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visual stimulation-induced mild stress enhances cognitive behavior in cynomolgus monkey.cortisol is a well-known endogenous glucocorticoid that serves as a stress indicator. it is normally released under stressful condition to warn about imminent danger and thus is critical for survival of the species. however, it is unclear how cortisol relates to cognitive process under physiological condition in high-order primates such as non-human primates (nhp). here, we report that a slight but significant increase in blood cortisol level by mild stress is positively correlated with the cogn ...201829491446
reduced red blood cell deformability in plasmodium knowlesi malaria.the simian parasite plasmodium knowlesi can cause severe and fatal human malaria. however, little is known about the pathogenesis of this disease. in falciparum malaria, reduced red blood cell deformability (rbc-d) contributes to microvascular obstruction and impaired organ perfusion. in p knowlesi infection, impaired microcirculatory flow has been observed in macaca mulatta (rhesus macaques), unnatural hosts who develop severe and fatal disease. however, rbc-d has not been measured in human inf ...201829487058
spontaneous hypertrophic cardiomyopathy in a cynomolgus macaque (macaca fascicularis).the term cardiomyopathy is used to describe heart disease resulting from an abnormality in the myocardium. it is rare in cynomolgus macaques (macaca fascicularis). here, we report a case of hypertrophic cardiomyopathy in an 11-year-old male cynomolgus macaque. macroscopically, the interventricular septum (ivs) and the left ventricular (lv) and right ventricular (rv) walls of the heart were thickened. histologically, cardiomyocytes showed hypertrophy and disarray with interstitial fibrosis, and s ...201829479140
circulating liver-specific micrornas in cynomolgus monkeys.circulating micrornas (mirnas) can potentially be used as sensitive and specific biomarkers for tissue injury. however, the usefulness of circulating mirnas as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific mirnas. therefore, a systematic investigation was performed to address this point. we identified organ-specific mirnas from cynomolgus monkeys by next-generation sequencing analysis, which revealed ...201829479135
spontaneous findings in the eyes of cynomolgus monkeys ( macaca fascicularis) of mauritian origin.spontaneous findings noted in the eyes of mauritian cynomolgus monkeys are described and descriptions are supplemented with illustrations. findings observed after extensive histopathologic examinations (20 to 44 sections per eye) from 20 control, 17 treatment-naive stock monkeys, and 2 findings noted in drug-treated monkeys that were considered to be spontaneous are included. also included are findings from 361 control monkeys of routine toxicity studies performed at our laboratories, for most o ...201829478386
human igg subclass cross-species reactivity to mouse and cynomolgus monkey fcγ receptors.in therapeutic antibody discovery and early development, mice and cynomolgus monkey are used as animal models to assess toxicity, efficacy and other properties of candidate molecules. as more candidate antibodies are based on human immunoglobulin (igg) subclasses, many strategies are pursued to simulate the human system in the test animal. however, translation rate from a successful preclinical trial to an approved drug is extremely low. this may partly be due to differences in interaction of hu ...201829476755
[investigation of two blood parasitic protozoa infection in farmed macaca fascicularis in guangxi zhuang autonomous region].to investigate the infection situation of blood parasitic protozoa in farmed macaca fascicularis in an animal breeding ground in nanning, guangxi zhuang autonomous region, so as to provide the evidence for the prevention and control of human blood parasitic protozoa.201629469289
the development of new factor xa inhibitors based on amide synthesis.factor xa (fxa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive targets for oral anticoagulants of new generation.201829468977
polymorphisms of cytochrome p450 2b6 (cyp2b6) in cynomolgus and rhesus macaques.cytochrome p450 2b6 (cyp2b6) is an important drug-metabolizing enzyme and is expressed in liver. although human cyp2b6 variants account for variable enzyme properties among individuals and populations, cyp2b6 genetic variants have not been investigated in cynomolgus macaques, widely used in drug metabolism studies.201829468688
pilot study of delayed icos/icos-l blockade with αcd40 to modulate pathogenic alloimmunity in a primate cardiac allograft model.inducible costimulator (icos) is rapidly upregulated with t-cell stimulation and may represent an escape pathway for t-cell costimulation in the setting of cd40/cd154 costimulation blockade. induction treatment exhibited no efficacy in a primate renal allograft model, but rodent transplant models suggest that the addition of delayed icos/icos-l blockade may prolong allograft survival and prevent chronic rejection. here, we ask whether icos-ig treatment, timed to anticipate icos upregulation, pro ...201829464205
generation and characterization of a novel small biologic alternative to proprotein convertase subtilisin/kexin type 9 (pcsk9) antibodies, ds-9001a, albumin binding domain-fused anticalin protein.since it was recently reported that an antibody for proprotein convertase subtilisin/kexin type 9 (pcsk9) reduces the risk of cardiovascular events in a clinical context, pcsk9 inhibition is thought to be an attractive therapy for dyslipidemia. in the present study, we created a novel small biologic alternative to pcsk9 antibodies called ds-9001a, comprising an albumin binding domain fused to an artificial lipocalin mutein (abd-fused anticalin protein), which can be produced by a microbial produ ...201829463608
integrated pharmacokinetic/pharmacodynamic model of a bispecific cd3xcd123 dart molecule in nonhuman primates: evaluation of activity and impact of immunogenicity.purpose: flotetuzumab (mgd006 or s80880) is a bispecific molecule that recognizes cd3 and cd123 membrane proteins, redirecting t cells to kill cd123-expressing cells for the treatment of acute myeloid leukemia. in this study, we developed a mathematical model to characterize mgd006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys.experimental design: thirty-two animals received multiple escalating doses (100-300-600-1,000 ng/kg/day) via intrave ...201829463552
