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https://www.readbyqxmd.com/read/28333316/convergent-balancing-selection-on-the-mu-opioid-receptor-in-primates
#1
Carolyn G Sweeney, Juliette M Rando, Helen N Panas, Gregory M Miller, Donna M Platt, Eric J Vallender
The mu opioid receptor is involved in many natural processes including stress response, pleasure, and pain. Mutations in the gene also have been associated with opiate and alcohol addictions as well as with responsivity to medication targeting these disorders. Two common and mutually exclusive polymorphisms have been identified in humans, A118G (N40D), found commonly in non-African populations, and C17T (V6A), found almost exclusively in African populations. While A118G has been studied extensively for associations and in functional assays, C17T is much less well understood...
March 15, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/28332004/social-setting-social-rank-and-hpa-axis-response-in-cynomolgus-monkeys
#2
Vanessa A Jimenez, Daicia C Allen, Megan N McClintick, Kathleen A Grant
RATIONALE: Hypothalamic-pituitary-adrenal (HPA) axis activity under different social settings in non-human primates is understudied. OBJECTIVE: The aim of this study is to evaluate the response of pituitary-adrenal hormones (adrenocorticotropic hormone (ACTH) and cortisol) to pharmacological challenges of the HPA axis in male cynomolgus macaques under different social settings. METHODS: Male cynomolgus macaques (Macaca fascicularis, n = 11) were individually (A) and socially housed (B) in alternation, over consecutive months, in an ABA design...
March 22, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28331086/nectin-4-interactions-govern-measles-virus-virulence-in-a-new-model-of-pathogenesis-squirrel-monkeys-simia-sciureus
#3
Sébastien Delpeut, Bevan Sawatsky, Xiao-Xiang Wong, Marie Frenzke, Roberto Cattaneo, Veronika von Messling
In addition to humans, only certain non-human primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species-dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys (Simia sciureus), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28328941/cynomolgus-monkeys-are-successfully-and-persistently-infected-with-hepatitis-e-virus-genotype-3-hev-3-after-long-term-immunosuppressive-therapy
#4
Noemi Rovaris Gardinali, Juliana Rodrigues Guimarães, Juliana Gil Melgaço, Yohan Britto Kevorkian, Fernanda de Oliveira Bottino, Yasmine Rangel Vieira, Aline Campos de Azevedo da Silva, Douglas Pereira Pinto, Laís Bastos da Fonseca, Leandro Schiavo Vilhena, Edilson Uiechi, Maria Cristina Carlan da Silva, Julio Moran, Renato Sérgio Marchevsky, Oswaldo Gonçalves Cruz, Rodrigo Alejandro Arellano Otonel, Amauri Alcindo Alfieri, Jaqueline Mendes de Oliveira, Ana Maria Coimbra Gaspar, Marcelo Alves Pinto
Epidemiological studies found that hepatitis E virus genotype 3 (HEV-3) infection was associated with chronic hepatitis and cirrhosis in immunocompromised patients. Our study aimed to investigate the relationship between the host immunosuppressive status and the occurrence of HEV-related chronic hepatitis. Here we describe a successful experimental study, using cynomolgus monkeys previously treated with tacrolimus, a potent calcineurin inhibitor immunosuppressant, and infected with a Brazilian HEV-3 strain isolated from naturally infected pigs...
2017: PloS One
https://www.readbyqxmd.com/read/28324011/a-novel-fc-fgf21-with-improved-resistance-to-proteolysis-increased-affinity-towards-%C3%AE-klotho-and-enhanced-efficacy-in-mice-and-cynomolgus-monkeys
#5
Shanaka Stanislaus, Randy Hecht, Junming Yie, Todd Hager, Michael Hall, Chris Spahr, Wei Wang, Jennifer Weiszmann, Yang Li, Liying Deng, Dwight Winters, Stephen Smith, Lei Zhou, Yuesheng Li, Murielle M Véniant, Jing Xu
FGF21 is a natural hormone that modulates glucose, lipid, and energy metabolism. Previously, we engineered an Fc fusion FGF21 variant with two mutations, Fc-FGF21(RG), to extend the half-life and reduce aggregation and in vivo degradation of FGF21. We now describe a new variant developed to reduce the extreme C-terminal degradation and improve the binding affinity to β-Klotho. We demonstrate, by introducing one additional mutation located at the C-terminus of FGF21 (A180E) that the new molecule, Fc-FGF21(RGE), has gained many improved attributes...
