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https://www.readbyqxmd.com/read/28098436/bringing-3d-tumor-models-to-the-clinic-predictive-value-for-personalized-medicine
#1
REVIEW
Kathrin Halfter, Barbara Mayer
Current decision-guiding algorithms in cancer drug treatment are based on decades of research and numerous clinical trials. For the majority of patients, this data is successfully applied for a systemic disease management. For a number of patients however, treatment stratification according to clinically based risk criteria will not be sufficient. The most effective treatment options are ideally identified prior to the start of clinical drug therapy. This review will discuss the implementation of three-dimensional (3D) cell culture models as a preclinical testing paradigm for the efficacy of clinical cancer treatment...
January 18, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/28098336/preclinical-evaluation-of-intravenous-nax-810-2-a-novel-galr2-preferring-analog-for-anticonvulsant-efficacy-and-pharmacokinetics
#2
Cameron S Metcalf, Brian D Klein, Daniel R McDougle, Liuyin Zhang, Dan Kaufmann, Grzegorz Bulaj, H Steve White
OBJECTIVE: Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice...
January 18, 2017: Epilepsia
https://www.readbyqxmd.com/read/28097811/fc-silent-anti-cd154-domain-antibody-effectively-prevents-non-human-primate-renal-allograft-rejection
#3
Steven C Kim, Walter Wakwe, Laura B Higginbotham, David V Mathews, Cynthia P Breeden, Allison C Stephenson, Joe Jenkins, Elizabeth Strobert, Karen Price, Laura Price, Robert Kuhn, Haiqing Wang, Aaron Yamniuk, Suzanne Suchard, Alton B Farris, Thomas C Pearson, Christian P Larsen, Mandy L Ford, Anish Suri, Steven Nadler, Andrew B Adams
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004)...
January 17, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28097603/comprehensive-preclinical-evaluation-of-a-multi-physics-model-of-liver-tumor-radiofrequency-ablation
#4
Chloé Audigier, Tommaso Mansi, Hervé Delingette, Saikiran Rapaka, Tiziano Passerini, Viorel Mihalef, Marie-Pierre Jolly, Raoul Pop, Michele Diana, Luc Soler, Ali Kamen, Dorin Comaniciu, Nicholas Ayache
PURPOSE: We aim at developing a framework for the validation of a subject-specific multi-physics model of liver tumor radiofrequency ablation (RFA). METHODS: The RFA computation becomes subject specific after several levels of personalization: geometrical and biophysical (hemodynamics, heat transfer and an extended cellular necrosis model). We present a comprehensive experimental setup combining multimodal, pre- and postoperative anatomical and functional images, as well as the interventional monitoring of intra-operative signals: the temperature and delivered power...
January 17, 2017: International Journal of Computer Assisted Radiology and Surgery
https://www.readbyqxmd.com/read/28097503/blended-chitosan-paste-for-infection-prevention-preliminary-and-preclinical-evaluations
#5
Joel M Berretta, Jessica A Jennings, Harry S Courtney, Karen E Beenken, Mark S Smeltzer, Warren O Haggard
BACKGROUND: Local drug delivery devices offer a promising method for delivering vancomycin and amikacin for musculoskeletal wounds. However, current local delivery devices such as beads and sponges do not necessarily allow for full coverage of a wound surface with eluted antibiotics and do not address the need for reducing the antibiotic diffusion distance to help prevent contamination by bacteria or other microorganisms. We blended chitosan/polyethylene glycol (PEG) pastes/sponges to increase biocompatibility and improve antibiotic coverage within the wound...