protective effects of the complement inhibitor compstatin cp40 in hemorrhagic shock.trauma-induced hemorrhagic shock (hs) plays a decisive role in the development of immune, coagulation, and organ dysfunction often resulting in a poor clinical outcome. imbalanced complement activation is intricately associated with the molecular danger response and organ damage after hs. thus, inhibition of the central complement component c3 as turnstile of both inflammation and coagulation is hypothesized as a rational strategy to improve the clinical course after hs.applying intensive care c ...201929461464
model of traumatic spinal cord injury for evaluating pharmacologic treatments in cynomolgus macaques (macaca fasicularis).here we present the results of experiments involving cynomolgus macaques, in which a model of traumatic spinal cord injury (tsci) was created by using a balloon catheter inserted into the epidural space. prior to the creation of the lesion, we inserted an emg recording device to facilitate measurement of tail movement and muscle activity before and after tsci. this model is unique in that the impairment is limited to the tail: the subjects do not experience limb weakness, bladder impairment, or ...201829460723
a model of anterior cruciate ligament injury in cynomolgus monkeys developed via arthroscopic surgery.the anterior cruciate ligament (acl) is an important structure that maintains the stability of knee joints. animal models of acl injury are helpful to explore its underlying mechanisms, and strategies for prevention, treatment and rehabilitation. therefore, the aim of the present study was to develop an efficient model of acl injury in cynomolgus monkeys via arthroscopic techniques. in the present study, 18 cynomolgus monkeys were randomly divided into a model group (n=6), a sham operation group ...201829456631
immunologic effects of chronic administration of tofacitinib, a janus kinase inhibitor, in cynomolgus monkeys and rats - comparison of juvenile and adult responses.tofacitinib, an oral janus kinase (jak) inhibitor for treatment of rheumatoid arthritis, targets jak1, jak3, and to a lesser extent jak2 and tyk2. jak1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (t-dependent antibody response (tdar), mit ...201829454012
prime and boost vaccination elicit a distinct innate myeloid cell immune response.understanding the innate immune response to vaccination is critical in vaccine design. here, we studied blood innate myeloid cells after first and second immunization of cynomolgus macaques with the modified vaccinia virus ankara. the inflammation at the injection site was moderate and resolved faster after the boost. the blood concentration of inflammation markers increased after both injections but was lower after the boost. the numbers of neutrophils, monocytes, and dendritic cells were trans ...201829449630
characterization of ectopic myelinated nerve fibers in the retina of a cynomolgus monkey (macaca fascicularis).we report histopathology of retinal myelination discovered in a cynomolgus monkey. it consisted of a uniform population of spindle cells arranged in fascicles within the retina at the optic disk. the present case is remarkable in that there is a paucity of reports describing myelinated retinal nerve fibers in monkeys.201829446843
talaromycosis (penicilliosis) in a cynomolgus macaque.a sexually mature chinese-origin female macaca fascicularis assigned to the high-dose group in a 26-week toxicology study with an experimental immunomodulatory therapeutic antibody (a cd40 l antagonist fusion protein) was euthanized at the scheduled terminal sacrifice on study day 192. the animal was healthy at study initiation and remained clinically normal throughout the study. on study day 141, abnormal clinical pathology changes were found during a scheduled evaluation; splenomegaly was dete ...201829444633
discovery and development of odm-204: a novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting cyp17a1.we report the discovery of a novel nonsteroidal dual-action compound, odm-204, that holds promise for treating patients with castration-resistant prostate cancer (crpc), an advanced form of prostate cancer characterised by high androgen receptor (ar) expression and persistent activation of the ar signaling axis by residual tissue androgens. for odm-204, has a dual mechanism of action. the compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting cyp17a1, the prer ...201929438723
an antigen-free, plasmacytoid dendritic cell-targeting immunotherapy to bolster memory cd8+ t cells in nonhuman primates.the priming, boosting, and restoration of memory cytotoxic cd8+ t lymphocytes by vaccination or immunotherapy in vivo is an area of active research. particularly, nucleic acid-based compounds have attracted attention due to their ability to elicit strong ag-specific ctl responses as a vaccine adjuvant. nucleic acid-based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer ag(s); however, so far they have lacked efficacy in clinical trials ...201829431693
metabolite identification of the antimalarial naphthoquine using liquid chromatography-tandem high-resolution mass spectrometry in combination with multiple data-mining tools.naphthoquine (nq) is one of important partner drugs of artemisinin-based combination therapy (act), which is recommended for the treatment of uncomplicated plasmodium falciparum. nq shows a high cure rate after a single oral administration. it is absorbed quickly (time to peak concentration 2-4 h) and has a long elimination half-life (255 h). however, the metabolism of nq has not been clarified. in this work, the metabolite profiling of nq was studied in six liver microsomal incubates (human, cy ...201829430676
a cross-species comparison of abnormal behavior in three species of singly-housed old world monkeys.abnormal behavior occurs in a number of captive nonhuman primate species and is often used as an indicator of welfare. however, reported levels of abnormal behavior often vary across species, making general welfare judgments difficult. the purpose of this study was to assess differences in levels of abnormal behavior and associated risk factors across three species of old world monkeys in order to identify similarities and differences across species. the subjects were 415 (109 females) cynomolgu ...201829422700
inotropic effects of nicorandil on cardiac contractility assessed by left ventricular pressure-volume relationship analyses in anesthetized monkeys.nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (katp) channel agonist; however, its effects on integrated cardiac function have not been fully understood. this study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. nicorandil was given intravenously at therapeutic doses of 0.2 ...201829420355
marmoset cytochrome p450 2b6, a propofol hydroxylase expressed in liver.1. the common marmoset (callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. cytochrome p450 (p450) 2b enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available. 2. marmoset p450 2b6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. phylogenetic analysis using amino acid sequences indicated that ...201829417863