January 26, 2017: Endocrinology
https://www.readbyqxmd.com/read/28321043/immunolocalization-of-novel-corticomedullary-tubule-injury-markers-in-cynomolgus-monkeys-treated-with-amphotericin-b
#6
J Eric McDuffie, Jing Ying Ma, Yunhai Zhang, Frederic S Almy, Xiaoyun Wu, Ke Li, Manisha Sonee, Ryan Meng, Michele Rizzolio, Sandra S Snook
Amphotericin B (AmpB) nephrotoxicity was used to assess the utility of drug‑induced kidney injury (DIKI) biomarkers in an exploratory study in male cynomolgus monkeys. All animals had quantifiable levels of AmpB in plasma on days 1 and 4. There were no clinical signs of AmpB‑induced toxicity in this study. The gold standard method used to confirm AmpB‑induced DIKI was anatomic pathology which revealed microscopic lesions with varying grades of severity. Immunolocalization of alpha‑1 microglobulin (α‑1M), kidney injury molecule 1 (KIM‑1), osteopontin (OPN) and neutrophil gelatinase‑associated lipocalin (NGAL) proteins was evaluated in formalin‑fixed, paraffin‑embedded monkey kidney tissue sections...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28317872/preclinical-evaluation-of-the-efficacy-pharmacokinetics-and-immunogenicity-of-js-001-a-programmed-cell-death-protein-1-pd-1-monoclonal-antibody
#7
Jie Fu, Fang Wang, Li-Hou Dong, Jing Zhang, Cheng-Lian Deng, Xue-Li Wang, Xin-Yao Xie, Jing Zhang, Ruo-Xian Deng, Li-Bo Zhang, Hai Wu, Hui Feng, Bo Chen, Hai-Feng Song
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28315649/comparison-of-saliva-collection-methods-for-the-determination-of-salivary-cortisol-levels-in-rhesus-macaques-macaca-mulatta-cynomolgus-macaques-macaca-fascicularis-and-african-green-monkeys-chlorocebus-aethiops
#8
Kamala J Rapp-Santos, Louis A Altamura, Sarah L Norris, Luis A Lugo-Roman, Pedro J Rico, Christian C Hofer
The ability to quickly and accurately determine cortisol as a biomarker for stress is a valuable tool in assessing the wellbeing of NHP. In this study, 2 methods of collecting saliva (a commercial collection device and passive drool) and the resulting free salivary cortisol levels were compared with total serum cortisol concentration in rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis) and African green monkeys (Chlorocebus aethiops) at 2 collection time points. Serum and salivary cortisol levels were determined using a competitive quantitative ELISA...
March 1, 2017: Journal of the American Association for Laboratory Animal Science: JAALAS
https://www.readbyqxmd.com/read/28315648/morphologic-and-doppler-findings-from-hepatic-ultrasonography-of-normal-cynomolgus-monkeys-macaca-fascicularis
#9
Kyo Won Lee, Chan Woo Cho, Ji Eun Lee, Hyojun Park, Gyu-Seong Choi, Woo Kyoung Jeong, Jae Berm Park, Sungjoo Kim
The present study evaluated the anatomic and ultrasonographic features of the liver in normal cynomolgus monkeys (Macaca fascicularis). Healthy, male, cynomolgus monkeys from Cambodia (n = 25; mean age, 58.1 mo) were sedated with ketamine (7 mg/kg) and examined by using 2D and Doppler ultrasonography. We measured the diameters of the vascular structures and bile duct, determined the velocities of the hepatic artery and portal vein, and calculated the resistance index of the hepatic artery. Vessel diameters were: proper hepatic artery, 1...
