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tak-071, a muscarinic m1 receptor positive allosteric modulator, attenuates scopolamine-induced quantitative electroencephalogram power spectral changes in cynomolgus monkeys.activation of the muscarinic m1 receptor is a promising approach to improve cognitive deficits associated with cholinergic dysfunction in alzheimer's disease, dementia with lewy bodies, and schizophrenia. tak-071 is an m1-selective positive allosteric modulator that improves cognitive deficits induced by scopolamine, a non-selective muscarinic receptor antagonist, with reduced side effects on gastrointestinal function in rats. in this study, we explored changes in quantitative electroencephalogr ...201930856192
intranodal angiomyomatous hamartoma in a cynomolgus monkey.we describe here an angiomyomatous hamartoma in the right axillary lymph node of a three-year-old male cynomolgus monkey ( macaca fascicularis), used as a control subject in a short-term toxicity study. this is a very rare lesion that has been reported almost exclusively in inguinal lymph nodes, and to date only in human beings. in the present case, light microscopy revealed partial replacement of the lymph node parenchyma by a disorganized, irregular vascular network, sparsely distributed smoot ...201930585127
effects of housing conditions on behaviors and biochemical parameters in juvenile cynomolgus monkeys (macaca fascicularis).to investigate the effects of environmental enrichment on laboratory monkeys, we studied behavioral and physiological differences following changes in housing conditions. ten male and female juvenile cynomolgus monkeys were first housed in pairs for 8 weeks after quarantine/acclimatization (singly housed) and subsequently housed alone for the next 8 weeks. monkeys were subjected to evaluations of body weight gain, stereotypic or affiliative behaviors, cortisol, 4-ethylphenyl sulfate (4eps) and c ...201930584201
preclinical development of the tlr9 agonist dv281 as an inhaled aerosolized immunotherapeutic for lung cancer: pharmacological profile in mice, non-human primates, and human primary cells.cpg-motif-containing oligodeoxynucleotides (cpg-odn) activate innate immunity through toll-like receptor (tlr) 9 signaling and generate local immune responses when delivered directly to the lung. herein we describe pharmacological studies in mice, cynomolgus monkeys, and in human primary cells which support the development of dv281, a c-class cpg-odn, as an inhaled aerosolized immunotherapeutic for lung cancer to be combined with an inhibitor of the anti-programmed cell death protein 1 (pd‑1) im ...201930502651
preclinical safety evaluation of oncolytic herpes simplex virus type 2.oncolytic virotherapy is a new and safe therapeutic strategy based on the inherent cytotoxicity of oncolytic viruses and their ability to replicate and spread within tumors in a selective manner. in a previous study, a new type of oncolytic herpes simplex virus type 2 (ohsv-2, named oh2) was constructed to treat human cancers. that study demonstrated that oh2 is genetically and biologically stable. its antitumor activity was maintained, even after passaging the virus for >20 generations. to adva ...201930499341
stroke longitudinal volumetric measures correlate with the behavioral score in non-human primates.stroke is the second leading cause of death worldwide. brain imaging data from experimental rodent stroke models suggest that size and location of the ischemic lesion relate to behavioral outcome. however, such a relationship between these two variables has not been established in non-human primate (nhp) models. thus, we aimed to evaluate whether size, location, and severity of stroke following controlled middle cerebral artery occlusion (mcao) in nhp model correlated to neurological outcome. fo ...201930481566
encoding prediction signals during appetitive and aversive pavlovian conditioning in the primate lateral hypothalamus.the lateral hypothalamus (lh), which plays a role in homeostatic functions such as appetite regulation, is also linked to arousal and motivational behavior. however, little is known about how these components are encoded in the lh. thus cynomolgus monkeys were conditioned with two distinct contexts, i.e., an appetitive context with available rewards and an aversive context with predicted air puffs. different lh neuron groups encoded different degrees of expectation, predictability, and risks of ...201930485150
successful inflammation imaging of non-human primate hearts using an antibody specific for tenascin-c.inflammation after myocardial infarction (mi) may be a major factor influencing ventricular remodeling, leading to congestive heart failure and arrhythmia. therefore, inflammation in the heart needs to be monitored. tenascin-c (tnc) is an extracellular matrix molecule not normally expressed, but it is strongly upregulated when associated with active inflammation. based on this characteristic, we successfully imaged in vivo inflammatory lesions in rat models using 111indium (111in)-labeled anti-t ...201930464121
an investigational rnai therapeutic targeting factor xii (aln-f12) for the treatment of hereditary angioedema.hereditary angioedema (hae) is a genetic disorder mostly caused by mutations in the c1 esterase inhibitor gene (c1inh) that results in poor control of contact pathway activation and excess bradykinin generation. bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of hae. we hypothesized that the use of rna interference (rnai) to reduce plasma factor xii (fxii), which initiates the contact pathway signaling cascade, would reduce con ...201930463937
humanised effector-null fcγriia antibody inhibits immune complex-mediated proinflammatory responses.immune complexes (ics) play a critical role in the pathology of autoimmune diseases. the aim of this study was to generate and characterise a first-in-class anti-fcγriia antibody (ab) vib9600 (previously known as medi9600) that blocks igg immune complex-mediated cellular activation for clinical development.201930459279
elevated membrane cholesterol disrupts lysosomal degradation to induce β-amyloid accumulation: the potential mechanism underlying augmentation of β-amyloid pathology by type 2 diabetes mellitus.the endocytic membrane trafficking system is altered in the brains of early-stage alzheimer disease (ad) patients, and endocytic disturbance affects the metabolism of β-amyloid (aβ) protein, a key molecule in ad pathogenesis. it is widely accepted that type 2 diabetes mellitus (t2dm) is one of the strongest risk factors for development of ad. supporting this link, experimentally induced t2dm enhances ad pathology in various animal models. spontaneous t2dm also enhances aβ pathology with severe e ...201930448407
non-synonymous genetic variants of flavin-containing monooxygenase 3 (fmo3) in cynomolgus macaques.polymorphic human flavin-containing monooxygenase (fmo) 3 is an important drug-metabolizing enzyme for nitrogen- or sulfur-containing compounds. cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding fmo3 molecular and enzymatic similarities to humans; however, genetic polymorphisms have not been investigated in macaques. in this study, re-sequencing of fmo3 in 64 cynomolgus and 32 rhesus macaques found a total of 18 non-synonymous variants. n ...201930420260