rna-seq analysis of the transcriptome of the liver of cynomolgus monkeys with type 2 diabetes.genetic and environmental factors such as high-fat diet are involved in the development of type 2 diabetes mellitus (t2dm). cynomolgus monkey shares similar genetic makeup, tissue structures, physiology and metabolic function to human. this study aimed to establish t2dm model in cynomolgus monkey and compare expression profiles of hepatic genes and their associated pathways in normal cynomolgus monkeys and those with t2dm. we employed rna-seq technique and identified 1451 differentially expresse ...201829414690
discovery of a cynomolgus monkey family with retinitis pigmentosa.to accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. in this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (macaca fascicularis) pedigree.201829411010
preclinical evaluation of the mono-pegylated recombinant human interleukin-11 in cynomolgus monkeys.the mono-pegylated recombinant human interleukin-11 (rhil-11) was evaluated for its pharmacology and toxicology profile in non-human primates. this pegylated il-11 (peg-il11) showed a much prolonged circulating half-life of 67h in cynomolgus monkeys as compared to its un-pegylated counterpart (~3h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhil-11 ...201829407773
in vivo study of paraspinal muscle weakness using botulinum toxin in one primate model.it has been generally speculated that paraspinal muscle weakness is related to the spinal degeneration including intervertebral disc failure. the purpose of this study was to investigate the effects of paraspinal muscle weakness induced by the botulinum toxin type-a on the lumbar spine and behavior pattern in an in-vivo primate model which has an upright locomotion similar to that of humans.201829407350
in vivo characterization of two 18f-labeled pde10a pet radioligands in nonhuman primate brains.positron emission tomography (pet) with phosphodiesterase 10a (pde10a) specific radioligands provides a noninvasive and quantitative imaging tool to access the expression of this enzyme in vivo under normal and diseased conditions. we recently reported two potent 18f-labeled pde10a radioligands (18f-tz19106b and 18f-tz8110); initial evaluation in rats and nonhuman primates indicated stable metabolic profiles and excellent target-to-nontarget ratio (striatum/cerebellum) for both tracers. herein, ...201829400443
a case report of spontaneous staphylococcal meningitis in a cynomolgus monkey.this report describes a suppurative meningitis in a young cynomolgus. the animal had neutrophil aggregation in the subarachnoid space and hemorrhage in bilateral adrenal glands. staphylococcus was identified by fish in brain. to our knowledge, this is the first case of staphylococcal meningitis with waterhouse-friderichsen syndrome in a cynomolgus monkey.201829399828
cloning of macaque monkeys by somatic cell nuclear transfer.generation of genetically uniform non-human primates may help to establish animal models for primate biology and biomedical research. in this study, we have successfully cloned cynomolgus monkeys (macaca fascicularis) by somatic cell nuclear transfer (scnt). we found that injection of h3k9me3 demethylase kdm4d mrna and treatment with histone deacetylase inhibitor trichostatin a at one-cell stage following scnt greatly improved blastocyst development and pregnancy rate of transplanted scnt embryo ...201829395327
therapeutic effects of anti-cd154 antibody in cynomolgus monkeys with advanced rheumatoid arthritis.rheumatoid arthritis is one major chronic inflammatory systemic autoimmune disease. the cd154-cd40 interactions play a critical role in the regulation of immune responses and the maintenance of autoimmunity. therefore, we aimed to determine whether anti-cd154 antibody treatment show positive effects on immunomodulation and clinical improvement of sustained severe rheumatoid arthritis in cynomolgus monkeys. arthritis was induced using chicken type ii collagen (cii) and arthritic monkey were divid ...201829391506
analysis of carboxylesterase 2 transcript variants in cynomolgus macaque liver.carboxylesterase (ces) is important for the detoxification of a wide range of drugs and xenobiotics. in this study, the hepatic level of ces2 mrna was examined in cynomolgus macaques used widely in preclinical studies for drug metabolism. three ces2 mrnas were present in cynomolgus macaque liver. the mrna level was highest for cynomolgus ces2a (formerly ces2v3), much lower for cynomolgus ces2b (formerly ces2v1) and extremely low for cynomolgus ces2c (formerly ces2v2). most various transcript var ...201929384423
mycobacterium leprae genomes from naturally infected nonhuman primates.leprosy is caused by the bacterial pathogens mycobacterium leprae and mycobacterium lepromatosis. apart from humans, animals such as nine-banded armadillos in the americas and red squirrels in the british isles are naturally infected with m. leprae. natural leprosy has also been reported in certain nonhuman primates, but it is not known whether these occurrences are due to incidental infections by human m. leprae strains or by m. leprae strains specific to nonhuman primates. in this study, compl ...201829381722
molecular genetic identification of isolates of the hepatitis a virus (hav) from monkeys at adler primate center.the aim of this study was to assess prevalence and genetic variability of hepatitis a virus (hav) isolates in monkeys born and kept at adler primate center, as well as in imported animals.201829380396
human gip(3-30)nh2inhibits g protein-dependent as well as g protein-independent signaling and is selective for the gip receptor with high-affinity binding to primate but not rodent gip receptors.gip(3-30)nh2is a high affinity antagonist of the gip receptor (gipr) in humans inhibiting insulin secretion via g protein-dependent pathways. however, its ability to inhibit g protein-independent signaling is unknown. here we determine its action on arrestin-recruitment and receptor internalization in recombinant cells. as gip is adipogenic, we evaluate the inhibitory actions of gip(3-30)nh2in human adipocytes. finally, we determine the receptor selectivity of gip(3-30)nh2among other human and a ...201829378179
metamaterial-based transmit and receive system for whole-body magnetic resonance imaging at ultra-high magnetic fields.magnetic resonance imaging (mri) at ultra-high fields (uhf), such as 7 t, provides an enhanced signal-to-noise ratio and has led to unprecedented high-resolution anatomic images and brain activation maps. although a variety of radio frequency (rf) coil architectures have been developed for imaging at uhf conditions, they usually are specialized for small volumes of interests (voi). so far, whole-body coil resonators are not available for commercial uhf human whole-body mri systems. the goal of t ...201829370245
