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https://www.readbyqxmd.com/read/29342230/metformin-as-an-anti-cancer-agent-actions-and-mechanisms-targeting-cancer-stem-cells
#1
Nipun Saini, Xiaohe Yang
Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse...
October 7, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29341020/mri-in-the-study-of-animal-models-of-stroke
#2
Pedro Ramos-Cabrer, Daniel Padro
Stroke consists of the loss of cerebral functions resulting from the interruption of blood supply to a region of the brain, and represents the second cause of death and the leading cause of major disability in adults in Europe. Stroke is a very active field of research at preclinical and clinical levels, and Magnetic Resonance Imaging (MRI) is one of the most powerful tools that scientist and clinicians have for the study of the onset, evolution and consequences of this devastating disease, as well as for the monitoring of the success of available treatments, or for the development of novel therapeutic strategies...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29341013/rodent-abdominal-adipose-tissue-imaging-by-mr
#3
Bhanu Prakash Kn, Jadegoud Yaligar, Sanjay K Verma, Venkatesh Gopalan, S Sendhil Velan
Rodents including rats and mice are important models to study obesity, diabetes, and metabolic syndrome in a preclinical setting. Translational and longitudinal imaging of these rodents permit investigation of metabolic diseases and identification of imaging biomarkers suitable for clinical translation. Here we describe the imaging protocols for achieving quantitative abdominal imaging in small animals followed by segmentation and quantification of fat volumes.
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29341006/mapping-functional-connectivity-in-the-rodent-brain-using-electric-stimulation-fmri
#4
Laura Pérez-Cervera, José María Caramés, Luis Miguel Fernández-Mollá, Andrea Moreno, Begoña Fernández, Elena Pérez-Montoyo, David Moratal, Santiago Canals, Jesús Pacheco-Torres
Since its discovery in the early 90s, BOLD signal-based functional Magnetic Resonance Imaging (fMRI) has become a fundamental technique for the study of brain activity in basic and clinical research. Functional MRI signals provide an indirect but robust and quantitative readout of brain activity through the tight coupling between cerebral blood flow and neuronal activation, the so-called neurovascular coupling. Combined with experimental techniques only available in animal models, such as intracerebral micro-stimulation, optogenetics or pharmacogenetics, provides a powerful framework to investigate the impact of specific circuit manipulations on overall brain dynamics...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29341001/dynamic-susceptibility-contrast-mri-in-small-animals
#5
Pilar López-Larrubia
The use of magnetic resonance imaging (MRI) for studying the cerebral perfusion mechanisms is well proved and contrasted in the clinical and research setups. This methodology is a promising tool in assessing numerous brain diseases like intracranial tumors, neurodegeneration processes, mental disorders, injuries and so on. In the preclinical environment, perfusion MRI offers a powerful resource for characterizing pathological models and specially identifying biomarkers to monitor the illness and validate the efficacy of therapeutical approaches...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29340822/a-preclinical-animal-study-of-a-novel-simple-and-secure-duct-and-vessel-occluder-for-laparoscopic-surgery
#6
Amir Szold, Arnold Miller, Nir Lilach, Ana-Maria Botero-Anug, Raanan Miller, Steven D Schwaitzberg
BACKGROUND: Secure occlusion of large blood vessels and ductal structures is critical to all surgeries and remains a challenge in many minimally invasive procedures. This study compares in vivo use of the Amsel Occluder (AO) for secure laparoscopic blood vessel and duct closure, with one of the many commercially available hemoclips (Ligaclip®), in the porcine model. METHODS: Laparoscopic closure of vessels and ducts was performed on 12 swine to compare the ease of use, safety and efficacy of the AO with a hemoclip, as well as the tissue response at > 30 days (10 swine)...
