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intradermal vaccination prevents anti-mog autoimmune encephalomyelitis in macaques.autoimmune demyelinating diseases (add) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. a cure for chronic add could be obtained by appropriate immunomodulation.201931492559
both diet and helicobacter pylori infection contribute to atherosclerosis in pre- and postmenopausal cynomolgus monkeys.a number of viruses and bacterial species have been implicated as contributors to atherosclerosis, potentially providing novel pathways for prevention. epidemiological studies examining the association between helicobacter pylori and cardiovascular disease have yielded variable results and no studies have been conducted in nonhuman primates. in this investigation, we examined the relationship between h. pylori infection and atherosclerosis development in socially housed, pre- and postmenopausal ...201931490998
jak3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys.islet transplantation is efficacious to prevent severe hypoglycemia and glycemic liability of selected patients of type 1 diabetes. however, since calcineurin inhibitor (cni) causes β-cell and nephrotoxicity, alternative drug(s) with similar potency and safety profile to cni will be highly desirable. here we tested whether jak3 inhibitor, tofacitinib could be used instead of tacrolimus in cit07 immunosuppression regimen in cynomolgus nonhuman primate (nhp) model. five independent streptozotocin ...201931483188
physiological and drug-induced changes in blood levels of adrenal steroids and their precursors in cynomolgus monkeys: an application of steroid profiling by lc-ms/ms for evaluation of the adrenal toxicity.the adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. however, methods to evaluate the adrenal toxicity are limited. the aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. with this aim, physiological and d ...201931474739
utilization of lipopolysaccharide challenge in cynomolgus macaques to assess il-10 receptor antagonism.the current era of drug discovery has been marked by a significant increase in the development of immune modulating agents to address a range of diseases such as cancer, chronic inflammation, and other conditions of dysregulated immunity. non-clinical evaluation of these agents in animal models can be challenging, as the presence of an active immune state is often required in order to detect the effects of the test agent. modulation of interleukin (il)-10 signaling represents this type of situat ...201931464151
the cynomolgus macaque mhc polymorphism in experimental medicine.among the non-human primates used in experimental medicine, cynomolgus macaques (macaca fascicularis hereafter referred to as mafa) are increasingly selected for the ease with which they are maintained and bred in captivity. macaques belong to old world monkeys and are phylogenetically much closer to humans than rodents, which are still the most frequently used animal model. our understanding of the mafa genome has progressed rapidly in recent years and has greatly benefited from the latest tech ...201931455025
partial sequence analyses of exon 7 of the abo locus of cynomolgus (macaca fascicularis) and rhesus (m. mulatta) macaques: indeterminate phenotypes show the presence of the o blood group.compatibility tests to identify a, b, and o alleles are critical for establishing suitable donor-recipient matches among experimental animals. using a qpcr-based snp probe assay, we have identified a, b, ab, and indeterminate blood group phenotypes in cynomolgus and rhesus macaques. we have hypothesized, albeit without molecular confirmation, that the indeterminate phenotype represents homozygosity for the null o allele at the macaque abo locus. the indeterminate phenotype represents the unsucce ...201931448567
preclinical development of a high affinity α-synuclein antibody, medi1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo.there are no approved drug therapies that can prevent or slow the progression of parkinson's disease (pd). accumulation and aggregation of α-synuclein protein is observed throughout the nervous system in pd. α-synuclein is a core component of lewy bodies and neurites that neuropathologically define pd, suggesting that α-synuclein may be a key causative agent in pd. recent experimental data suggest that pd progression may arise due to spreading of pathological forms of extracellular α-synuclein t ...201931445162
macular thickness measurements of healthy, naïve cynomolgus monkeys assessed with spectral-domain optical coherence tomography (sd-oct).the purpose of this study was to measure central macular thickness in an unprecedented number of cynomolgus monkeys. macular thickness was measured with heidelberg spectral-domain oct in 320 eyes of healthy and treatment-naïve cynomolgus monkeys (80 males and 80 females). the macula was successfully measured in all 320 eyes. macular thickness was not significantly different between the sexes. the mean central macular thickness was 244 μm (+/- 21 μm). macular thicknesses in the quadrants were 327 ...201931589624
