markoska, Eva Schepers, Raymond Vanholder, Griet Glorieux, Philippe Schmitt-Kopplin, Silke S Heinzmann
Background: Chronic kidney disease (CKD) is a recognized global health problem. While some CKD patients remain stable after initial diagnosis, others can rapidly progress towards end-stage renal disease (ESRD). This makes biomarkers capable of detecting progressive forms of CKD extremely valuable, especially in non-invasive biofluids such as urine. Screening for metabolite markers using non-targeted metabolomic techniques like nuclear magnetic resonance spectroscopy is increasingly applied to CKD research...
March 14, 2018: Nephrology, Dialysis, Transplantation
Rick J Jansen, Bruce H Alexander, Richard B Hayes, Anthony B Miller, Sholom Wacholder, Timothy R Church
When some individuals are screen-detected before the beginning of the study, but otherwise would have been diagnosed symptomatically during the study, this results in different case-ascertainment probabilities among screened and unscreened participants, referred to here as lead-time-biased case-ascertainment (LTBCA). In fact, this issue can arise even in risk-factor studies nested within a randomized screening trial; even though the screening intervention is randomly allocated to trial arms, there is no randomization to potential risk-factors and uptake of screening can differ by risk-factor strata...
2018: PloS One
Vasudevan Bakthavatchalu, Katherine J Wert, Yan Feng, Anthony Mannion, Zhongming Ge, Alexis Garcia, Kathleen E Scott, Tyler J Caron, Carolyn M Madden, Johanne T Jacobsen, Gabriel Victora, Rudolf Jaenisch, James G Fox
Immune-compromised mouse models allow for testing the preclinical efficacy of human cell transplantations and gene therapy strategies before moving forward to clinical trials. However, CRISPR/Cas9 gene editing of the Wsh/Wsh mouse strain to create an immune-compromised model lacking function of Rag2 and Il2rγ led to unexpected morbidity and mortality. This warranted an investigation to ascertain the cause and predisposing factors associated with the outbreak. Postmortem examination was performed on 15 moribund mice...
2018: PloS One
Ellen Grober, Amy E Veroff, Richard B Lipton
Introduction: Free and Cued Selective Reminding Test (FCSRT) performance identifies patients with preclinical disease at elevated risk for developing Alzheimer's dementia, predicting diagnosis better than other memory tests. Methods: Based on literature mapping FCSRT performance to clinical outcomes and biological markers, and on longitudinal preclinical data from the Baltimore Longitudinal Study of Aging, we developed the Stages of Objective Memory Impairment (SOMI) model...
2018: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Xuzhi He, Jazmina L Cruz, Shannon Joseph, Nicola Pett, Hui Yi Chew, Zewen K Tuong, Satomi Okano, Gabrielle Kelly, Margaret Veitch, Fiona Simpson, James W Wells
The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer...
February 23, 2018: Oncotarget
Huan Tong, Li-Geng Duan, Hong-Ying Zhou, Shi Feng
The hepatic VX2 carcinoma model in rabbits is widely used for the preclinical study of hepatocellular carcinoma. In the present study, a modification was made to the conventional method to establish the animal model, as the conventional method gives rise to frequent tumor seeding due to the drop-out of tumor fragments. In order to evaluate each distinct method of establishing the model, the rabbits were divided into two groups: Group A (the conventional method; n=20) and group B (the modified method; n=20)...
April 2018: Oncology Letters
M-P Ledoux, J Denis, Y Nivoix, R Herbrecht
Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment...
March 15, 2018: Journal de Mycologie Médicale
Mitchell E Menezes, Praveen Bhoopathi, Anjan K Pradhan, Luni Emdad, Swadesh K Das, Chunqing Guo, Xiang-Yang Wang, Devanand Sarkar, Paul B Fisher
Subtraction hybridization identified genes displaying differential expression as metastatic human melanoma cells terminally differentiated and lost tumorigenic properties by treatment with recombinant fibroblast interferon and mezerein. This approach permitted cloning of multiple genes displaying enhanced expression when melanoma cells terminally differentiated, called melanoma differentiation associated (mda) genes. One mda gene, mda-7, has risen to the top of the list based on its relevance to cancer and now inflammation and other pathological states, which based on presence of a secretory sequence, chromosomal location, and an IL-10 signature motif has been named interleukin-24 (MDA-7/IL-24)...
2018: Advances in Cancer Research
Roberta Gualdani, Maria Maddalena Cavalluzzi, Francesco Tadini-Buoninsegni, Marino Convertino, Philippe Gailly, Anna Stary-Weinzinger, Giovanni Lentini
BACKGROUND/AIMS: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking. METHODS: We tested the affinity of lubeluzole, its enantiomer, and the racemate for hERG channel using the patch-clamp technique...
March 10, 2018: Cellular Physiology and Biochemistry
H Zatorski, P Mosinska, M Storr, J Fichna
There is an unmet need for effective pharmacological therapies for the treatment of gastroparesis and other upper gastrointestinal (GI) motility disorders, which reduce patients' quality of life and are a burden to the healthcare system. Ghrelin is an endogenous growth hormone secretagogue receptor ligand and has been shown to exert prokinetic effects on GI motility. Nevertheless, considering the short half-life of ghrelin its use in clinical practice is limited. Thus, ghrelin receptor agonists with enhanced pharmacokinetics were developed; they accelerate gastric emptying and improve symptoms of gastroparesis in animal models and humans...
December 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
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