January 17, 2017: Clinical Orthopaedics and related Research
https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#6
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28097011/a-selective-gpr40-ffar1-agonist-ly2881835-provides-immediate-and-durable-glucose-control-in-rodent-models-of-type-2-diabetes
#7
Yanyun Chen, Min Song, Jonathan P Riley, Charlie C Hu, Xianbu Peng, Donalyn Scheuner, Krister Bokvist, Pranab Maiti, Steven D Kahl, Chahrzad Montrose-Rafizadeh, Chafiq Hamdouchi, Anne Reifel Miller
LY2881835 is a selective, potent, and efficacious GPR40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY2881835 was tested in primary islets from WT mice but not in islets from GPR40 KO mice. Furthermore, LY2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY2881835 lowered glucose during OGTTs in WT mice but not in GPR40 KO mice...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097008/preclinical-findings-predicting-efficacy-and-side-effect-profile-of-ly2940094-an-antagonist-of-nociceptin-receptors
#8
Jeffrey M Witkin, Linda M Rorick-Kehn, Mark J Benvenga, Benjamin L Adams, Scott D Gleason, Karen M Knitowski, Xia Li, Steven Chaney, Julie F Falcone, Janice W Smith, Julie Foss, Kirsti Lloyd, John T Catlow, David L McKinzie, Kjell A Svensson, Vanessa N Barth, Miguel A Toledo, Nuria Diaz, Celia Lafuente, Alma Jiménez, Alfonso Benito, Conception Pedregal, Maria A Martínez-Grau, Anke Post, Michael A Ansonoff, John E Pintar, Michael A Statnick
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP (-/-) mice...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28097003/application-of-a-systems-pharmacology-model-for-translational-prediction-of-herg-mediated-qtc-prolongation
#9
Verena Gotta, Zhiyi Yu, Frank Cools, Karel van Ammel, David J Gallacher, Sandra A G Visser, Frederick Sannajust, Pierre Morissette, Meindert Danhof, Piet H van der Graaf
Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only)...
December 2016: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28095907/the-targeted-smac-mimetic-sw-iv-134-is-a-strong-enhancer-of-standard-chemotherapy-in-pancreatic-cancer
#10
Yassar M Hashim, Suwanna Vangveravong, Narendra V Sankpal, Pratibha S Binder, Jingxia Liu, S Peter Goedegebuure, Robert H Mach, Dirk Spitzer, William G Hawkins
BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs...
January 17, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28095847/the-biomedical-piglet-establishing-reference-intervals-for-haematology-and-clinical-chemistry-parameters-of-two-age-groups-with-and-without-iron-supplementation
#11
Domenico Ventrella, Francesco Dondi, Francesca Barone, Federica Serafini, Alberto Elmi, Massimo Giunti, Noemi Romagnoli, Monica Forni, Maria L Bacci
BACKGROUND: The similarities between swine and humans in physiological and genomic patterns, and the great correlation in size and anatomy, make pigs extremely useful in preclinical studies. New-born piglets can represent a model for congenital and genetic diseases in new-born children. It is known that piglets may have significant differences in clinicopathological results compared to adult pigs. Therefore, adult laboratory reference intervals cannot be applied to piglets. The aim of this study was to compare haematological and chemical variables in piglets of two ages and determinate age-related reference intervals for commercial hybrid young pigs...
January 17, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28095745/toward-the-definition-of-a-new-worst-case-paradigm-for-the-preclinical-evaluation-of-posterior-spine-stabilization-devices
#12
Luigi La Barbera, Tomaso Villa
Mechanical reliability tests on posterior spine stabilization devices are based on standard F1717 by the American Society for Testing and Materials, which describes how to assemble the implant with vertebrae-like test blocks in a corpectomy model. A recent study proposed to revise the standard to describe the anatomical worst-case scenario, instead of the average one currently implemented, and introduce the unsupported screw length as a mechanical parameter. This article investigates the implications of such revisions on the endurance properties of an implant already on the market...
January 1, 2017: Proceedings of the Institution of Mechanical Engineers. Part H, Journal of Engineering in Medicine
https://www.readbyqxmd.com/read/28095650/bone-tissue-engineering-in-oral-peri-implant-defects-in-preclinical-in-vivo-research-a-systematic-review-and-meta-analysis
#13
REVIEW
Siddharth Shanbhag, Nikolaos Pandis, Kamal Mustafa, Jens R Nyengaard, Andreas Stavropoulos
Regeneration and establishment of osseointegration within oral peri-implant bone defects remains a clinical challenge. Bone tissue engineering (BTE) is emerging as a promising alternative to autogenous and/or biomaterial-based bone grafting. The objective of this systematic review was to answer the focused question: in animal models, do cell-based BTE strategies enhance bone regeneration and/or implant osseointegration in experimental peri-implant defects, compared to grafting with autogenous bone or only biomaterial scaffolds? Electronic databases were searched for controlled animal studies reporting on peri-implant defects and implantation of mesenchymal stem cells (MSC) or other cells seeded on biomaterial scaffolds, following PRISMA guidelines...