adjuvanting influenza hemagglutinin vaccine with a human pulmonary surfactant-mimicking synthetic compound sf-10 induces local and systemic cell-mediated immunity in mice.we reported previously that intranasal instillation of a synthetic human pulmonary surfactant with a carboxy vinyl polymer as a viscosity improver, named sf-10, shows potent adjuvanticity for humoral immunity in mice and cynomolgus monkeys. sf-10 effectively induces influenza hemagglutinin vaccine (hav)-specific iga in nasal and lung washes and igg in sera with their neutralizing activities. since cd8+ t cell-mediated protection is an important requirement for adaptive immunity, we investigated ...201829370185
simultaneous quantification of endogenous and exogenous plasma glucose by isotope dilution lc-ms/ms with indirect mrm of the derivative tag.quantification of endogenous and exogenous plasma glucose can help more comprehensively evaluate the glucose metabolic status. a ratio-based approach using isotope dilution liquid chromatography tandem mass spectrometry (id lc-ms/ms) with indirect multiple reaction monitoring (mrm) of the derivative tag was developed to simultaneously quantify endo-/exogenous plasma glucose. using diluted d-[13c6] glucose as tracer of exogenous glucose, 12c6/13c6 glucoses were first derivatized and then data wer ...201829362854
curcumin as an in vivo selective intestinal breast cancer resistance protein inhibitor in cynomolgus monkeys.to estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (bcrp), in vivo approaches in nonclinical settings are desired in drug development. clinical observation has identified curcumin as a promising candidate for in vivo selective bcrp inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. this study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal bcrp function in cynomolgus monkeys and to ...201829358184
biotherapeutics in non-clinical development: strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing.biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. considerable non-clinical experience in the development of proteins (e.g. insulin) and antibodies has been accumulated over the past thirty years. in order to improve the efficacy and the safety of these biotherapeutics, fc modifications (e.g. fc silent antibody versions), combinations (antibody-drug conjugates, protein-nanoparticle combinations), and new const ...201829355662
in vitro model for predicting bioavailability of subcutaneously injected monoclonal antibodies.monoclonal antibodies (mabs), which are now more frequently administered by subcutaneous (sc) injection rather than intravenously, have become a tremendously successful drug format across a wide range of therapeutic areas. preclinical evaluations of mabs to be administered by sc injection are typically performed in species such as mice, rats, minipigs, and cynomolgus monkeys to obtain critical information regarding formulation performance and prediction of pk/pd outcomes needed to select clinica ...201829355621
glutazumab, a novel long-lasting glp-1/anti-glp-1r antibody fusion protein, exerts anti-diabetic effects through targeting dual receptor binding sites.glucagon like-peptide-1 (glp-1)-based drugs have been proposed as mono- or combined therapy for type 2 diabetes mellitus. thus we characterized a novel antibody fusion protein engineered by linking the human glp-1 derivative to a humanized glp-1 receptor (glp-1r) antibody via a peptide linker.201829355505
disrupting cd147-rap2 interaction abrogates erythrocyte invasion by plasmodium falciparum.effective vaccines against malaria caused by plasmodium falciparum are still lacking, and the molecular mechanism of the host-parasite interaction is not fully understood. here we demonstrate that the interaction of rap2, a parasite-secreted rhoptry protein that functions in the parasitophorous vacuole formation stage of the invasion, and cd147 on the host erythrocyte is essential for erythrocyte invasion by p falciparum and is independent from all previously identified interactions involved. im ...201829352039
lack of remuscularization following transplantation of human embryonic stem cell-derived cardiovascular progenitor cells in infarcted nonhuman primates.human pluripotent stem cell-derived cardiovascular progenitor cells (hpsc-cvpcs) should be thoroughly investigated in large animal studies before testing in clinical trials.201829343525
metabolism and pharmacokinetics of a potent n-acylindole antagonist of the oxe receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ete) in rats and monkeys.we previously identified the indole 264 as a potent in vitro antagonist of the human oxe receptor that mediates the actions of the powerful eosinophil chemoattractant 5-oxo-ete. no antagonists of this receptor are currently commercially available or are being tested in clinical studies. the lack of a rodent ortholog of the oxe receptor has hampered progress in this area because of the unavailability of commonly used mouse or rat animal models. in the present study, we examined the feasibility of ...201829339225
technique for orthotopic liver transplantation in cynomolgus monkeys (macaca fascicularis).recent studies investigating new strategies to modulate the immune system have utilized animal models of liver transplantation (lt). however, the anhepatic phase (ahp) remains a crucial problem in lt. the aim of the present study is to introduce a technique for successful orthotopic lt in cynomolgus monkeys using an early-reperfusion strategy.201829333420
non-destructive determination of muscle architectural variables through the use of dicect.the fascicular architecture of skeletal muscle dictates functional parameters such as force production and contractile velocity. muscle microarchitecture is typically determined by means of manual dissection, a technique that is inherently destructive to specimens. furthermore, fascicle lengths and pennation angles are commonly assessed at only a limited number of sampling sites per muscle. we present the results of a digital technique to non-destructively assess muscle architectural variables f ...201829330959
sustained plasma hepcidin suppression and iron elevation by anticalin-derived hepcidin antagonist in cynomolgus monkey.anaemia of chronic disease (acd) has been linked to iron-restricted erythropoiesis imposed by high circulating levels of hepcidin, a 25 amino acid hepatocyte-derived peptide that controls systemic iron homeostasis. here, we report the engineering of the human lipocalin-derived, small protein-based anticalin prs-080 hepcidin antagonist with high affinity and selectivity.201829329501