evaluation of preclinical safety profile of sph3127, a direct renin inhibitor, after 28-day repeated oral administration in sprague-dawley rats and cynomolgus monkeys.sph3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable adme (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase ι clinical trial. in this work, the subchronic toxicity of sph3127 in sprague-dawley rats and cynomolgus monkeys has been characterized. rats and monkeys received sph3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 d ...201931585137
an allosteric anti-tryptase antibody for the treatment of mast cell-mediated severe asthma.severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. we show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-ige treatment. we generated a noncompetitive inhibitory antibody against human β-tryptase, which ...201931585081
organic anion-transporting polypeptide genes are not induced by the pregnane x receptor activator rifampin: studies in hepatocytes in vitro and in monkeys in vivo.induction potentials of the pregnane x receptor (pxr) activator rifampin (rif) on transporter genes [e.g., organic anion-transporting polypeptides (oatps)] are still in its infancy or remain controversial in the field. the present investigations characterized changes in transporter gene expression by rif in sandwich-cultured hepatocytes from multiple donors of human and cynomolgus monkey using real-time quantitative reverse transcription polymerase chain reaction method. three-day treatment of r ...201931582395
long-term outcome and rejection after allogeneic uterus transplantation in cynomolgus macaques.uterus transplantation (utx) is an option for women with uterine factor infertility to have a child, but is still in the experimental stage. therefore, allogeneic animal models of utx are required for resolution of clinical issues. in this study, long-term outcomes were evaluated in four recipients (cases 1-4) after allogeneic utx in cynomolgus macaques. immunosuppression with antithymocyte globulin induction and a triple maintenance regimen was used. postoperative ultrasonography and biopsy of ...201931581534
adverse vacuolation in multiple tissues in cynomolgus monkeys following repeat-dose administration of a pegylated protein.pegylation is considered a safe mechanism to enhance the pharmacokinetics (pk) and pharmacodynamics (pd) of biotherapeutics. previous studies using pegylation as a pk enhancement tool have reported benign peg-related vacuolation in multiple tissues. this paper establishes a threshold for peg burden beyond which there are alterations in tissue architecture that could potentially lead to dysfunction. as part of the nonclinical safety assessment of compound a, a 12 kda protein conjugated to a 40 kd ...201931580884
intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes.several studies have demonstrated that intrastriatal injections of fibrillar α-synuclein in rodent brain induced a parkinson's disease-like propagation of lewy body pathology with significant nigrostriatal neurodegeneration. this study evaluated the pathological features when exogenous α-synuclein preformed fibrils were injected into the putamen of non-human primates. eight cynomolgus monkeys received unilateral intraputamen injections of α-synuclein preformed fibrils and four monkeys received s ...201931580415
vaccines inducing immunity to lassa virus glycoprotein and nucleoprotein protect macaques after a single shot.lassa fever is a major threat in western africa. the large number of people living at risk for this disease calls for the development of a vaccine against lassa virus (lasv). we generated live-attenuated lasv vaccines based on measles virus and mopeia virus platforms and expressing different lasv antigens, with the aim to develop a vaccine able to protect after a single shot. we compared the efficacy of these vaccines against lasv in cynomolgus monkeys. the vaccines were well tolerated and prote ...201931578242
controlled-release mitochondrial protonophore (crmp) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates.nonalcoholic fatty liver disease (nafld) is estimated to affect up to one-third of the general population, and new therapies are urgently required. our laboratory previously developed a controlled-release mitochondrial protonophore (crmp) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides. although we previously demonstrated that crmp safely reverses hypertriglyceridemia, fatty liver, hepatic inflammation, and fibrosis in diet-induced rodent models of obesity, th ...201931578240