a cynomolgus monkey model of temporal lobe epilepsy.temporal lobe epilepsy (tle) with hippocampal sclerosis is the most common type of drug-resistant epilepsy. non-human primates are attractive models for studying the pathogenic mechanisms of tle, with the goal of developing new drugs and interventions. in this study, we developed and tested a cynomolgus monkey (macaca fascicularis) model of tle. a total of 5 cynomolgus monkeys received3-4 weekly unilateral hippocampal injections of kainic acid (ka) to induce repetitive acute seizures. animals we ...201930423353
oral delivery of the anti-tumor necrosis factor α domain antibody, v565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys.v565 is a novel oral anti-tumor necrosis factor (tnf)-α domain antibody being developed for topical treatment of inflammatory bowel disease (ibd) patients. protein engineering rendered the molecule resistant to intestinal proteases. here we investigate the formulation of v565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys.201930395728
development of cdx-1140, an agonist cd40 antibody for cancer immunotherapy.limitations of immunotherapy include poorly functioning events early in the immune response cycle, such as efficient antigen presentation and t cell priming. cd40 signaling in dendritic cells leads to upregulation of cell surface costimulatory and mhc molecules and the generation of cytokines, which promotes effective priming of cd8+ effector t cells while minimizing t cell anergy and the generation of regulatory t cells. this naturally occurs through interaction with cd40 ligand (cd40l) express ...201930382327
population genetics of the abo locus within the rhesus (macaca mulatta) and cynomolgus (m. fascicularis) macaque hybrid zone.knowledge of the macaque abo blood group system has been critical in the development of nonhuman primates (nhps) as a translational model. serving not only as a useful homologue of the disease-linked abo system in humans, macaque abo blood groups must be typed in colonies prior to performing experimental procedures requiring blood transfusion or transplantation. while the rates of blood type incompatibility and the distributions of a, b and ab blood groups are known in large samples of rhesus (m ...201930387553
development and long-term evaluation of ocular surface conditions using ovariectomized cynomolgus monkey.we aim to use the ovariectomized cynomolgus monkey to observe the effect of long-term changes of sex hormone levels on ocular surface.201930383547
cortical bone mineral density is increased by the cathepsin k inhibitor ono-5334, which leads to a robust increase in bone strength: results from a 16-month study in ovariectomised cynomolgus monkeys.this study evaluated the long-term effects of the cathepsin k inhibitor ono-5334 on bone mass and strength in ovariectomised (ovx) cynomolgus monkeys. animals were assigned to one of the following six groups: sham (non-ovx), ovx control treated with vehicle, ono-5334 1.2, 6 or 30 mg/kg/day, p.o., or alendronate (aln) 0.05 mg/kg/2 weeks, i.v. for 16 months. peripheral quantitative computed tomography (pqct) analysis revealed that ono-5334 increased not only trabecular bone mineral density (bmd) b ...201930357565
comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (ds-8201a), a her2-targeting antibody-drug conjugate, in cynomolgus monkeys.trastuzumab deruxtecan (ds-8201a) is an antibody-drug conjugate (adc) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (her2) conjugated to a topoisomerase i inhibitor (dxd) at a drug-to-antibody ratio (dar) of 7-8. here, we examined the pharmacokinetic (pk) profiles of ds-8201a and dxd in cynomolgus monkeys, a cross-reactive species. following intravenous (iv) administration of ds-8201a, the linker was stable in plasma, and systemic dxd exposure was low. dxd ...201930351177
serotonin and norepinephrine transporter occupancy of tramadol in nonhuman primate using positron emission tomography.tramadol, a centrally acting analgesic drug, has relatively high affinity to serotonin transporter and norepinephrine transporter in addition to μ-opioid receptor. based on this characteristic, tramadol is expected to have an antidepressant effect.201930346535
negative lusitropic property of nifekalant identified using ventricular pressure-volume loop analyses in anesthetized monkeys.the present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class iii antiarrhythmic drug, in an isoflurane-anesthetized monkey. nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. left ventricular (lv) pressure-volume (pv) analysi ...201930333366
differences in cytoarchitecture of broca's region between human, ape and macaque brains.areas 44 and 45 have been identified in non-human primates as homologs of the human broca region. distribution of large and smaller pyramids and the ventro-lateral localization in the posterior frontal lobe enable their identification in non-human primates. since only humans hold the ability of language, it has been hypothesized that differences in microstructure may, together with other anatomical factors, e.g., white matter tract connectivity, volumes of cortical areas and their molecular diff ...201930333085
crispr/cas9-mediated disruption of shank3 in monkey leads to drug-treatable autism-like symptoms.monogenic mutations in the shank3 gene, which encodes a postsynaptic scaffold protein, play a causative role in autism spectrum disorder (asd). although a number of mouse models with shank3 mutations have been valuable for investigating the pathogenesis of asd, species-dependent differences in behaviors and brain structures post considerable challenges to use small animals to model asd and to translate experimental therapeutics to the clinic. we have used clustered regularly interspersed short p ...201930329048
protective efficacy and long-term immunogenicity in cynomolgus macaques by ebola virus glycoprotein synthetic dna vaccines.there remains an important need for prophylactic anti-ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines.201930304515
antidiabetic effect of abextide, a long-acting exendin-4 analogue in cynomolgus monkeys.abextide, synthesized by conjugating an albumin-binding moiety-truncated evans blue-to glucagon-like peptide 1 receptor (glp-1r) agonist exendin-4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. the aim of this study is to evaluate the pharmacodynamics of abextide in nonhuman primates. two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. during the whole experiment period, no abnormalities such as swelling at the inj ...201930300471
asymptomatic natural human infections with the simian malaria parasites plasmodium cynomolgi and plasmodium knowlesi.in southeast asia, plasmodium knowlesi, a parasite of long-tailed macaques (macaca fascicularis), is an important cause of human malaria. plasmodium cynomolgi also commonly infects these monkeys, but only one naturally acquired symptomatic human case has been reported previously.201930295822