generation of a precise oct4-hrgfp knockin cynomolgus monkey model via crispr/cas9-assisted homologous recombination. 201829327727
generation of knock-in cynomolgus monkey via crispr/cas9 editing. 201829327726
both systemic and intra-articular immunization with citrullinated peptides are needed to induce arthritis in the macaque.anti-citrullinated peptides antibodies (acpas) have high specificity for the diagnosis of rheumatoid arthritis (ra), but their role in the pathophysiology is not fully established. the main genetic risk factor for ra, the shared epitope in major histocompatibility complex class ii, is associated with acpas. among certain non-human primates, 8% carry the shared epitope called h6 haplotype, and being similar to humans, are ideal candidates to study the role of acpas in ra. the goal of this study w ...201729326703
blood rna signatures prospectively discriminate controllers from progressors early after low-dose m. tuberculosis infection of cynomolgus macaques.the cynomolgus macaque model of low-dose mycobacterium tuberculosis (mtb) infection recapitulates clinical aspects of human tb pathology but it is unknown whether the two systems are sufficiently similar that host-based signatures of tb will be predictive across species. by blind prediction, we demonstrate that a subset of genes comprising a human signature for tb risk is simultaneously predictive in humans and macaques and prospectively discriminates progressor from controller animals 3-6 weeks ...201829325117
brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a longitudinal voxel-based morphometry and diffusion tensor imaging study.in animal models of parkinson's disease (pd), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mptp) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. however, brain structural changes in response to mptp remain unclear. this study aimed to investigate in vivo longitudinal changes in gray matter (gm) volume and white matter (wm) microstructure in primate models administered with mptp. in six cynomolgus monkeys, high-resolution magnetic resonance imaging (mri ...201829320500
selective cd28 inhibition modulates alloimmunity and cardiac allograft vasculopathy in anti-cd154-treated monkeys.selective cd28 inhibition is actively pursued as an alternative to b7 blockade using cytotoxic t lymphocyte antigen 4 ig based on the hypothesis that the checkpoint immune regulators cytotoxic t lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. we previously showed that blocking cd28 using a monovalent nonactivating reagent (single-chain anti-cd28 fv fragment linked to alpha-1 antitrypsin [sc28at]) synergizes with calcineurin inhibitors in nonhuman primat ...201829319621
usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. to assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (glu) levels, the effect of gatifloxacin (gflx) which was frequently associated with glu abnormality and qt/qtc prolongations in the clinic on blood glu and electrocardiogram (ecg) parameters was investigated in cynomolgus monkeys (n=4) given gflx orally ...201829311442
dual blockade of interleukin-1β and interleukin-17a reduces murine arthritis pathogenesis but also leads to spontaneous skin infections in nonhuman primates.despite the efficacy of biologics for treatment of rheumatoid arthritis (ra), many patients show inadequate responses and likely require neutralization of multiple mediators. neutralization of both interleukin (il)-1β and il-17a with monoclonal antibodies showed greater efficacy than either agent alone in a mouse arthritis model with cooperative inhibition of key inflammatory factors, il-6, granulocyte colony-stimulating factor (g-csf), and cxc chemokine ligand (cxcl)1. given the potential clini ...201829311111
proprioceptive changes in bilateral knee joints following unilateral anterior cruciate ligament injury in cynomolgus monkeys.background the anterior cruciate ligament (acl) is one of the most important structures maintaining stability of knee joints, and the proprioception of the acl plays a key role in it. if the acl is injured in the unilateral knee joint, it changes nerve electrophysiology, morphology, and quantity of the proprioceptors in the bilateral acl. the aim of this study was to explore the proprioceptive changes in the bilateral knee joints following unilateral acl injury, and to provide a theoretical foun ...201829305572
long-term nonhuman primate renal allograft survival without ongoing immunosuppression in recipients of delayed donor bone marrow transplantation.we have previously reported successful induction of renal allograft tolerance in nonhuman primates (nhp) after an initial posttransplant period of conventional immunosuppression (delayed tolerance) using a nonmyeloablative conditioning regimen consisting of anti-cd154 and anti-cd8 mabs plus equine antithymocyte globulin (atgam) and donor bone marrow transplantation (dbmt). because these reagents are not currently clinically available, the protocol was revised to be applicable to human recipients ...201829300231
a single amino acid change in the marburg virus glycoprotein arises during serial cell culture passages and attenuates the virus in a macaque model of disease.marburg virus (marv) causes disease with high case fatality rates, and there are no approved vaccines or therapies. licensing of marv countermeasures will likely require approval via the fda's animal efficacy rule, which requires well-characterized animal models that recapitulate human disease. this includes selection of the virus used for exposure and ensuring that it retains the properties of the original isolate. the consequences of amplification of marv for challenge studies are unknown. her ...201829299527
adct-402, a pbd dimer-containing antibody drug conjugate targeting cd19-expressing malignancies.human cd19 antigen is a 95-kda type i membrane glycoprotein in the immunoglobulin superfamily whose expression is limited to the various stages of b-cell development and differentiation and is maintained in the majority of b-cell malignancies, including leukemias and non-hodgkin lymphomas of b-cell origin. coupled with its differential and favorable expression profile, cd19 has rapid internalization kinetics and is not shed into the circulation, making it an ideal target for the development of a ...201829298756
characterization of a candidate tetravalent vaccine based on 2'-o-methyltransferase mutants.dengue virus (denv) is one of the most widespread arboviruses. the four denv serotypes infect about 400 million people every year, causing 96 million clinical dengue cases, of which approximately 500'000 are severe and potentially life-threatening. the only licensed vaccine has a limited efficacy and is only recommended in regions with high endemicity. we previously reported that 2'-o-methyltransferase mutations in denv-1 and denv-2 block their capacity to inhibit type i ifns and render the viru ...201829298302