sequelae of fetal infection in a non-human primate model of listeriosis.listeria monocytogenes (lm) is a common environmental bacterium that thrives on vegetation and soil matter, but can infect humans if contaminated food products are ingested, resulting in severe disease in immunosuppressed populations, including pregnant women and newborns. to better understand how the unique immunological milieu of pregnancy increases susceptibility to infection, we study listeriosis in cynomolgus macaques, a non-human primate that closely resembles humans in placentation and in ...201931572310
persistent crimean-congo hemorrhagic fever virus infection in the testes and within granulomas of non-human primates with latent tuberculosis.crimean-congo hemorrhagic fever (cchf) is the most medically important tick-borne viral disease of humans and tuberculosis is the leading cause of death worldwide by a bacterial pathogen. these two diseases overlap geographically, however, concurrent infection of cchf virus (cchfv) with mycobacterial infection has not been assessed nor has the ability of virus to persist and cause long-term sequela in a primate model. in this study, we compared the disease progression of two diverse strains of c ...201931557262
non-human primate papillomaviruses share similar evolutionary histories and niche adaptation as the human counterparts.given high genetic diversity of papillomaviruses (pv) and complex scenario of virus-host interaction, the genetic basis underlying the mechanisms of hpv carcinogenicity is not well understood. in an effort to evaluate the origin and evolution of pv pathogenicity, we collected paired oral, perianal, and genital swabs from a wild macaque population. of the 117 surveyed macaques, 88 (75.2%) were positive for pv dna in one or more sites, mostly common from genital swabs, followed by oral and periana ...201931552003
nonclinical safety of tildrakizumab, a humanized anti-il-23p19 monoclonal antibody, in nonhuman primates.tildrakizumab (also known as mk-3222), is a high-affinity, humanized, immunoglobin g1κ monoclonal antibody targeting the p19 subunit of interleukin-23 recently approved for the treatment of moderate to severe plaque psoriasis in the us, europe, and australia. the safety profile of tildrakizumab was characterized in nonclinical studies using a pharmacologically relevant cynomolgus monkey model. in repeat-dose toxicity studies, cynomolgus monkeys were chronically treated with subcutaneous (sc) inj ...201931536773
a vp35 mutant ebola virus lacks virulence but can elicit protective immunity to wild-type virus challenge.zaire ebolavirus (ebov) vp35 protein is a suppressor of type i interferon (ifn) production, an inhibitor of dendritic cell maturation, and a putative virulence determinant. here, a recombinant ebov encoding a mutant vp35 virus (vp35m) is demonstrated to activate rig-i-like receptor signaling and innate antiviral pathways. when inoculated into cynomolgus macaques, vp35m exhibits dramatic attenuation as compared to wild-type ebov (wtebov), with 20 or 300 times the standard 100% lethal challenge do ...201931533029
improvement of sperm cryo-survival of cynomolgus macaque (macaca fascicularis) by commercial egg-yolk-free freezing medium with type iii antifreeze protein.when nonhuman primate sperm undergoes cryopreservation in an egg yolk medium there is an increased risk that the egg yolk might adversely affect the sperm due to containing of avian pathogens. although commercial egg-yolk-free medium for human sperm cryopreservation has been used for macaque sperm, the cryo-survival remains less than optimal. the present study, therefore, was conducted to determine the optimal concentration of antifreeze protein (afp) iii supplemented in a commercial egg-yolk-fr ...201931635783
group-specific archaeological signatures of stone tool use in wild macaques.stone tools in the prehistoric record are the most abundant source of evidence for understanding early hominin technological and cultural variation. the field of primate archaeology is well placed to improve our scientific knowledge by using the tool behaviours of living primates as models to test hypotheses related to the adoption of tools by early stone-age hominins. previously we have shown that diversity in stone tool behaviour between neighbouring groups of long-tailed macaques (macaca-fasc ...201931635691
visualising reactive oxygen species in live mammals and revealing of ros-related system.of all the aerobic respiration by-products, cytotoxic superoxide derived from mitochondrial-leaked electrons, is the only one known to be disposed of intracellularly. is this fate the only destiny for mitochondrial-leaked electrons? when cynomolgus monkeys were injected intravenously with reactive oxygen species (ros) indicators, the connective tissues of dura mater, facial fascia, pericardium, linea alba, dorsa fascia and other body parts, emitted specific and intense fluorescent signals. moreo ...201931631710