rolipram plus sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model.cardiopulmonary bypass (cpb) recovery is complicated by lung inflammation from bone marrow (bm)-derived polymorphonuclear leukocytes (pmns) and monocytes (mo). although sivelestat reduces inflammatory mediators and rolipram inhibits pmn and mo activation, any kinetic effects to improve cpb recovery in vivo are unknown. we hypothesized that intraoperative co-administration of these compounds would reduce cpb-induced lung inflammation through downregulation of pmn and mo recruitment. a 2-h cpb was ...201930284168
repeated injection of kmrc011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys.high-dose radiation-induced tissue damage is a major limiting factor in the medical application of nuclear technology. herein, we tested 28-day repeated-dose toxicity of kmrc011, an agonist of toll-like receptor (tlr) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. kmrc011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional ...201930277593
an ex vivo bladder model with detrusor smooth muscle removed to analyse biologically active mediators released from the suburothelium.studies of urothelial cells, bladder sheets or lumens of filled bladders have suggested that mediators released from urothelium into suburothelium (subu)/lamina propria (lp) activate mechanisms controlling detrusor excitability. none of these approaches, however, has enabled direct assessment of availability of mediators at subu/lp during filling. we developed an ex vivo mouse bladder preparation with intact urothelium and subu/lp but no detrusor, which allows direct access to the subu/lp surfac ...201930289177
establishment of an in vitro cytotoxicity assay platform using primary monkey cardiomyocytes.to establish an in vitro cytotoxicity assay platform using monkey cardiomyocytes, we isolated primary cardiomyocytes from fetal cynomolgus monkeys at different gestation days (from day 39 to 90) using the trypsin and collagenase digestion method, which was identical to the standard procedure for rat cardiomyocytes. under these conditions, the primary cells obtained from monkeys at gestation day 63 or earlier showed spontaneous beating, with >80% cells being viable from all fetuses. transcriptome ...201930261314
immunohistological study of monkey foveal retina.the fovea centralis, an anatomically concave pit located at the center of the macula, is avascular, hypoxic, and characteristic of stem-cell niches of other tissues. we hypothesized that in the fovea, undifferentiated retinal-stem-cell-like cells may exist, and that neurogenesis may occur. hence, we performed an immunohistological study using cynomolgus monkey retinas. after preparing frozen tissue sections of the retina including the foveal pit, immunostaining was performed for glial fibrillary ...201930918305
targeting multiple myeloma with amg 424, a novel anti-cd38/cd3 bispecific t-cell-recruiting antibody optimized for cytotoxicity and cytokine release.despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. t-cell-redirected lysis triggered by bispecific antibodies recruiting t cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and cd38 is a tumor-associated antigen with near-universal expression in multiple myeloma. thus, an anti-cd38/cd3 bispecific t-cell-recruiting antibody has the potential to be an effective new therapeuti ...201930918018
effects of the cathepsin k inhibitor ono-5334 and concomitant use of ono-5334 with methotrexate on collagen-induced arthritis in cynomolgus monkeys.we examined whether the cathepsin k inhibitor, ono-5334, administered alone or in combination with methotrexate (mtx), could ameliorate joint destruction evoked by collagen-induced arthritis (cia) in female cynomolgus monkeys. cia was induced by immunizing with bovine type ii collagen. ono-5334 (30 mg/kg/day) was orally administered once daily and mtx (10 mg/body/day) twice weekly for 9 weeks. x-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal ...201930906325
granulovacuolar degeneration in brains of senile cynomolgus monkeys.neurons with histopathological changes consistent with granulovacuolar degeneration (gvd) were found in brain sections from aged cynomolgus monkeys (macaca fascicularis) with clinical and pathological signs of cognitive aging. to our knowledge, this is the first reported description of gvd in non-human primates. gvd-like lesions were found also in age-matched cognitively healthy subjects, albeit in lower numbers, suggesting that they may relate to aging and the increase may have tendency to incr ...201930899220
toxicologic pathology forum*: opinion on sexual maturity and fertility assessment in long-tailed macaques ( macaca fascicularis) in nonclinical safety studies.if nonhuman primates represent the only relevant species for nonclinical safety evaluation of biotechnology-derived products, male and female fertility effects can be assessed in repeat dose toxicity studies given that sexually mature monkeys are used. this opinion piece provides recommendations for determining sexual maturity and when/how fertility assessments should be conducted in the cynomolgus monkey. male sexual maturity should be proven by presence of sperm in a semen sample, female sexua ...201930898082
phenotypic distinctions between the nodose and jugular trpv1-positive vagal sensory neurons in the cynomolgus monkey.vagal capsaicin-sensitive afferent c-fibers play an important role in the maintenance of visceral homeostasis and contribute to symptoms in visceral diseases. based on their developmental origin two functionally distinct types of vagal c-fibers are recognized: those with neurons in the vagal nodose ganglia (derived from epibranchial placodes) and in the vagal jugular ganglia (from neural crest). studies in nonprimate species demonstrated that the vagal nodose and jugular c-fibers differ in activ ...201930896676
generation of macrophages from cynomolgus-monkey bone marrow as a model to evaluate effects of drugs on innate immunity.macrophages are innate immune cells that play important roles in various physiological and pathological processes. evaluation of pro-inflammatory effects of drugs on macrophages has become commonplace in preclinical drug development prior to human clinical trials. despite their body-wide distribution, tissue macrophages are often difficult to collect from large animals and humans in a noninvasive manner. therefore, in vitro-differentiated macrophages are important tools to facilitate cross-speci ...201930982234
sting agonists activate latently infected cells and enhance siv-specific responses ex vivo in naturally siv controlled cynomolgus macaques.to achieve a functional cure for hiv, treatment regimens that eradicate latently hiv-infected cells must be established. for this, many groups have attempted to reactivate latently-infected cells to induce cytopathic effects and/or elicit cytotoxic t lymphocyte (ctl)/nk cell-mediated immune responses to kill these cells. we believe that not only the reactivation of latently-infected cells, but also the induction of strong ctl responses, would be required for this. here, we used typical immune ac ...201930976083