tlr2 agonism reverses chemotherapy-induced neutropenia in macaca fascicularis.neutropenia is a common consequence of radiation and chemotherapy in cancer patients. the resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. granulocyte colony-stimulating factor (g-csf) is known to stimulate neutrophil production and is widely used as a treatment of chemotherapy-induced neutropenia. a small-molecule g-csf secretagogue without a requirement for refrigerated supply chain would offer a more convenient and cost-effective treat ...201729296907
retosiban prevents stretch-induced human myometrial contractility and delays labor in cynomolgus monkeys.stretch of the myometrium promotes its contractility and is believed to contribute to the control of parturition at term and to the increased risk of preterm birth in multiple pregnancies.201829293998
treatment of paraquat-induced lung injury with an anti-c5a antibody: potential clinical application.complement activation product c5a plays a critical role in systemic inflammatory response syndrome induced by viruses, bacteria, and toxic agents including paraquat poisoning. this study is to explore the efficiency of anti-c5a-based intervention on systemic inflammatory responses induced by paraquat poisoning.201829293144
genome-wide mosaicism in divergence between zoonotic malaria parasite subpopulations with separate sympatric transmission cycles.plasmodium knowlesi is a significant cause of human malaria transmitted as a zoonosis from macaque reservoir hosts in south-east asia. microsatellite genotyping has indicated that human infections in malaysian borneo are an admixture of two highly divergent sympatric parasite subpopulations that are, respectively, associated with long-tailed macaques (cluster 1) and pig-tailed macaques (cluster 2). whole-genome sequences of clinical isolates subsequently confirmed the separate clusters, although ...201829292549
[effect of pushing manipulation on qiaogong acupoint on hemodynamics in cynomolgus monkeys with mild carotid atherosclerotic plaques].to explore the hemodynamic changes in cynomolgus monkeys with mild carotid atherosclerotic (cas) plaques after therapy with pushing manipulation on qiaogong acupoint (mpq).201729292250
a novel quantification method for serine hydrolases in cellular expression system using fluorophosphonate-biotin probe.in the present study, we established a quantitative western blotting method to measure the expression level of recombinant serine hydrolases based on their catalytic mechanism. fluorophosphonate (fp)-biotin was selected as a universal probe to quantify their expression levels, since fp moiety irreversibly inhibits serine hydrolases through strong stoichiometric binding to active serine residue. the linearity of detection using fp-biotin was assessed on three serine hydrolases; human carboxyleste ...201829289670
rna expression profiling of nonhuman primate renal allograft rejection identifies tolerance.tolerance induction to prevent allograft rejection is a long-standing clinical goal. however, convincing and dependable tolerance identification remains elusive. hypothesizing that intragraft rna expression is informative in both rejection and tolerance, we profile intrarenal allograft rna expression in a mixed chimerism renal allograft model of cynomolgus monkeys and identify biologically significant tolerance. analysis of 67 genes identified 3 dominant factors, each with a different pattern of ...201829288556
the 17,18-epoxyeicosatetraenoic acid-g protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques.metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-epoxyeicosatetraenoic acid (17,18-epete) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.201829288079
rna expression profiling of renal allografts in a nonhuman primate identifies variation in nk and endothelial gene expression.rna transcript expression estimates are a promising method to study the mechanisms and classification of renal allograft rejections. here we use the nanostring platform to profile rna expression in renal allografts in a nonhuman primate (nhp), the cynomolgus monkey. we analyzed protocol and indication 278 archival renal allograft samples, both protocol and indication from 76 animals with diagnoses of chronic antibody-mediated rejection (camr), acute cellular rejection (tcmr), and mixed (both cam ...201829286578
an anti-gdnf family receptor alpha 1 (gfra1) antibody-drug conjugate for the treatment of hormone receptor-positive breast cancer.luminal a (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. in an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized glial cell line-derived neurotrophic factor (gdnf) family receptor alpha 1 (gfra1) antibody-drug conjugates (adc) using a cleavable valine-citrulline-mmae (vcmmae) linker-payload. rnaseq and ihc analysis confirmed the abundant expression of gfra1 in luminal a breast cancer tissues, whe ...201829282299
combinatorial inputs to the ventral striatum from the temporal cortex, frontal cortex, and amygdala: implications for segmenting the striatum.the canonical striatal map, based predominantly on frontal corticostriatal projections, divides the striatum into ventromedial-limbic, central-association, and dorsolateral-motor territories. while this has been a useful heuristic, recent studies indicate that the striatum has a more complex topography when considering converging frontal and nonfrontal inputs from distributed cortical networks. the ventral striatum (vs) in particular is often ascribed a "limbic" role, but it receives diverse inf ...201829279863
genetic polymorphisms of drug-metabolizing cytochrome p450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans.cynomolgus monkeys (macaca fascicularis, old world monkeys) and common marmosets (callithrix jacchus, new world monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. major drug-metabolizing cytochrome p450 (p450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset p450 enzymes have generally similar substrate recognition func ...201729277691
formulation and in vivo pharmacokinetic evaluation of ethyl cellulose-coated sustained release multiple-unit system of tacrolimus.a novel once-a-day sustained-release (sr) system of tacrolimus (fk506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (ec) polymer as release retardant. drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. subsequently, the drug-layered pellets were recoated with ec polymer (0.5-1.5 mg) using a fluid bed granulator. drug release from the reservoir-type pellets was ma ...201829277422