single low-dose vsv-ebov vaccination protects cynomolgus macaques from lethal ebola challenge.ebola virus (ebov), variant makona, was the causative agent of the 2013-2016 west african epidemic responsible for almost 30,000 human infections and over 11,000 fatalities. during the epidemic, the development of several experimental vaccines was accelerated through human clinical trials. one of them, the vesicular stomatitis virus (vsv)-based vaccine vsv-ebov, showed promising efficacy in a phase 3 clinical trial in guinea and is currently used in the ongoing ebov outbreak in the northeastern ...201931631035
paracrine-endocrine fgf chimeras as potent therapeutics for metabolic diseases.the development of a clinically useful fibroblast growth factor 21 (fgf21) hormone has been impeded by its inherent instability and weak fgf receptor (fgfr) binding affinity. there is an urgent need for innovative approaches to overcome these limitations.201931631034
pharmacokinetics and intraocular pressure-lowering activity of tak-639, a novel c-type natriuretic peptide analog, in rabbit, dog, and monkey.tak-639 is a topical, 9-amino acid, synthetic, c-type natriuretic peptide analog in development for the treatment of primary open-angle glaucoma and ocular hypertension. this study investigated the impact of tak-639 on intraocular pressure (iop), the levels of tak-639 in aqueous humor, and the pharmacokinetic/pharmacodynamic relationship of tak-639 following topical ocular administration to normotensive female dutch belted rabbits, beagle dogs, and cynomolgus monkeys. in the iop studies, rabbits ...201931626797
a green tea-triggered genetic control system for treating diabetes in mice and monkeys.cell-based therapies are recognized as the next frontier in medicine, but the translation of many promising technologies into the clinic is currently limited by a lack of remote-control inducers that are safe and can be tightly regulated. here, we developed therapeutically active engineered cells regulated by a control system that is responsive to protocatechuic acid (pca), a metabolite found in green tea. we constructed multiple genetic control technologies that could toggle a pca-responsive on ...201931645456
transgenic mouse models expressing human and macaque prion protein exhibit similar prion susceptibility on a strain-dependent manner.cynomolgus macaque has been used for the evaluation of the zoonotic potential of prion diseases, especially for classical-bovine spongiform encephalopathy (classical-bse) infectious agent. prp amino acid sequence is considered to play a key role in the susceptibility to prion strains and only one amino acid change may alter this susceptibility. macaque and human-prp sequences have only nine amino acid differences, but the effect of these amino acid changes in the susceptibility to dissimilar pri ...201931666632
high diversity and novel enteric viruses in fecal viromes of healthy wild and captive thai cynomolgus macaques (macaca fascicularis).cynomolgus macaques are common across south east asian countries including thailand. the national primate research center of thailand, chulalongkorn university (nprct-cu) captures wild-borne cynomolgus macaque for research use. limited information is available on the enteric viruses and possible zoonotic infections into or from cynomolgus macaques. we characterized and compare the fecal virome of two populations; healthy wild-originated captive cynomolgus macaques (n = 43) reared in nprct-cu and ...201931652508
comparative genomics analysis reveals high levels of differential retrotransposition among primates from the hominidae and the cercopithecidae families.mobile elements (mes), making ∼50% of primate genomes, are known to be responsible for generating inter- and intra-species genomic variations and play important roles in genome evolution and gene function. using a bioinformatics comparative genomics approach, we performed analyses of species-specific mes (ss-mes) in eight primate genomes from the families of hominidae and cercopithecidae, focusing on retrotransposons. we identified a total of 230,855 ss-mes, with which we performed normalization ...201931651947
in vitro induction of human embryonic stem cells into the midbrain dopaminergic neurons and transplantation in cynomolgus monkey.a simple, rapid, efficient, and specialized culture system was successfully developed in this study to induce human embryonic stem cells into dopaminergic neurons in vitro. it only took 5 days to generate quickly and directly a large number of homogeneous neural stem cell (nsc) spheres by the introduction of small molecules ldn (inhibitor of bmp [bone morphogenetic protein] pathway that inhibits bmp type i receptors alk2 and alk3), sb431542 (inhibitor of tgf-β/activin/dodal pathway that inhibits ...201931651190
