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https://www.readbyqxmd.com/read/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#1
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28319448/rationale-and-design-of-a-phase-1-clinical-trial-to-evaluate-hsv-g207-alone-or-with-a-single-radiation-dose-in-children-with-progressive-or-recurrent-malignant-supratentorial-brain-tumors
#2
Alicia M Waters, James M Johnston, Alyssa T Reddy, John Fiveash, Avi Madan-Swain, Kara Kachurak, Asim K Bag, G Yancey Gillespie, James M Markert, Gregory K Friedman
Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors...
March 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28318889/non-invasive-liver-ablation-using-histotripsy-preclinical-safety-study-in-an-in%C3%A2-vivo-porcine-model
#3
Eli Vlaisavljevich, Gabe Owens, Jonathan Lundt, Dejan Teofilovic, Kimberly Ives, Alexander Duryea, Jim Bertolina, Theodore H Welling, Zhen Xu
This study investigates the safety profile for use of histotripsy, a non-invasive ultrasonic ablation method currently being developed for the treatment of liver cancer, for liver ablation in an in vivo porcine model. Histotripsy treatments were applied to the liver and hepatic veins of 22 porcine subjects, with half of the subjects receiving systemic heparinization. Vital signs (heart rate, blood pressure, temperature, electrocardiogram and SpO2) were monitored throughout the procedure and for 1 h post-treatment...
March 16, 2017: Ultrasound in Medicine & Biology
https://www.readbyqxmd.com/read/28317185/an-astroglial-basis-of-major-depressive-disorder-an-overview
#4
REVIEW
Qian Wang, Wei Jie, Ji-Hong Liu, Jian-Ming Yang, Tian-Ming Gao
Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player...
March 20, 2017: Glia
https://www.readbyqxmd.com/read/28317156/synthesis-and-anticonvulsant-properties-of-new-3-3-diphenyl-2-5-dioxo-pyrrolidin-1-yl-acetamides-and-3-3-diphenyl-propionamides
#5
Jolanta Obniska, Anna Rapacz, Sabina Rybka, Małgorzata Góra, Paweł Żmudzki, Krzysztof Kamiński
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28315722/risk-mitigation-for-children-exposed-to-drugs-during-gestation-a-critical-role-for-animal-preclinical-behavioral-testing
#6
REVIEW
Irving Zucker
Many drugs with unknown safety profiles are administered to pregnant women, placing their offspring at risk. I assessed whether behavioral outcomes for children exposed during gestation to antidepressants, anxiolytics, anti-seizure, anti-nausea and sedative medications can be predicted by more extensive animal studies than are part of the FDA approval process. Human plus rodent data were available for only 8 of 33 CNS-active drugs examined. Similar behavioral and cognitive deficits, including autism and ADHD emerged in human offspring and in animal models of these disorders after exposure to fluoxetine, valproic acid, carbamazepine, phenytoin, phenobarbital, acetaminophen and ibuprofen...
March 15, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28315465/early-preclinical-evaluation-of-dihydropyrimidin-thi-ones-as-potential-anticonvulsant-drug-candidates
#7
Mariana Matias, Gonçalo Campos, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
Although significant advances are occurring in epilepsy research, about 30% of epileptic patients are still inadequately controlled by standard drug therapy. For this reason, it continues to be important to develop new chemical entities through which epilepsy could be effectively controlled. In this study, the anticonvulsant activity of forty-two dihydropyrimidin(thi)ones was explored and their efficacy was evaluated in rodents against the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole tests...
March 14, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28315377/patient-derived-xenografts-a-platform-for-accelerating-translational-research-in-prostate-cancer
#8
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 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28315268/sigma-1-receptor-antagonists-a-new-class-of-neuromodulatory-analgesics
#9
Cristina Sánchez-Fernández, José Manuel Entrena, José Manuel Baeyens, Enrique José Cobos
The sigma-1 receptor is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system. Sigma-1 receptors interact with a variety of protein targets to modify their function. These targets include several G-protein-coupled receptors such as the μ-opioid receptor, and ion channels such as the N-methyl-D-aspartate receptor (NMDAR). Sigma-1 antagonists modify the chaperoning activity of sigma-1 receptor by increasing opioid signaling and decreasing NMDAR responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28314990/an-apparent-clinical-pharmacokinetic-drug-drug-interaction-between-bevacizumab-and-the-anti-placental-growth-factor-monoclonal-antibody-ro5323441-via-a-target-trapping-mechanism
#10
Ka Wang, Franziska Schaedeli Stark, Tilman Schlothauer, Angelika Lahr, Valerie Cosson, Jianguo Zhi, Kai Habben, Jean Tessier, Eginhard Schick, Roland F Staack, Oliver Krieter
PURPOSE: RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug-drug interaction observed when RO5323441 was administered in combination with bevacizumab. METHODS: The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4)...