March 1, 2017: Journal of the American Association for Laboratory Animal Science: JAALAS
https://www.readbyqxmd.com/read/28315356/the-effect-of-angiotensin-receptor-neprilysin-inhibitor-sacubitril-valsartan-on-central-nervous-system-amyloid-%C3%AE-concentrations-and-clearance-in-the-cynomolgus-monkey
#10
Heidi A Schoenfeld, Tim West, Philip B Verghese, Mary Holubasch, Neeta Shenoy, David Kagan, Chiara Buono, Wei Zhou, Marc DeCristofaro, Julie Douville, Geoffrey G Goodrich, Keith Mansfield, Chandra Saravanan, Frederic Cumin, Randy L Webb, Randall J Bateman
Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology...
March 15, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28315351/-3-h-bmt-046091-a-potent-and-selective-radioligand-to-determine-aak1-distribution-and-target-engagement
#11
Justin V Louis, Yifeng Lu, Rick Pieschl, Yung Tian, Yang Hong, Kumaran Dandapani, Sreenivasulu Naidu, Reeba K Vikramadithyan, Carolyn Dzierba, Sarat Kumar Sarvasiddhi, Susheel J Nara, Joanne Bronson, John E Macor, Charlie Albright, Walter Kostich, Yu-Wen Li
Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [(3)H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors...
March 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28304254/clinical-trypanosoma-cruzi-disease-after-cardiac-transplantation-in-a-cynomolgus-macaque-macaca-fascicularis
#12
Elana R Rybak, Steve Shipley, Ivan Tatarov, Tianshu Zhang, Wenji Sun, Gheorghe Braileanu, Lars Burdorf, Evelyn Sievert, Agnes M Azimzadeh, Louis J DeTolla, Richard N Pierson Iii
A cynomolgus macaque received a heterotopic cardiac allograft as part of a transplant study, with monoclonal antibodies targeted to specific immune costimulation molecules (CD154, CD28) but no traditional immunosuppressive therapy after surgery. Clinical anemia was detected on postoperative day (POD) 35 and had worsened (Hgb, 2.3 g/dL; Hct = 7.3%) by POD 47, despite type-matched whole-blood transfusions. After a total of 4 blood transfusions, hematologic parameters were improved (Hgb, 5.9 g/dL; Hct, 18.7%)...
December 1, 2016: Comparative Medicine
https://www.readbyqxmd.com/read/28304252/utility-of-orchidometric-parameters-for-assessing-sexual-maturation-in-male-cynomolgus-macaques-macaca-fascicularis
#13
Michael L Mirsky, Susan Portugal, Harshan Pisharath, Jodi L Osowski, Laura Kearney
Testicular volume is one of several parameters that have been used in preclinical toxicology to facilitate the identification of sexually mature male cynomolgus macaques when semen evaluation is unavailable. Furthermore, testicular volume provides additional information to pathologists to aid in the interpretation of microscopic findings. Orchidometry has been proposed as a useful tool for assessing testicular volume. To assess its utility for this purpose, we used orchidometry to measure testicular volume in untreated control male cynomolgus macaques during preclinical toxicology studies...
December 1, 2016: Comparative Medicine
https://www.readbyqxmd.com/read/28302764/-18-f-gp1-a-novel-fluorine-18-labeled-tracer-designed-for-pet-imaging-of-thrombi-with-high-detection-sensitivity-and-low-background
#14
Jessica Lohrke, Holger Siebeneicher, Markus Berger, Michael Reinhardt, Mathias Berndt, Andre Mueller, Marion Zerna, Norman Koglin, Felix Oden, Marcus Bauser, Matthias Friebe, Ludger M Dinkelborg, Joachim Huetter, Andrew W Stephens
Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks and pulmonary embolism are major causes of morbidity and mortality worldwide. GPIIb/IIIa is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small molecule tracer for positron emission tomography (PET) imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches...
March 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28300674/structure-activity-studies-on-polymyxin-derivatives-carrying-three-positive-charges-only-reveal-a-new-class-of-compounds-with-strong-antibacterial-activity
#15
Martti Vaara, Timo Vaara, Jonathan M Tyrrell
Recent years have brought in an increased interest to develop improved polymyxins. The currently used polymyxins, i.e. polymyxin B and colistin (polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear "panhandle" part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a polymyxin derivative NAB739 which lacks the positive charges in the linear part...