in vitro culture of cynomolgus monkey embryos beyond early gastrulation.gastrulation is a key event in embryonic development when the germ layers are specified and the basic animal body plan is established. the complexities of primate gastrulation remain a mystery because of the difficulties in accessing primate embryos at this stage. here, we report the establishment of an in vitro culture (ivc) system that supports the continuous development of cynomolgus monkey blastocysts beyond early gastrulation up to 20 days after fertilization. the ivc embryos highly recapit ...201931672918
dissecting primate early post-implantation development using long-term in vitro embryo culture.the transition from peri-implantation to gastrulation in mammals entails the specification and organization of the lineage progenitors into a body plan. technical and ethical challenges have limited understanding of the cellular and molecular mechanisms that underlie this transition. we established a culture system that enabled the development of cynomolgus monkey embryos in vitro for up to 20 days. cultured embryos underwent key primate developmental stages, including lineage segregation, bilam ...201931672917
application of bmp-bone cement and fgf-gel on periodontal tissue regeneration in nonhuman primates.the ultimate challenge of tissue engineering research is the translation of experimental knowledge into clinical application. in the preclinical testing phase of any new therapy, animal models remain the gold standard. therefore, the methodological choice of a suitable model is critical to meet the requirements for a safe clinical application of the developed treatment. for instance, we have shown in rats that the application of calcium phosphate cement (cpc)/propylene glycol alginate (pga) with ...201931701811
immunoaffinity lc-ms/ms to quantify a pegylated anti-factor d fab biotherapeutic in cynomolgus monkey serum.aim: to develop a sensitive hybrid immunoaffinity lc-ms/ms monkey serum assay to quantify multiple components of anti-factor d; a complex pegylated fab biotherapeutic explored as a therapy for age-related macular degeneration. materials & methods: immunoaffinity enrichment of pegylated anti-factor d fab, including fully conjugated, partially conjugated and unconjugated (i.e., free) fab species, using a capture reagent coupled to magnetic beads was performed. the surrogate peptides derived from t ...201931701759
mhc class i allele diversity in cynomolgus macaques of vietnamese origin.cynomolgus macaques (macaca fascicularis, mafa) have been used as important experimental animal models for carrying out biomedical researches. the results of biomedical experiments strongly depend on the immunogenetic background of animals, especially on the diversity of major histocompatibility complex (mhc) alleles. however, there is much less information available on the polymorphism of mhc class i genes in cynomolgus macaques, than is currently available for humans. in this study, we have id ...201931720104
potential for imaging the high-affinity state of the 5-ht1b receptor: a comparison of three pet radioligands with differing intrinsic activity.over the last decade, a few radioligands have been developed for pet imaging of brain 5-ht1b receptors. the 5-ht1b receptor is a g-protein-coupled receptor (gpcr) that exists in two different agonist affinity states. an agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-ht, than an antagonist ligand. it is of interest to know whether the intrinsic activity of a pet radioligand for the 5-ht1b receptor impacts on its ability to detect cha ...201931754940
electrocardiography abnormalities in macaques after infection with encephalitic alphaviruses.eastern (eeev) and venezuelan (veev) equine encephalitis viruses (eevs) are related, (+) ssrna arboviruses that can cause severe, sometimes fatal, encephalitis in humans. eevs are highly infectious when aerosolized, raising concerns for potential use as biological weapons. no licensed medical countermeasures exist; given the severity/rarity of natural eev infections, efficacy studies require animal models. cynomolgus macaques exposed to eev aerosols develop fever, encephalitis, and other clinica ...201931744158
cyclophosphamide and fludarabine monophosphate dose optimization for the non-myeloablative condition in non-human primates to induce transient mixed chimerism via bone marrow transplantation.bone marrow preconditioning using cyclophosphamide (cp) is generally used for bone marrow transplantation (bmt). however, because of cp's hepatotoxicity and nephrotoxicity, additional fludarabine (fdr) administration and a reduced dose of cp are used for reduced-intensity preconditioning. recently, preclinical studies using non-human primates (nhps) were performed to induce immune tolerance after solid organ transplantation by conducting bmt simultaneously. however, dose optimization of cp and f ...201931737196