multigenic dna vaccine induces protective cross-reactive t cell responses against heterologous influenza virus in nonhuman primates.recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. we investigated immunogenicity and protective efficacy of a multi-antigen (ma) universal influenza dna vaccine consisting of ha, m2, and np antigens in cynomolgus macaques. following challenge with a heterologous pandemic h1n1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. the ma dna vaccine indu ...201729267331
needle-free delivery of measles virus vaccine to the lower respiratory tract of non-human primates elicits optimal immunity and protection.needle-free measles virus vaccination by aerosol inhalation has many potential benefits. the current standard route of vaccination is subcutaneous injection, whereas measles virus is an airborne pathogen. however, the target cells that support replication of live-attenuated measles virus vaccines in the respiratory tract are largely unknown. the aims of this study were to assess the in vivo tropism of live-attenuated measles virus and determine whether respiratory measles virus vaccination shoul ...201729263877
nicotinic alpha 7 receptor agonists evp-6124 and bms-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning.agonists at the nicotinic acetylcholine alpha 7 receptor (nachr α7) subtype have the potential to treat cognitive deficits in patients with alzheimer's disease (ad) or schizophrenia. visuo-spatial paired associates learning (vspal) is a task that has been shown to reliably predict conversion from mild cognitive impairment to ad in humans and can also be performed by nonhuman primates. reversal of scopolamine-induced impairment of vspal performance may represent a translational approach for the d ...201729261656
sensory properties of the caudal aspect of the macaque's superior parietal lobule.in the superior parietal lobule (spl), the anterior part (area pe) is known to process somatosensory information, while the caudalmost part (areas v6av and v6) processes visual information. here we studied the visual and somatosensory properties of the areas pec and v6ad located in between the somatosensory and visual domains of spl. about 1500 neurons were extracellularly recorded in 19 hemispheres of 12 monkeys (macaca fascicularis). visual and somatosensory properties of single neurons were g ...201729260370
abaloparatide, a novel pth receptor agonist, increased bone mass and strength in ovariectomized cynomolgus monkeys by increasing bone formation without increasing bone resorption.abaloparatide, a novel pth1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality.201829260289
physiologic correlates of interactions between adult male and immature long-tailed macaques (macaca fascicularis).interactions between adult males and immature members of the same species are rare in most mammals; in contrast, an estimated 40% of primate species are characterized by an involvement of males in the social life of infants and juveniles. the proximate mechanisms of male-infant interactions are largely unstudied, and very few direct benefits for males have been proposed, especially in uniparental species in which the identity of the male parent is uncertain. in this study, we aimed to assess the ...201729256366
dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (cyp11b2) with in vivo activity.6,7-dihydro-5h-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (cyp11b2) with selectivity over the highly homologous enzyme cortisol synthase (cyp11b1). these compounds are unique among inhibitors of cyp11b2 in their lack of a strong-heme binding group such as a pyridine or imidazole. poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. while the enzyme responsible for the reductive metabolism remains unknown, ...201829254646
prevalence and risk factors of japanese encephalitis virus (jev) in livestock and companion animal in high-risk areas in malaysia.japanese encephalitis (je) is vector-borne zoonotic disease which causes encephalitis in humans and horses. clinical signs for japanese encephalitis virus (jev) infection are not clearly evident in the majority of affected animals. in malaysia, information on the prevalence of jev infection has not been established. thus, a cross-sectional study was conducted during two periods, december 2015 to january 2016 and march to august in 2016, to determine the prevalence and risk factors in jev infecti ...201729243139
müller glial cells of the primate foveola: an electron microscopical study.previous studies on the ultrastructure of the primate foveola suggested the presence of an inverted cone-like structure which is formed by 25-35 specialized müller cells overlying the area of high photoreceptor density. we investigated the ultrastructure of the müller cells in the foveola of a human and macaque retina. sections through the posterior poles of an eye of a 40 years-old human donor and an eye of an adult cynomolgus monkey (macaca fascicularis) were investigated with transmission ele ...201829242027
multivalent fcγ-receptor engagement by a hexameric fc-fusion protein triggers fcγ-receptor internalisation and modulation of fcγ-receptor functions.engagement of fcγ-receptors triggers a range of downstream signalling events resulting in a diverse array of immune functions. as a result, blockade of fc-mediated function is an important strategy for the control of several autoimmune and inflammatory conditions. we have generated a hexameric-fc fusion protein (hexameric-fc) and tested the consequences of multi-valent fcγ-receptor engagement in in vitro and in vivo systems. in vitro engagement of hexameric-fc with fcγrs showed complex binding i ...201729213127
novel d-galactosamine-induced cynomolgus monkey model of acute liver failure.to establish a simplified, reproducible d-galactosamine-induced cynomolgus monkey model of acute liver failure having an appropriate treatment window.201729204057
the pparα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions.a number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (pparα). the molecular and cellular events by which pparα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. the weight of evidence relevant to the hypothesized mode of action (moa) for pparα ac ...201829197930
erratum: samhd1 polymorphisms were significantly correlated with hiv/siv virus load in pbmc from chinese rhesus macaques and cynomolgus macaques 201729197320