January 16, 2018: Surgical Endoscopy
https://www.readbyqxmd.com/read/29340025/the-novel-atm-inhibitor-az31-enhances-antitumor-activity-in-patient-derived-xenografts-that-are-resistant-to-irinotecan-monotherapy
#7
Justin Greene, Anna Nguyen, Stacey M Bagby, Gemma N Jones, W M Tai, Kevin S Quackenbush, Anna Schreiber, Wells A Messersmith, Kalpana M Devaraj, Patrick Blatchford, S Gail Eckhardt, Elaine B Cadogan, Gareth D Hughes, Aaron Smith, Todd M Pitts, John J Arcaroli
Irinotecan, a standard of care therapy for CRC, elicits cytotoxic effects by generating double strand breaks resulting in DNA damage. The activation of the ATM pathway plays a fundamental role in regulating the cellular response and repair to DNA damage. The objective of this preclinical study was to determine whether ATM inhibition would enhance sensitivity to irinotecan treatment. Treatment effects of AZ31, irinotecan or AZ31 + irinotecan were investigated in CRC cell lines and CRC patient derived xenografts...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#8
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339550/relative-target-affinities-of-t-cell-dependent-bispecific-antibodies-determine-biodistribution-in-a-solid-tumor-mouse-model
#9
Danielle Mandikian, Nene Takahashi, Amy A Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B Joseph, Mark S Dennis, Saileta Prabhu, Teemu T Junttila, C Andrew Boswell
Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339440/repurposing-tin-mesoporphyrin-as-an-immune-checkpoint-inhibitor-shows-therapeutic-efficacy-in-preclinical-models-of-cancer
#10
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29338843/current-status-of-animal-models-of-posttraumatic-stress-disorder-behavioral-and-biological-phenotypes-and-future-challenges-in-improving-translation
#11
REVIEW
Jessica Deslauriers, Mate Toth, Andre Der-Avakian, Victoria B Risbrough
Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species...
November 20, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29338610/cns-side-effects-of-immune-checkpoint-inhibitors-preclinical-models-genetics-and-multimodality-therapy
#12
Gwendolyn J McGinnis, Jacob Raber
Following cancer treatment, patients often report behavioral and cognitive changes. Novel cancer immunotherapeutics have the potential to produce sustained cancer survivorship, meaning patients will live longer with the side effects of treatment. Given the role of inflammatory pathways in mediating behavioral and cognitive impairments seen in cancer, we aim in this review to discuss emerging evidence for the contribution of immune checkpoint blockade to exacerbate these CNS effects. We discuss ongoing studies regarding the ability of immune checkpoint inhibitors to reach the brain and how treatment responses to checkpoint inhibitors may be modulated by genetic factors...
September 2017: Immunotherapy
https://www.readbyqxmd.com/read/29338496/repeated-lipopolysaccharide-exposure-modifies-immune-and-sickness-behaviour-response-in-an-animal-model-of-chronic-inflammation
#13
Ksenia Musaelyan, Steven Aldridge, Andrea Du Preez, Martin Egeland, Patricia A Zunszain, Carmine M Pariante, Sandrine Thuret, Cathy Fernandes
Repeated lipopolysaccharide exposure is often used in longitudinal preclinical models of depression. However, the potential phenotypic differences from acute depression-mimicking effects are rarely described. This study compared chronic lipopolysaccharide administration of doses previously used in depression research to a new mode of escalating dose injections. Adult male BALB/c mice ( n=8/group) were injected intraperitoneally with either a single 0.83 mg/kg dose, a repeated 0.1 mg/kg lipopolysaccharide dose or a dose which escalated weekly from 0...
January 1, 2018: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/29338381/effect-of-the-diabetic-state-on-islet-engraftment-and-function-in-a-large-animal-model-of-islet-kidney-transplantation
#14
Prashanth Vallabhajosyula, Atsushi Hirakata, Matthew Weiss, Adam Griesemer, Akira Shimizu, Hanzhou Hong, Andreas Habertheuer, Vaja Tchipashvili, Kazuhiko Yamada, David H Sachs
In islet transplantation, in addition to immunologic and ischemic factors, the diabetic/hyperglycemic state of the recipient has been proposed, although not yet validated, as a possible cause of islet toxicity, contributing to islet loss during the engraftment period. Using a miniature swine model of islet transplantation, we have now assessed the effect of a persistent state of hyperglycemia on islet engraftment and subsequent function. An islet-kidney (IK) model previously described by our laboratory was utilized...
November 2017: Cell Transplantation
https://www.readbyqxmd.com/read/29337695/automated-fabrication-of-photopatterned-gelatin-hydrogels-for-organ-on-chips-applications
#15
Janna C Nawroth, Lisa L Scudder, Ryan T Halvorson, Jason Tresback, John P Ferrier, Sean P Sheehy, Alex Cho, Suraj Kannan, Ilona Sunyovszki, Josue A Goss, Patrick H Campbell, Kevin Kit Parker
Organ-on-chip platforms aim to improve preclinical models for organ-level responses to novel drug compounds. Heart-on-a-chip assays in particular require tissue engineering techniques that rely on labor-intensive photolithographic fabrication or resolution-limited 3D printing of micropatterned substrates, which limits turnover and flexibility of prototyping. We present a rapid and automated method for large scale on-demand micropatterning of gelatin hydrogels for organ-on-chip applications using a novel biocompatible laser-etching approach...