determination of a no observable effect level for endotoxin following a single intravitreal administration to cynomolgus monkeys.purpose: to characterize the inflammatory response and determine the no-observable-effect level (noel) in cynomolgus monkey eyes after intravitreal (itv) injection of endotoxin. methods: the inflammatory response to endotoxin was assessed in a single-dose study in monkeys at doses of 0.01 to 0.51 endotoxin units (eu)/eye. tolerability was assessed by clinical ophthalmic examinations, intraocular pressure measurements, fundus color photography, optical coherence tomography, and anatomic pathology ...201930964386
discovery of a novel egfr-targeting antibody-drug conjugate, shr-a1307, for the treatment of solid tumors resistant or refractory to anti-egfr therapies.although inhibiting egfr-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the egfr signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the egfr functionality. given the fact that overexpression of egfr is commonly seen in many cancers, an egfr-targeting antibody-drug conjugate (adc) can selectively ...201930962319
trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in cynomolgus macaques.trace amine-associated receptor 1 (taar1) is a g-protein coupled receptor with affinity for the trace amines. taar1 agonists have pro-cognitive, antidepressant-, and antipsychotic-like properties in both rodents and non-human primates (nhps). taar1 agonism also increases wakefulness and suppresses rapid-eye movement (rem) sleep in mice and rats and reduces cataplexy in two mouse models of narcolepsy. we investigated the effects of taar1 agonism in cynomolgus macaques, a diurnal species that exhi ...201930954024
associations between sounds and actions in early auditory cortex of nonhuman primates.an individual may need to take different actions to the same stimulus in different situations to achieve a given goal. the selection of the appropriate action hinges on the previously learned associations between stimuli, actions, and outcomes in the situations. here, using a go/no-go paradigm and a symmetrical reward, we show that early auditory cortex of nonhuman primates represents such associations, in both the spiking activity and the local field potentials. sound-evoked neuronal responses ...201930946010
adverse event following live attenuated chikungunya vaccine in a cynomolgus macaque with pre-existing chronic hydrocephalus.a cynomolgus macaque (macaca fascicularis) with a pre-existing, undiagnosed, subclinical but severe cerebral hydrocephalus was enrolled in a study of long-term immunogenicity of the ires/chik vaccine. the animal began showing signs of neurological dysfunction post-vaccination, which progressed and ultimately resulted in euthanasia. the underlying brain abnormality was revealed at necropsy and was subsequently investigated with gross and microscopic examination. this becomes the first reported ca ...201930945306
capacitation of human naïve pluripotent stem cells for multi-lineage differentiation.human naïve pluripotent stem cells (pscs) share features with the pre-implantation epiblast. they therefore provide an unmatched opportunity for characterising the developmental programme of pluripotency in homo sapiens here, we confirm that naïve pscs do not respond directly to germ layer induction, but must first acquire competence. capacitation for multi-lineage differentiation occurs without exogenous growth factor stimulation and is facilitated by inhibition of wnt signalling. whole-transcr ...201930944104
probucol induces the generation of lipid peroxidation products in erythrocytes and plasma of male cynomolgus macaques.we previously reported that probucol, a lipid lowering agent, protected mice from malaria infection via depletion in plasma α-tocopherol. the antioxidant α-tocopherol in host circulation is necessary for the malaria parasites to protect themselves from oxidative stress in erythrocytes where high amounts of reactive oxygen species are generated. to assess the potential for the clinical application of probucol as an anti-malarial therapy, it was necessary to determine the effects of probucol by us ...201930936625
visualization of early events in mrna vaccine delivery in non-human primates via pet-ct and near-infrared imaging.visualization of the spatio-temporal trafficking of vaccines after their delivery would help evaluate the efficacy of candidate formulations and aid their rational design for preclinical and translational studies. here, we show that a dual radionuclide-near-infrared probe allows for quantitative, longitudinal and non-invasive monitoring, via positron emission tomography-computed tomography and near-infrared imaging of cynomolgus macaques, of the trafficking dynamics to draining lymph nodes of a ...201930936432
estimating the amount of chronic wasting disease infectivity passing through abattoirs and field slaughter.chronic wasting disease (cwd) is a highly infectious, naturally occurring, transmissible spongiform encephalopathy (tse, or prion disease) affecting many cervid species. cwd has been widely circulating in north america since it was first reported in 1967. in 2016, the first european case of prion disease in deer was reported and confirmed in norway. there have since been several confirmed several cases in reindeer and moose and in one red deer in norway, and recently in a moose in finland. there ...201930935503
mycoplasma ocular infection in subretinal graft transplantation of ips cells-derived retinal pigment epithelial cells.to report occurrence of acute severe inflammation after surgical implantation of mycoplasma-infected induced pluripotent stem cell-derived rpe (ips-rpe) cells into the eyes of healthy primates, and determine the immunopathological mechanisms of the inflammation.201930933257
effects of cervical rotatory manipulation on internal carotid artery in hemodynamics using an animal model of carotid atherosclerosis: a safety study.background spinal manipulation, particularly in cervical rotatory manipulation (crm), has become increasingly popular in physical therapies, with satisfying effect. however, it is still unclear whether crm affects internal carotid arteries (ica) with mild carotid atherosclerosis (cas), especially in hemodynamics. material and methods nine cynomolgus monkeys were randomly divided into 3 groups: the cas-crm, the cas, and the blank control groups. cas models were developed in the left ica in the ca ...201930928990
long-tailed macaque response to deforestation in a plasmodium knowlesi-endemic area.land-use changes can impact infectious disease transmission by increasing spatial overlap between people and wildlife disease reservoirs. in malaysian borneo, increases in human infections by the zoonotic malaria plasmodium knowlesi are hypothesised to be due to increasing contact between people and macaques due to deforestation. to explore how macaque responses to environmental change impact disease risks, we analysed movement of a gps-collared long-tailed macaque in a knowlesi-endemic area in ...201930927165