comparative study of human and cynomolgus t-cell depletion with rabbit anti-thymocyte globulin (ratg) treatment-for dose adjustment in a non-human primate kidney transplantation model.rabbit-antithymocyte globulin (ratg) is commonly used in kidney transplantation (kt) as an induction agent and is also commonly used in non-human primate (nhp) kt models. however, the optimal dose has not been reported. in this study, we evaluated which cumulative dose of ratg was most appropriate for transplantation in nhps. cynomolgus monkeys were treated with intravenous 5 mg/kg ratg (thymoglobulin®, genzyme ltd., uk) twice, on days 0 and 2 (a total of 10 mg/kg, n=2), or 4 times, on days 0, 1 ...201931737194
disparate tuberculosis disease development in macaque species is associated with innate immunity.while tuberculosis continues to afflict mankind, the immunological mechanisms underlying tb disease development are still incompletely understood. advanced preclinical models for tb research include both rhesus and cynomolgus macaques (macaca mulatta and macaca fascicularis, respectively), with rhesus typically being more susceptible to acute progressive tb disease than cynomolgus macaques. to determine which immune mechanisms are responsible for this dissimilar disease development, we profiled ...201931736945
correlation between antidrug antibodies, pre-existing antidrug reactivity, and immunogenetics (mhc class ii alleles) in cynomolgus macaque.immunogenicity of biomolecules is one of the largest concerns in biological therapeutic drug development. adverse immune responses as a result of immunogenicity to biotherapeutics range from mild hypersensitivity reactions to potentially life-threatening anaphylactic reactions and can negatively impact human health and drug efficacy. numerous confounding patient-, product- or treatment-related factors can influence the development of an immune reaction against therapeutic proteins. the goal of t ...201931776588
clade f aavhscs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates.the biodistribution of aavhsc7, aavhsc15, and aavhsc17 following systemic delivery was assessed in cynomolgus macaques (macaca fascicularis). animals received a single intravenous (iv) injection of a self-complementary aavhsc-enhanced green fluorescent protein (egfp) vector and tissues were harvested at two weeks post-dose for anti-egfp immunohistochemistry and vector genome analyses. iv delivery of aavhsc vectors produced widespread distribution of egfp staining in glial cells throughout the ce ...201931770409
brain activation in a cynomolgus macaque model of chymopapain-induced discogenic low back pain: a preliminary study.there is currently a lack of translatable, preclinical models of low back pain (lbp). chymopapain, a proteolytic enzyme used to treat lumbar intervertebral disc (ivd) herniation, could induce discogenic lbp. the current study developed a behavioral model of discogenic lbp in nonhuman primates. significant brain activation is observed in clinical lbp. thus, the current study also sought to define brain activation over time in a macaque with discogenic lbp.201931768458
mrgx2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions.activation of mrgx2, an orphan g protein-coupled receptor expressed on mast cells, leads to degranulation and histamine release. human mrgx2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine-like adverse drug reactions of injected therapeutic agents. we set out to identify mrgx2 orthologues from other mammalian species used in nonclinical stages of drug development. previously, the only ...201931832205
a primate model of severe malarial anaemia: a comparative pathogenesis study.severe malarial anaemia (sma) is the most common life-threatening complication of plasmodium falciparum infection in african children. sma is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including cd35). however, a deeper mechanistic understanding of the pathogenesis requires improved animal models. in this comparative study of two closely related macaque species, we interro ...201931831787
monkeys mutant for pkd1 recapitulate human autosomal dominant polycystic kidney disease.autosomal dominant polycystic kidney disease (adpkd) caused by pkd1 mutations is one of the most common hereditary disorders. however, the key pathological processes underlying cyst development and exacerbation in pre-symptomatic stages remain unknown, because rodent models do not recapitulate critical disease phenotypes, including disease onset in heterozygotes. here, using crispr/cas9, we generate adpkd models with pkd1 mutations in cynomolgus monkeys. as in humans and mice, near-complete pkd1 ...201931822676