translational development of microbiome-based therapeutics: kinetics of e. coli nissle and engineered strains in humans and nonhuman primates.understanding the pharmacology of microbiome-based therapeutics is required to support the development of new medicines. strains of e. coli nissle (ecn) were genetically modified and administered to cynomolgus monkeys at doses of 1 × 109and 1 × 1012colony-forming units (cfu)/day for 28 days. a clinical study to evaluate the exposure and clearance of ecn in healthy volunteers was also performed. healthy subjects received oral doses of ecn, 2.5 to 25 × 109cfu 3 times daily for 28 days or a single ...201729194983
immunogenicity of recombinant measles vaccine expressing fusion protein of respiratory syncytial virus in cynomolgus monkeys.respiratory syncytial virus (rsv) is a common cause of respiratory infections in infants. effective vaccines are currently being sought, but no vaccine is thus far available. in our previous study, recombinant aik-c measles vaccine expressing the rsv fusion protein (mvaik/rsv/f) was developed and protective immunity against rsv demonstrated in cotton rats. in the present study, the immunogenicity and protective effects were investigated in three cynomolgus monkeys immunized with mvaik/rsv/f. neu ...201829194753
whole body and cns biodistribution of rhhns in cynomolgus monkeys after intrathecal lumbar administration: treatment implications for patients with mps iiia.mucopolysaccharidosis iii type a (mps iiia; sanfilippo syndrome), a genetic lysosomal disorder causing a deficiency of heparan n-sulfatase (hns), leads to progressive cognitive decline from an early age. an effective enzyme replacement therapy (ert) for mps iiia requires central nervous system (cns) biodistribution. recombinant human heparan n-sulfatase (rhhns), an investigatory ert for mps iiia, has been formulated for intrathecal (it) administration since intravenous (iv) administration cannot ...201729194406
safety evaluation of lipid nanoparticle-formulated modified mrna in the sprague-dawley rat and cynomolgus monkey.the pharmacology, pharmacokinetics, and safety of modified mrna formulated in lipid nanoparticles (lnps) were evaluated after repeat intravenous infusion to rats and monkeys. in both species, modified mrna encoding the protein for human erythropoietin (hepo) had predictable and consistent pharmacologic and toxicologic effects. pharmacokinetic analysis conducted following the first dose showed that measured hepo levels were maximal at 6 hours after the end of intravenous infusion and in excess of ...201829191134
subretinal and intravitreal retinal injections in monkeys.ocular anatomy and physiology in cynomolgus monkeys (macacca fascicularis) are very similar to that found in the human visual system. therefore and despite significant ethical and economical implications, these animals constitute an excellent model system for toxicology and biodistribution studies in the development of new and meaningful treatment strategies for ocular disorders. the methods for delivery of investigational new drugs (inds) to the ocular tissue are virtually identical to the meth ...201829188519
whole mitochondrial genomic and y-chromosomal phylogenies of burmese long-tailed macaque (macaca fascicularis aurea) suggest ancient hybridization between fascicularis and sinica species groups.macaca fascicularis aurea (burmese long-tailed macaque) is 1 of the 10 subspecies of macaca fascicularis. despite having few morphological differences from other subspecies, a recent phylogeographic study showed that m. f. aurea is clearly distinct genetically from macaca fascicularis fascicularis (common long-tailed macaque) and suggests that m. f. aurea experienced a disparate evolutionary pathway versus other subspecies. to construct a detailed evolutionary history of m. f. aurea and its rela ...201829186474
designing an immunocyte-targeting delivery system by use of beta-glucan.a β-1,3-d-glucan called schizophyllan (spg) can form a novel complex with homo oligodeoxynucleotides (odns) via the combination of hydrogen bonding and hydrophobic interactions. dectin-1 is a major receptor involved in the recognition of β-1,3-d-glucans and expressed on antigen presenting cells (apcs) including macrophages, dendritic cells, monocytes, neutrophils, and a subset of t cells. therefore, the spg/odn complex can be used as apcs cell-specific delivery of functional odns including unmet ...201829174675
intranasal infection and contact transmission of zika virus in guinea pigs.zika virus (zikv) is primarily transmitted to humans through mosquito bites or sexual contact. the excretion and persistence of contagious zikv in various body fluids have been well documented in zikv patients; however, the risk of direct contact exposure remains unclear. here, we show that guinea pigs are susceptible to zikv infection via subcutaneous inoculation route; infected guinea pigs exhibit seroconversion and significant viral secretion in sera, saliva, and tears. notably, zikv is effic ...201729162827
discovery and validation of pyridoxic acid and homovanillic acid as novel endogenous plasma biomarkers of organic anion transporter (oat) 1 and oat3 in cynomolgus monkeys.perturbation of organic anion transporter (oat) 1- and oat3-mediated transport can alter the exposure, efficacy, and safety of drugs. although there have been reports of the endogenous biomarkers for oat1/3, none of these have all of the characteristics required for a clinical useful biomarker. cynomolgus monkeys were treated with intravenous probenecid (prob) at a dose of 40 mg/kg in this study. as expected, prob increased the area under the plasma concentration-time curve (auc) of coadminister ...201829162614
pigeon paramyxovirus type 1 from a fatal human case induces pneumonia in experimentally infected cynomolgus macaques (macaca fascicularis).although avian paramyxovirus type 1 is known to cause mild transient conjunctivitis in human beings, there are two recent reports of fatal respiratory disease in immunocompromised human patients infected with the pigeon lineage of the virus (ppmv-1). in order to evaluate the potential of ppmv-1 to cause respiratory tract disease, we inoculated a ppmv-1 isolate (hppmv-1/netherlands/579/2003) from an immunocompromised human patient into three healthy cynomolgus macaques (macaca fascicularis) and e ...201729162154
the cellular composition and glia-neuron ratio in the spinal cord of a human and a nonhuman primate: comparison with other species and brain regions.the cellular composition of brains shows largely conserved, gradual evolutionary trends between species. in the primate spinal cord, however, the glia-neuron ratio was reported to be greatly increased over that in the rodent spinal cord. here, we re-examined the cellular composition of the spinal cord of one human and one nonhuman primate species by employing two different counting methods, the isotropic fractionator and stereology. we also determined whether segmental differences in cellular co ...201829150977
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