functional and molecular characterization of udp-glucuronosyltransferase 2 family in cynomolgus macaques.udp-glucuronosyltransferases (ugts) are essential enzymes metabolizing endogenous and exogenous chemicals. however, characteristics of ugts have not been fully investigated in molecular levels of cynomolgus macaques, one of non-human primates widely used in preclinical drug metabolism studies. in this study, three ugt2a cdnas (ugt2a1, 2a2, and 2a3) were isolated and characterized along with seven ugt2bs previously identified in cynomolgus macaques. several transcript variants were found in cynom ...201930836059
differences in monocyte: lymphocyte ratio and tuberculosis disease progression in genetically distinct populations of macaques.monocyte:lymphocyte ratio (m:l) has been identified as a risk factor in development of tb disease in children and those undergoing treatment for hiv in co-infected individuals. retrospective analysis was performed using m:l data collected from tb modelling studies performed in rhesus macaques of indian genotype (rm), cynomolgus macaque of chinese genotype (ccm) and cynomolgus macaque of mauritian genotype (mcm), which found that the more susceptible populations (rm and mcm) had higher m:l ratios ...201930833652
chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.domoic acid (da) is an excitatory neurotoxin produced by marine algae and responsible for amnesiac shellfish poisoning in humans. current regulatory limits (˜0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of da below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. as da-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic da e ...201930826346
correlation between genotypes and geographic distribution of entamoeba nuttalli isolates from wild long-tailed macaques in central thailand.entamoeba nuttalli found in non-human primates is the phylogenetically closest species to entamoeba histolytica and is potentially pathogenic. however, infection of wild long-tailed macaques (macaca fascicularis) with e. nuttalli has not been found. in this study, the prevalence of entamoeba infections in wild long-tailed macaques was examined in seven locations in six provinces of thailand. the positive rate for e. nuttalli in 214 fecal samples was 43.9% using pcr, but no infection with e. hist ...201930822548
preclinical safety evaluation of the adrenomedullin-binding antibody adrecizumab in rodents, dogs and non-human primates.adrenomedullin (adm) is a vasoactive peptide in sepsis. the non-neutralizing adm-binding antibody adrecizumab improved outcome in animal models of systemic inflammation and sepsis. herein, we evaluated the preclinical safety of adrecizumab in various animal species. first, wistar rats received vehicle, 100, 200 or 400 mg/kg/day of adrecizumab intravenously (n = 20 each) on days 1, 4, 8 and 14. an additional set of rats received vehicle or 400 mg/kg/day (n = 10 each) on the same days and were fol ...201930822437
distinguishing analgesic drugs from non-analgesic drugs based on brain activation in macaques with oxaliplatin-induced neuropathic pain.the antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. however, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. in severe instances, dose reduction or curtailing treatment may be necessary. while a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. this failure could be r ...201930817933
ionis-pkkrx a novel antisense inhibitor of prekallikrein and bradykinin production.kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by c1-esterase inhibitor (c1-inh). in hereditary angioedema (hae), genetic mutations result in deficient or dysfunctional c1-inh and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. ionis-pkkrx is a second-generation 2'-o-(2-methoxyethyl)-modified chimeric antisense o ...201930817230
pharmacokinetics, tissue distribution, plasma protein binding, and metabolism study of mefunidone, a novel pirfenidone derivative.mefunidone (mfd), a novel derivation of pirfenidone (pfd), exhibits promising anti-renal fibrosis activity. to avoid early development failures and attrition in clinical phase 1, an evaluation of the preclinical pharmacokinetic (pk) properties of mfd was conducted in this study. the absolute bioavailability was evaluated in sprague dawley rats and cynomolgus monkeys, who received an intragastric or intravenous administration at the dose of 31.25 mg/kg and 10 mg/kg, respectively. tissue distribut ...201930815895
paromomycin sulfate is an effective treatment for balantidiasis in captive cynomolgus monkeys.there are few effective antimicrobial agents against balantidium coli infection. the effect of paromomycin sulfate (ps) against b. coli was confirmed in this study of 596 captive cynomolgus monkeys. in several trials, the minimum dose and duration of oral administration of ps were 25 mg/day for 5 + 5 days, with a 2-day withdrawal interval. to facilitate daily ps administration, pumpkin cakes supplemented with ps were made, which not only resulted in precise effects but also increased the efficie ...201930814394
synthesis and evaluation of two new candidate high-affinity full agonist pet radioligands for imaging 5-ht1b receptors.the serotonin 1b receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. over recent years 5-ht1b receptor binding in human brain has been examined with pet using radioligands that are partial but not full agonists. to explore how the intrinsic activity of a pet radioligand may affect imaging performance, two high-affinity full 5-ht1b receptor agonists (az11136118, 4; and az11895987, 5) were selected from a large compound library and radiolabele ...201930811975
characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging.recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (csf) and related hydrodynamics. increased understanding of csf dynamics may lead to improved detection of central nervous system (cns) diseases and optimized delivery of csf based cns therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. before significant strides can be made toward the research and development ...201930811449
five years of successful inducible transgene expression following locoregional adeno-associated virus delivery in nonhuman primates with no detectable immunity.anti-transgene immune responses elicited after intramuscular (i.m.) delivery of recombinant adeno-associated virus (raav) have been shown to hamper long-term transgene expression in large-animal models of raav-mediated gene transfer. to overcome this hurdle, an alternative mode of delivery of raav vectors in nonhuman primate muscles has been described: the locoregional (lr) intravenous route of administration. using this injection mode, persistent inducible transgene expression for at least 1 ye ...201930808235
the frequencies of immunosuppressive cells in adipose tissue differ in human, non-human primate, and mouse models.although the metabolic properties of white adipose tissue have been extensively characterized, the tissue's immune properties are now attracting renewed interest. early experiments in a mouse model suggested that white adipose tissue contains a high density of regulatory t cells (tregs), and so it was assumed that all adipose tissue has an immunosuppressive profile-even though the investigation was limited to visceral body fat in relatively old male mice. this observation was also corroborated b ...201930804937