functional characterization of the selective pan-allele anti-sirpα antibody adu-1805 that blocks the sirpα-cd47 innate immune checkpoint.accumulating preclinical data indicate that targeting the sirpα/cd47 axis alone or in combination with existing targeted therapies or immune checkpoint inhibitors enhances tumor rejection. although several cd47-targeting agents are currently in phase i clinical trials and demonstrate activity in combination therapy, high and frequent dosing was required and safety signals (acute anemia, thrombocytopenia) were recorded frequently as adverse events. based on the restricted expression pattern of si ...201931801627
a novel fully-human potency-matched dual cytokine-antibody fusion protein targets carbonic anhydrase ix in renal cell carcinomas.certain cytokines synergize in activating anti-cancer immunity at the site of disease and it may be desirable to generate biopharmaceutical agents, capable of simultaneous delivery of cytokine pairs to the tumor. in this article, we have described the cloning, expression and characterization of il2-xe114-tnfmut, a dual-cytokine biopharmaceutical featuring the sequential fusion of interleukin-2 (il2) with the xe114 antibody in scfv format and a tumor necrosis factor mutant (tnfmut). the fusion pr ...201931799191
major histocompatibility complex-matched arteries have similar patency to autologous arteries in a mauritian cynomolgus macaque major histocompatibility complex-defined transplant model. 201931795826
thrombospondin 1 (thbs1) promotes follicular angiogenesis, luteinization, and ovulation in primates.angiogenesis is essential to both ovulation and the formation of the corpus luteum. the thrombospondin (thbs) family of glycoproteins plays diverse roles in regulation of angiogenesis, but the role of these vascular regulators in ovulation and luteinization remain to be elucidated. using the cynomolgus macaque as a model for human ovulation, we demonstrated that levels of thbs1 mrna and protein in preovulatory follicle granulosa cells increased after the ovulatory gonadotropin surge, with peak l ...201931787928
anti-mog autoantibodies pathogenicity in children and macaques demyelinating diseases.autoantibodies against myelin oligodendrocyte glycoprotein (anti-mog-abs) occur in a majority of children with acquired demyelinating syndromes (ads) and physiopathology is still under investigation. as cynomolgus macaques immunized with rhmog, all develop an experimental autoimmune encephalomyelitis (eae), we assessed relatedness between anti-mog-abs associated diseases in both species.201931785610
erythrocytes of the rhesus and cynomolgus monkeys.the monograph erythrocytes of the rhesus and cynomolgus monkeys is devoted to the cytologic, quantitative, generative normal and abnormal presentations of the erythrocytes in these two species of primates...201931833330
age-related changes in microbial composition and function in cynomolgus macaques.age can significantly affect human physiology and disease risk. recent studies have shown that age may affect the composition and function of the gut microbiota, but the underlying mechanisms remain largely unknown. non-human primates are an ideal model for uncovering how age shapes the gut microbiota, as their microbial composition is highly similar to that of humans and is not easily affected by confounding factors. here, using the 16s rrna and metagenomic sequencing methods, we characterized ...201931837260
vaccine protection against multidrug-resistant klebsiella pneumoniae in a nonhuman primate model of severe lower respiratory tract infection.klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. the relative high burden of asymptomatic colonization by k. pneumoniae is often compounded by multidrug resistance-a potential problem for individuals with significant comorbidities or other risk factors for infection. a carbapenem-resistant k. pneumoniae strain classified as multilocus sequence type 258 (st258) is widespread in the united states and is usually multidrug resistant. thus, treatment of st2 ...201931848292
insight into the origin of chikungunya virus in malaysian non-human primates via sequence analysis.chikungunya virus (chikv) is maintained in the sylvatic cycle in west africa and is transmitted by aedes mosquito species to monkeys. in 2006, four verified chikv isolates were obtained during a survey of arboviruses in monkeys (macaca fascicularis) in pahang state, peninsular malaysia. rna was extracted from the chikv isolates and used in reverse transcription polymerase chain reactions (rt-pcr) to amplify pcr fragments for sequencing. nucleic acid primers were designed to generate overlapping ...201931867449
adenovectors encoding rsv-f protein induce durable and mucosal immunity in macaques after two intramuscular administrations.respiratory syncytial virus (rsv) can cause severe respiratory disease, yet a licensed vaccine is not available. we determined the immunogenicity of two homologous and one heterologous intramuscular prime-boost vaccination regimens using replication-incompetent adenoviral vectors of human serotype 26 and 35 (ad26 and ad35), expressing a prototype antigen based on the wild-type fusion (f) protein of rsv strain a2 in adult, rsv-naive cynomolgus macaques. all regimens induced substantial, boostable ...201931885877