January 17, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28094810/aberrant-development-of-intrinsic-brain-activity-in-a-rat-model-of-caregiver-maltreatment-of-offspring
#14
C-G Yan, M Rincón-Cortés, C Raineki, E Sarro, S Colcombe, D N Guilfoyle, Z Yang, S Gerum, B B Biswal, M P Milham, R M Sullivan, F X Castellanos
Caregiver maltreatment induces vulnerability to later-life psychopathology. Clinical and preclinical evidence suggest changes in prefrontal and limbic circuitry underlie this susceptibility. We examined this question using a rat model of maternal maltreatment and methods translated from humans, resting-state functional magnetic resonance imaging (R-fMRI). Rat pups were reared by mothers provided with insufficient or abundant bedding for nest building from postnatal (PN) days 8 to 12 and underwent behavioral assessments of affect-related behaviors (forced swim, sucrose preference and social interaction) in adolescence (PN45) and early adulthood (PN60)...
January 17, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28094534/in-vitro-assessment-of-skin-irritation-potential-of-surfactant-based-formulations-by-using-a-3-d-skin-reconstructed-tissue-model-and-cytokine-response
#15
Russel M Walters, Lisa Gandolfi, M Catherine Mack, Michael Fevola, Katharine Martin, Mathew T Hamilton, Allison Hilberer, Nicole Barnes, Nathan Wilt, Jennifer R Nash, Hans A Raabe, Gertrude-Emilia Costin
The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDerm™ model system to evaluate tissue viability and primary cytokine interleukin-1α release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials...
December 2016: Alternatives to Laboratory Animals: ATLA
https://www.readbyqxmd.com/read/28094524/antimalarial-pyrido-1-2-a-benzimidazoles-lead-optimization-parasite-life-cycle-stage-profile-mechanistic-evaluation-killing-kinetics-and-in-vivo-oral-efficacy-in-a-mouse-model
#16
Kawaljit Singh, John Okombo, Christel Brunschwig, Ferdinand Ndubi, Linley Barnard, Chad Wilkinson, Peter M Njogu, Mathew Njoroge, Lizahn Laing, Marta Machado, Miguel Prudêncio, Janette Reader, Mariette E Botha, Sindisiwe H Nondaba, Lyn-Marie Birkholtz, Sonja Lauterbach, Alisje Churchyard, Theresa L Coetzer, Jeremy N Burrows, Clive Leonard Yeates, Paolo Denti, Lubbe Wiesner, Timothy J Egan, Sergio Wittlin, Kelly Chibale
Further structure activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials, have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of haemozoin formation possibly contributes to the mechanism of action.
January 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28094206/hepatocyte-growth-factor-in-physiology-and-infectious-diseases
#17
REVIEW
Ryu Imamura, Kunio Matsumoto
Hepatocyte growth factor (HGF) is a pleiotropic cytokine composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. The receptor for HGF was identified as the c-met proto-oncogene product of transmembrane receptor tyrosine kinase. HGF-induced signaling through the receptor Met provokes dynamic biological responses that support morphogenesis, regeneration, and the survival of various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons...
January 13, 2017: Cytokine
https://www.readbyqxmd.com/read/28093317/stem-cell-therapies-in-preclinical-models-of-stroke-is-the-aged-brain-microenvironment-refractory-to-cell-therapy
#18
Raluca Elena Sandu, Adrian Balseanu, Catalin Bogdan, Mark Slevin, Eugen Petcu, Aurel Popa-Wagner
: Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizingimpediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains...
January 13, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28092946/carcinogenesis-of-the-oral-cavity-environmental-causes-and-potential-prevention-by-black-raspberry
#19
Karam El-Bayoumy, Kun-Ming Chen, Shang-Min Zhang, Yuan-Wan Sun, Shantu Amin, Gary Stoner, Joseph B Guttenplan
Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical...
January 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28092646/ex-vivo-nonviral-gene-delivery-of-%C3%AE-opioid-receptor-to-attenuate-cancer-induced-pain
#20
Seiichi Yamano, Chi T Viet, Dongmin Dang, Jisen Dai, Shigeru Hanatani, Tadahiro Takayama, Hironori Kasai, Kentaro Imamura, Ron Campbell, Yi Ye, John C Dolan, William Myung Kwon, Stefan D Schneider, Brian L Schmidt
Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 (∼45-fold) relative to HGF-1 (human gingival fibroblasts) cells...
February 2017: Pain
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