nk cell immune responses differ after prime and boost vaccination.a better understanding of innate responses induced by vaccination is critical for designing optimal vaccines. here, we studied the diversity and dynamics of the nk cell compartment after prime-boost immunization with the modified vaccinia virus ankara using cynomolgus macaques as a model. mass cytometry was used to deeply characterize blood nk cells. the nk cell subphenotype composition was modified by the prime. certain phenotypic changes induced by the prime were maintained over time and, as a ...201930794328
development of an icosl and baff bispecific inhibitor amg 570 for systemic lupus erythematosus treatment.systemic lupus erythematous (sle) is a heterogeneous disease lacking highly effective treatment options. here we tested if targeting both baff and icosl has superior efficacy than single target inhibition in the mouse arthritis and lupus models. we also generated amg 570, an icosl and baff bispecific inhibitory molecule, for potential treatment of autoimmune diseases such as sle.201930789152
phase i study of pf‐04895162, a kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis.during a randomized phase 1 clinical trial the drug candidate, pf-04895162 (ica-105665), caused transaminase elevations (≥grade 1) in six of eight healthy subjects treated at 300 mg twice daily for 2-weeks (nct01691274). this was unexpected since studies in rats (<6 months) and cynomolgus monkeys (<9 months) treated up to 100 mg/kg/day did not identify the liver as a target organ. mechanistic studies showed pf-04895162 had low cytotoxic potential in human hepatocytes, but inhibited liver mitocho ...201930784208
characterization, biology, and expansion of regulatory t cells in the cynomolgus macaque for preclinical studies.reliable in vitro expansion protocols of regulatory t cells (tregs) are needed for clinical use. we studied the biology of mauritian cynomolgus macaque (mcm) tregs and developed four in vitro treg expansion protocols for translational studies. tregs expanded 3000-fold when artificial antigen presenting cells (aapcs) expressing human cd80, cd58 and cd32 were used throughout the culture. when donor peripheral blood mononuclear cells (pbmcs) were used as the single source of apcs followed by aapcs, ...201930768842
a novel anti-egfr mab ame55 with lower toxicity and better efficacy than cetuximab when combined with irinotecan.to improve efficacy and minimize toxicity of egfr inhibition treatment, we developed ame55, a novel anti-egfr igg1 with lower affinity to egfr than cetuximab (c225) from a human phage library. ame55 had lower bioactivity than cetuximab in vitro but similar antitumor efficacy as cetuximab in vivo. moreover, ame55 was more efficacious than cetuximab in a lovo cell xenograft tumor model when combined with irinotecan (cpt-11). ame55 concentrates in the mouse xenograft tumor and has less toxicity tha ...201930733972
mammosphere culture of mammary cells from cynomolgus macaques (macaca fascicularis).the mammary gland contains adult stem cells that are capable of self-renewal. although these cells hold an important role in the biology and pathology of the breast, the studies of mammary stem cells are few due to the difficulty of acquiring and expanding undifferentiated adult stem cell populations. in this study, we developed mammosphere cultures from frozen mammary cells of nulliparous cynomolgus macaques (macaca fascicularis) as a culture system to enrich mammary stem cells. small samples o ...201930732675
a comparative study for detecting cyp3a induction by cyp3a probe drugs and endogenous markers in cynomolgus monkeys.cyp3a probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-ohc) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-ohc/c) have been used as markers of cyp3a induction in cynomolgus monkeys, as with humans. however, there is limited information on their sensitivity and ability to detect cyp3a induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (rif; 20 mg/kg). in the present study, the cyp3a induction by rif over a rang ...201930724384
cd4cd8 double positive t cell responses during mycobacterium tuberculosis infection in cynomolgus macaques.tuberculosis (tb) kills millions of people every year. cd4 and cd8 t cells are critical in the immune response against tb. t cells expressing both cd4 and cd8 (cd4cd8 t cells) are functionally active and have not been examined in the context of tb.201930723927
pet imaging of dopamine release in the frontal cortex of manganese-exposed non-human primates.humans and non-human primates exposed to excess levels of manganese (mn) exhibit deficits in working memory and attention. frontal cortex and fronto-striatal networks are implicated in working memory and these circuits rely on dopamine for optimal performance. here, we aimed to determine if chronic mn exposure alters in vivo dopamine release (dar) in the frontal cortex of non-human primates. we used [11 c]-flb457 positron emission tomography with amphetamine challenge to measure dar in cynomolgu ...201930720866
intraocular pressure effects and mechanism of action of topical versus sustained-release bimatoprost.to assess the intraocular pressure (iop)-lowering effects of bimatoprost sustained-release implant (bimsr) in normotensive monkeys receiving topical bimatoprost.201930713809
apolipoprotein a-i mimetic peptide l-4f removes bruch's membrane lipids in aged nonhuman primates.multiple evidence lines support bruch's membrane lipid deposition as a major precursor of soft drusen and age-related macular degeneration as including a potentially treatable atherosclerosis-like progression in the subretinal pigment epithelium (rpe)-basal lamina space. we evaluated the effect of anti-inflammatory, antiatherogenic peptide l-4f on bruch's membrane of aged nonhuman primates in a dose-escalating study.201930707219
intrathecal delivery of aav vectors in cynomolgus macaques for cns gene therapy and gene expression analysis in microdissected motor neurons.this protocol describes a method of delivering adeno-associated viral (aav) vectors to the intrathecal space of nonhuman primates for cns-directed gene therapy. it includes the surgical implantation of the catheter, vector infusion, necropsy, laser-capture microdissection of motor neurons, and gene expression analysis. this method allows efficient and reproducible delivery, and would be of interest to test gene therapy vectors for the treatment of disorders of the central nervous system of nonhu ...201930706405
draft genome sequence of atopobacter sp. strain ah10, isolated from a vaginal swab from macaca fascicularis.a bacterial strain belonging to the genus atopobacter was isolated from a vaginal swab from a crab-eating macaque (macaca fascicularis). here, we report the draft genome sequence of this strain, ah10.201930701258