March 11, 2017: Peptides
https://www.readbyqxmd.com/read/28287337/generation-and-characterization-of-protective-antibodies-to-marburg-virus
#16
Jeffrey W Froude, Thibaut Pelat, Sebastian Miethe, Samantha E Zak, Anna Z Wec, Kartik Chandran, Jennifer Mary Brannan, Russell R Bakken, Michael Hust, Philippe Thullier, John M Dye
Marburg virus (MARV) and Ebola virus (EBOV) have been a source of epidemics and outbreaks for several decades. We present here the generation and characterization of the first protective antibodies specific for wild-type MARV. Non-human primates (NHP), cynomolgus macaques, were immunized with viral-replicon particles expressing the glycoproteins (GP) of MARV (Ci67 isolate). An antibody fragment (single-chain variable fragment, scFv) phage display library was built after four immunogen injections, and screened against the GP1-649 of MARV...
March 13, 2017: MAbs
https://www.readbyqxmd.com/read/28273087/an-aerosol-challenge-model-of-tuberculosis-in-mauritian-cynomolgus-macaques
#17
S A Sharpe, A D White, L Sibley, F Gleeson, G A Hall, R J Basaraba, A McIntyre, S O Clark, K Gooch, P D Marsh, A Williams, M J Dennis
BACKGROUND: New interventions for tuberculosis are urgently needed. Non-human primate (NHP) models provide the most relevant pre-clinical models of human disease and play a critical role in vaccine development. Models utilising Asian cynomolgus macaque populations are well established but the restricted genetic diversity of the Mauritian cynomolgus macaques may be of added value. METHODS: Mauritian cynomolgus macaques were exposed to a range of doses of M. tuberculosis delivered by aerosol, and the outcome was assessed using clinical, imaging and pathology-based measures...
2017: PloS One
https://www.readbyqxmd.com/read/28266719/ancestry-plasmodium-cynomolgi-prevalence-and-rhesus-macaque-admixture-in-cynomolgus-macaques-macaca-fascicularis-bred-for-export-in-chinese-breeding-farms
#18
Xinjun Zhang, Yuhuan Meng, Paul Houghton, Mingyu Liu, Sreetharan Kanthaswamy, Robert Oldt, Jillian Ng, Jessica Satkoski Trask, Ren Huang, Balbir Singh, Hongli Du, David Glenn Smith
BACKGROUND: Most cynomolgus macaques (Macaca fascicularis) used in the United States as animal models are imported from Chinese breeding farms without documented ancestry. Cynomolgus macaques with varying rhesus macaque ancestry proportions may exhibit differences, such as susceptibility to malaria, that affect their suitability as a research model. METHODS: DNA of 400 cynomolgus macaques from 10 Chinese breeding farms was genotyped to characterize their regional origin and rhesus ancestry proportion...
March 7, 2017: Journal of Medical Primatology
https://www.readbyqxmd.com/read/28265006/characterization-of-the-anti-pd-1-antibody-regn2810-and-its-antitumor-activity-in-human-pd-1-knock-in-mice
#19
Elena Burova, Aynur Hermann, Janelle Waite, Terra Potocky, Venus Lai, Seongwon Hong, Matt Liu, Omaira Allbritton, Amy Woodruff, Qi Wu, Amanda D'Orvilliers, Elena Garnova, Ashique Rafique, William Poueymirou, Joel Martin, Tammy Huang, Dimitris Skokos, Joel Kantrowitz, Jon Popke, Markus Mohrs, Douglas MacDonald, Ella Ioffe, William Olson, Israel Lowy, Andrew Murphy, Gavin Thurston
The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen presenting cells and cancer cells, resulting in suppression of T cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 (S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28262555/membrane-proximal-epitope-facilitates-efficient-t-cell-synapse-formation-by-anti-fcrh5-cd3-and-is-a-requirement-for-myeloma-cell-killing
#20
Ji Li, Nicola J Stagg, Jennifer Johnston, Michael J Harris, Sam A Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R James, Teemu T Junttila
The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys...
February 20, 2017: Cancer Cell
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