January 16, 2018: Biofabrication
https://www.readbyqxmd.com/read/29337578/physiologically-based-pharmacokinetic-modeling-in-lead-optimization-i-evaluation-and-adaptation-of-gastroplus-to-predict-bioavailability-of-medchem-series
#16
Pankaj R Daga, Michael B Bolger, Ian S Haworth, Robert Daniel Clark, Eric J Martin
When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly and projects have too little data to train local %F QSPR models. Mechanistic oral absorption and physiologically-based pharmacokinetic (PBPK) models simulate the dissolution, absorption, systemic distribution, and clearance of a drug in preclinical species and humans...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29336496/donepezil-reverses-dendritic-spine-morphology-adaptations-and-fmr1-epigenetic-modifications-in-hippocampus-of-adult-rats-after-adolescent-alcohol-exposure
#17
Patrick J Mulholland, Tara L Teppen, Kelsey M Miller, Hannah G Sexton, Subhash C Pandey, H Scott Swartzwelder
BACKGROUND: Adolescent intermittent ethanol (AIE) exposure produces persistent impairments in cholinergic and epigenetic signaling and alters markers of synapses in the hippocampal formation, effects that are thought to drive hippocampal dysfunction in adult rodents. Donepezil (Aricept), a cholinesterase inhibitor, is used clinically to ameliorate memory-related cognitive deficits. Given that donepezil also prevents morphological impairment in preclinical models of neuropsychiatric disorders, we investigated the ability of donepezil to reverse morphological and epigenetic adaptations in the hippocampus of adult rats exposed to AIE...
January 16, 2018: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/29335205/design-and-synthesis-of-2-4-5-6-7-tetrahydrothienopyridin-2-yl-benzoimidazole-carboxamides-as-novel-orally-efficacious-poly-adp-ribose-polymerase-parp-inhibitors
#18
Xuxing Chen, Xiajuan Huan, Qiufeng Liu, Yuqin Wang, Qian He, Cun Tan, Yi Chen, Jian Ding, Yechun Xu, Zehong Miao, Chunhao Yang
The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively...
January 8, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29334430/preclinical-therapeutic-efficacy-of-the-ciprofloxacin-eluting-sinus-stent-for-pseudomonas-aeruginosa-sinusitis
#19
Do-Yeon Cho, Dong-Jin Lim, Calvin Mackey, Daniel Skinner, Christopher Weeks, Gobind S Gill, Robert W Hergenrother, William E Swords, Bradford A Woodworth
BACKGROUND: The ciprofloxacin-coated sinus stent (CSS) has unique therapeutic potential to deliver antibiotics to the sinuses. The objective of this study is to evaluate the efficacy of the CSS stent in eliminating Pseudomonas aeruginosa infection in a rabbit model of sinusitis. METHODS: A ciprofloxacin-eluting sinus stent was created by coating ciprofloxacin/Eudragit RS100 on biodegradable poly-D/L-lactic acid (2 mg). After analyzing in-vitro inhibition of P aeruginosa (PAO-1 strain) biofilm formation, a total of 8 stents (4 shams, 4 CSSs) were placed unilaterally in rabbit maxillary sinuses via dorsal sinusotomy after inducing infection for 1 week with PAO-1...
January 15, 2018: International Forum of Allergy & Rhinology
https://www.readbyqxmd.com/read/29334372/pharmacological-blockade-of-asct2-dependent-glutamine-transport-leads-to-antitumor-efficacy-in-preclinical-models
#20
Michael L Schulte, Allie Fu, Ping Zhao, Jun Li, Ling Geng, Shannon T Smith, Jumpei Kondo, Robert J Coffey, Marc O Johnson, Jeffrey C Rathmell, Joe T Sharick, Melissa C Skala, Jarrod A Smith, Jordan Berlin, M Kay Washington, Michael L Nickels, H Charles Manning
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2...
January 15, 2018: Nature Medicine
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