molecular prevalence and subtyping of cryptosporidium hominis among captive long-tailed macaques (macaca fascicularis) and rhesus macaques (macaca mulatta) from hainan island, southern china.cryptosporidium is an important zoonotic parasite that is commonly found in non-human primates (nhps). consequently, there is the potential for transmission of this pathogen from nhps to humans. however, molecular characterization of the isolates of cryptosporidium from nhps remains relatively poor. the aim of the present work was to (i) determine the prevalence; and (ii) perform a genetic characterization of the cryptosporidium isolated from captive macaca fascicularis and m. mulatta on hainan ...201931039801
dissecting the contribution of oatp1b1 to hepatic uptake of statins using the oatp1b1 selective inhibitor estropipate.identification of a selective inhibitor of organic anion transporting polypeptide (oatp) 1b1 is critical in order to determine the contribution of oatp1b1-mediated uptake of investigational drugs into human hepatocytes for successful in vitro-to-in vivo extrapolation (ivive) of hepatic uptake and drug-drug interaction (ddi). the following study examined the inhibitory effects of estropipate (epp) on major sinusoidal drug uptake transporters and explored its utility regarding ivive of statin hepa ...201931039308
an anti-plvap antibody suppresses laser-induced choroidal neovascularization in monkeys.plasmalemma vesicle-associated protein (plvap, also called pv-1) is the only protein that forms endothelial diaphragms. plvap expression is very low in the normal blood-retinal barrier; however, pathological factors such as high glucose and vascular endothelial growth factor (vegf) induce its expression, leading to the exacerbation of cellular permeability. because the new blood vessels are fragile and leaky, plvap could possibly be considered a therapeutic target against retinovascular diseases ...201931026444
a highly effective and ultra-long-acting anti-glaucoma drug, with a novel periorbital delivery method.purpose: two features define the future of glaucoma therapeutics: (1) greatly improved ocular hypotensive efficacy and (2) a delivery method that improves patient convenience and compliance. a highly efficacious and extraordinarily long-acting ocular hypotensive agent pgn 9856-isopropyl ester represents a potential next-generation anti-glaucoma drug. a new periorbital drug delivery route was also investigated. methods: pgn 9856-isopropyl ester pharmacology was determined by employing human cells ...201931025909
comparison of gene expression in cynomolgus monkeys with preclinical type ii diabetes induced by different high energy diets.cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus (t2dm) were established by feeding middle-aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes-related genes.201931016286
plasmodium knowlesi and other malaria parasites in long-tailed macaques from the philippines.macaca fascicularis (long-tailed macaque) is the most widespread species of macaque in southeast asia and the only species of monkey found naturally in the philippines. the species is the natural host for the zoonotic malaria species, plasmodium knowlesi and plasmodium cynomolgi and for the potentially zoonotic species, plasmodium inui. moreover, other plasmodium species such as plasmodium coatneyi and plasmodium fieldi are also natural parasites of m. fascicularis. the aims of this study were t ...201931014342
depressed female cynomolgus monkeys (macaca fascicularis) display a higher second-to-fourth (2d:4d) digit ratio.this research aimed to provide evidence of a relationship between digit ratio and depression status in the cynomolgus monkey (macaca fascicularis). in stable cynomolgus monkey social groups, we selected 15 depressed monkeys based on depressive-like behavioral criteria and 16 normal control monkeys. all animals were video recorded for two weeks, with the duration and frequency of the core depressive behaviors and 58 other behaviors in 12 behavioral categories then evaluated via behavioral analysi ...201931011132
evaluation of analgesic patches in cynomolgus macaques (macaca fascicularis).opioids are widely used in veterinary and human medicine to manage pain. however, there is a paucity of information in the literature regarding the pharmacokinetics of opioid transdermal patches (tdp) in nhp. therefore, to determine whether opioid tdp attain therapeutic concentrations in nhp, the pharmacokinetics of fentanyl (25 μg/h) and buprenorphine (10 and 20 μg/h) tdp were evaluated in naïve, adult, male cynomolgus macaques (n = 4) in a crossover study. plasma opioid levels were determined ...201931010456
generation of an oct3/4 reporter cynomolgus monkey es cell line using crispr/cas9.cynomolgus monkey es (cyn es) cells can be generated in a similar manner as human es cells. however, cyn es cells are difficult to maintain in an undifferentiated state by untrained researchers. for easier culture, we generated an oct3/4-p2a tdtomato ires zeocinr cyn es cell line using crispr/cas9 genome editing technology. the stop codon of the endogenous oct3/4 locus was replaced with the p2a tdtomato ires zeocinr pa cassette by homologous recombination. this cell line enables us to isolate pl ...201931005787
comparison of mrna expression profiles of drug-metabolizing enzymes and transporters in fresh and cryopreserved cynomolgus monkey hepatocytes.in this study, freshly isolated and cryopreserved cynomolgus monkey hepatocytes were seeded on cell-able® plates with feeder cells to form spheroids and were cultured for 28 days. as a control, hepatocytes were also cultured with or without feeder cells on collagen-coated plates. we verified the mrna expression levels of drug-metabolizing enzyme-related genes and the leakage of enzymes (ast, alt, ldh, and γ-gtp) as indicators of cell survival. as a result, the patterns of target mrna expression ...201931174977
development of an intravaginal ring delivering simultaneously anastrozole and levonorgestrel: a pharmacokinetic perspective.intravaginal rings (ivrs) are an option for continuous administration of drugs in women. as an attractive approach for the treatment of endometriosis-associated pelvic pain, ivrs delivering a combination of the aromatase inhibitor anastrozole (atz) and the progestin levonorgestrel (lng) have been developed. this article describes the developmental pharmacokinetic (pk) aspects covering the characterization of in vitro release, preclinical ivr pk investigations in monkeys, and clinical pk consider ...201931174438
evaluation and use of an anti-cynomolgus monkey cd79b surrogate antibody-drug conjugate to enable clinical development of polatuzumab vedotin.polatuzumab vedotin is an antibody-drug conjugate (adc) being developed for non-hodgkin's lymphoma. it contains a humanized anti-cd79b igg1 monoclonal antibody linked to monomethyl auristatin e (mmae), an anti-mitotic agent. polatuzumab vedotin binds to human cd79b only. therefore, a surrogate adc that binds to cynomolgus monkey cd79b was used to determine cd79b-mediated pharmacological effects in the monkey and to enable first-in-human clinical trials.201931270798