March 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28314821/phases-of-hyper-and-hypo-connectivity-in-the-default-mode-and-salience-networks-track-with-amyloid-and-tau-in-clinically-normal-individuals
#11
Aaron P Schultz, Jasmeer P Chhatwal, Trey Hedden, Elizabeth C Mormino, Bernard J Hanseeuw, Jorge Sepulcre, Willem Huijbers, Molly LaPoint, Rachel F Buckley, Keith A Johnson, Reisa A Sperling
Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1-42, and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in preclinical AD have relied on associations with in-vivo measures of amyloid pathology. With the recent advent of in-vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks (Default Mode (DMN), Salience, Dorsal Attention (DAN), and Frontoparietal Control (FPCN)) as a function of global cortical amyloid (PiB-PET) and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal (IP) cortex...
March 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28314386/veliparib-in-combination-with-radiotherapy-for-the-treatment-of-mgmt-unmethylated-glioblastoma
#12
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/28314273/failure-of-inositol-trispyrophosphate-to-enhance-highly-effective-radiotherapy-of-gl261-glioblastoma-in-mice
#13
Sujatha Iyengar, David Schwartz
BACKGROUND/AIM: Inositol trispyrophosphate (ITPP), reported to cure hepatomas in a preclinical rat model and to have beneficial effects in several other solid tumor models, is currently in clinical trial for liver cancer. We investigated whether aggressive glioblastomas could be effectively treated with ITPP alone or in combination with radiation therapy (RT). MATERIALS AND METHODS: C57Bl/6 mice were intracranially injected with syngeneic GL261 glioblastoma cells and treated with hypofractionated radiation (5 Gy × 3), ITPP, or both...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28314175/choosing-wisely-preclinical-test-models-in-the-era-of-precision-medicine
#14
REVIEW
Konrad Klinghammer, Wolfgang Walther, Jens Hoffmann
Through the introduction of a steadily growing variety of preclinical test models drug development and biomarker research has advanced. Next to classical used 2D cell line cultures, tissue-slice cultures, 3D organoid cell cultures, genetically engineered mouse models, cell line derived mouse models and patient derived xenografts may be selected for a specific question. All models harbor advantages and disadvantages. This review focuses on the available preclinical test models, novel developments such as humanized mice and discusses for which question a particular model should be employed...
March 6, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28306152/assessment-of-ex-vivo-transport-function-in-isolated-rodent-brain-capillaries
#15
Gary N Y Chan, Ronald E Cannon
The blood-brain barrier plays an important role in neuroprotection; however, it can be a major obstacle for drug delivery to the brain. This barrier primarily resides in the brain capillaries and functions as an interface between the brain and peripheral blood circulation. Several anatomical and biochemical elements of the blood-brain barrier are essential to regulate the permeability of nutrients, ions, hormones, toxic metabolites, and xenobiotics into and out of the brain. In particular, high expression of ATP-driven efflux transporters at the blood-brain barrier is a major obstacle in the delivery of CNS pharmacotherapeutics to the brain...
March 17, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28304309/mouse-models-of-alzheimer-s-disease
#16
Gisela Esquerda-Canals, Laia Montoliu-Gaya, Jofre Güell-Bosch, Sandra Villegas
Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology...
March 10, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28304301/modeling-the-relationships-among-late-life-body-mass-index-cerebrovascular-disease-and-alzheimer-s-disease-neuropathology-in-an-autopsy-sample-of-1-421-subjects-from-the-national-alzheimer-s-coordinating-center-data-set
#17
Michael L Alosco, Jonathan Duskin, Lilah M Besser, Brett Martin, Christine E Chaisson, John Gunstad, Neil W Kowall, Ann C McKee, Robert A Stern, Yorghos Tripodis
The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum...
March 13, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28304189/physiological-remodeling-of-bifurcation-aneurysms-preclinical-results-of-the-eclips-device
#18
Thomas R Marotta, Howard A Riina, Ian McDougall, Donald R Ricci, Monika Killer-Oberpfalzer
OBJECTIVE Intracranial bifurcation aneurysms are complex lesions for which current therapy, including simple coiling, balloon- or stent-assisted coiling, coil retention, or intrasaccular devices, is inadequate. Thromboembolic complications due to a large burden of intraluminal metal, impedance of access to side branches, and a high recurrence rate, due largely to the unmitigated high-pressure flow into the aneurysm (water hammer effect), are among the limitations imposed by current therapy. The authors describe herein a novel device, eCLIPs, and its use in a preclinical laboratory study that suggests the device's design and functional features may overcome many of these limitations...
March 17, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28303914/restoring-brain-function-after-stroke-bridging-the-gap-between-animals-and-humans
#19
REVIEW
Nick S Ward
Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies...
March 17, 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/28303498/validation-of-a-preclinical-drug-screening-platform-for-pharmacoresistant-epilepsy
#20
Melissa L Barker-Haliski, Kristina Johnson, Peggy Billingsley, Jennifer Huff, Laura J Handy, Rizvana Khaleel, Zhenmei Lu, Matthew J Mau, Timothy H Pruess, Carlos Rueda, Gerald Saunders, Tristan K Underwood, Fabiola Vanegas, Misty D Smith, Peter J West, Karen S Wilcox
The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents...
March 16, 2017: Neurochemical Research
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