natural infection of captive cynomolgus monkeys (macaca fascicularis) with hepatitis e virus genotype 4.data on natural hev infection of infection in monkeys are limited. we report a case of hepatitis e virus genotype 4 infection in captive non-human primates (cynomolgus monkeys) imported from vietnam. phylogenetic analysis demonstrated that hev infection was not the result of spillover from single source of infection, but rather the persistent circulation of hev-4 among cynomolgus monkeys or multiple infections by related strains from a human or swine reservoir.201931270608
the pi3kδ selective inhibitor as2541019 suppresses donor-specific antibody production in rat cardiac and non-human primate renal allotransplant models.long-term graft survival after organ transplantation is difficult to achieve because of the development of chronic rejection. one cause of chronic rejection arises from antibody-mediated rejection (amr), which is dependent on the production of donor-specific antibodies (dsa). current immunosuppression in organ transplantation is effective in preventing acute t cell-mediated rejection, but the risk of dsa production and graft loss due to amr remains unchanged. phosphatidylinositol-3-kinase p110δ ...201931344556
the influence of masseter and temporalis sarcomere length operating ranges as determined by laser diffraction on architectural estimates of muscle force and excursion in macaques (macaca fascicularis and macaca mulatta).determine sarcomere length (ls) operating ranges of the superficial masseter and temporalis in vitro in a macaque model and examine the impact of position-dependent variation on ls and architectural estimates of muscle function (i.e., fiber length, pcsa) before and after ls-normalization.201931254839
identification and characterization of an octameric peg-protein conjugate system for intravitreal long-acting delivery to the back of the eye.innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 fc-fusion proteins and >10 immuno-cytokines. despite these innovations, technological advances are needed to address unmet medical needs with new pharmacological mechanisms. age-related eye diseases are among the most common causes of blindness and poor vision in the world. many suc ...201931251757
determination of il-23 pharmacokinetics by highly sensitive accelerator mass spectrometry and subsequent modeling to project il-23 suppression in psoriasis patients treated with anti-il-23 antibodies.the pro-inflammatory cytokine interleukin (il)-23 is a key modulator of the immune response, making it an attractive target for the treatment of autoimmune disease. correspondingly, several monoclonal antibodies against il-23 are either in development or approved for autoimmune indications such as psoriasis. despite being a clinical validated target, il-23 pharmacokinetics (e.g., il-23 synthesis and elimination rates) and the degree of target suppression (i.e., decrease in free "active" il-23) a ...201931250228
dynamics of vaginal and rectal microbiota over several menstrual cycles in female cynomolgus macaques.the composition of the microbiota in cynomolgus macaques is only partially characterized, although this animal model is often used to study pathogenesis and preventive strategies against infections. we thus performed, for the first time, a longitudinal characterization of the vaginal and rectal microbiota of five cycling female cynomolgus macaques. samples were collected weekly for 15 weeks and the v3/v4 regions of the16s rrna gene sequenced. sequences were analyzed with qiime for otu detection ...201931249812
electrophysiological characterization of sleep/wake, activity and the response to caffeine in adult cynomolgus macaques.most preclinical sleep studies are conducted in nocturnal rodents that have fragmented sleep in comparison to humans who are primarily diurnal, typically with a consolidated sleep period. consequently, we sought to define basal sleep characteristics, sleep/wake architecture and electroencephalographic (eeg) activity in a diurnal non-human primate (nhp) to evaluate the utility of this species for pharmacological manipulation of the sleep/wake cycle. adult, 9-11 y.o. male cynomolgus macaques (n = ...201931236518
protective effects of the francisella tularensis δpdpc mutant against its virulent parental strain schu p9 in cynomolgus macaques.tularemia is a severe infectious zoonotic disease caused by francisella tularensis. although f. tularensis is considered to be a potential biological weapon due to its high infectivity and mortality rate, no vaccine has been currently licensed. recently, we reported that f. tularensis schu p9 derived δpdpc strain lacking the pathogenicity determinant protein c gene conferred stable and good protection in a mouse lethal model. in this study, the protective effect of δpdpc was evaluated using a mo ...201931235714
transcon cnp, a sustained-release c-type natriuretic peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities associated with fibroblast growth factor receptor 3-related skeletal dysplasias.transcon cnp is a c-type natriuretic peptide (cnp-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic cnp levels upon weekly subcutaneous administration. transcon cnp is in clinical development for the treatment of comorbidities associated with achondroplasia. in both mice and cynomolgus monkeys, sustained exposure to cnp via transcon cnp was more efficacious in stimulating bone growth than intermittent cnp exposure. transcon cn ...201931235532
in vitro culture of embryos from the cynomolgus macaque (macaca fascicularis).the cynomolgus macaque (macaca fascicularis) has contributed significantly as an animal model in a variety of biological systems including reproductive biology. the first reported delivery of a cynomolgus infant born through ivf was in 1984, and since then the use of assisted reproductive technologies (arts) in the cynomolgus macaque for modeling primate early embryonic development has evolved to include studies on gene editing in primate embryos and embryonic stem cell chimerism. the significan ...201931230290
preclinical studies of a death receptor 5 fusion protein that ameliorates acute liver failure.acute liver failure (alf) is a life-threatening disease with a high mortality rate. there is an urgent need to develop new drugs with high efficacy and low toxicity. in this study, we produced a pharmaceutical-grade soluble death receptor 5 (sdr5)-fc fusion protein for treating alf and evaluated the pharmacology, safety, pharmacokinetics, efficacy, and mechanisms of sdr5-fc in mice, rats, and cynomolgus monkeys. sdr5-fc bound with high affinity to both human and monkey tumor necrosis factor-rela ...201931230087
characterization and population dynamics of germ cells in adult macaque testicular cultures.from a biological and clinical perspective, it is imperative to establish primate spermatogonial cultures. due to limited availability of human testicular tissues, the macaque (macaca fascicularis) was employed as non-human primate model. the aim of this study was to characterize the expression of somatic as well as germ cell markers in testicular tissues and to establish macaque testicular primary cell cultures.201931226129
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