characterization of a novel simian sapelovirus isolated from a cynomolgus monkey using plc/prf/5 cells.we isolated a novel simian sapelovirus (ssv), cam13, from fecal specimen of a cynomolgus monkey by using plc/prf/5 cells. the ssv infection of the cells induced an extensive cytopathic effect. two types of virus particles with identical diameter (~32 nm) but different densities (1.348 g/cm3 and 1.295 g/cm3) were observed in the cell culture supernatants. the rna genome of cam13 possesses 8,155 nucleotides and a poly(a) tail, and it has a typical sapelovirus genome organization consisting of a 5' ...201931882888
a comprehensive strategy for screening for xenotransplantation-relevant viruses in a second isolated population of göttingen minipigs.xenotransplantation using pig tissues and organs is under development in order to alleviate the increasing shortage of human transplants. since xenotransplantation may be associated with the transmission of porcine microorganisms to the human recipient, the donor pigs should be carefully analyzed, especially for the presence of potentially zoonotic viruses. göttingen minipigs (gömp) are potential donors of islet cells for the treatment of diabetes. despite the fact that all animals produced at e ...201931905731
frameless stereotactic targeting of the cerebellar dentate nucleus in nonhuman primates: translatable model for the surgical delivery of gene therapy.stereotactic targeting techniques in nonhuman primate (nhp) models are often utilized in the preclinical investigation of new drug therapies with the goal of demonstrating accurate and reliable delivery of a therapy to the target tissue. however, targeting certain neuroanatomical structures can be challenging. the deep cerebellar nuclei, specifically the dentate nucleus, are potential stereotactic targets for the treatment of certain ataxias. currently, there are no detailed techniques describin ...201931914453
seroprevalence of viral infections in captive rhesus and cynomolgus macaques.macaques serve as important animal models for biomedical research. viral infection of macaques can compromise animal health as well as the results of biomedical research, and infected animals constitute an occupational health risk. therefore, monitoring macaque colonies for viral infection is an important task. we used a commercial chip-based assay to analyze sera of 231 macaques for the presence of antibody responses against nine animal and human viruses. we report high seroprevalence of cytome ...201932110713
multivariate profiling of african green monkey and rhesus macaque t lymphocytes.the complexity of immune responses limits the usefulness of univariate methods in answering complex immunology questions. to demonstrate the utility of a multivariate approach, we employ such approach to compare t cells of african green monkeys (agms) and rhesus macaques (rms). among the most prominent distinguishing features we found were lower cd3 and higher cd28 surface expression in agms compared to rms. after in vitro stimulation, a larger proportion of agm t cells secreted cytokines, espec ...201930886198
signature microrna expression profile is associated with lipid metabolism in african green monkey.non-human primates (nhps) are important models of medical research on obesity and cardiovascular diseases. as two of the most commonly used nhps, cynomolgus macaque (cm) and african green monkey (agm) own different capacities in lipid metabolism of which the mechanism is unknown. this study investigated the expression profiles of lipid metabolism-related micrornas (mirnas) in cm and agm and their possible roles in controlling lipid metabolism-related gene expression.201930819205
survey of drug oxidation activities in hepatic and intestinal microsomes of individual common marmosets, a new nonhuman primate animal model.common marmosets (callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. information for major drug-metabolizing cytochrome p450 (p450) enzymes is now available that supports the use of this primate species as an animal model for drug development. here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human p450 probe oxidations.201930280664
highly efficient induction of primate ips cells by combining rna transfection and chemical compounds.induced pluripotent stem (ips) cells hold great promise for regenerative medicine and the treatment of various diseases. before proceeding to clinical trials, it is important to test the efficacy and safety of ips cell-based treatments using experimental animals. the common marmoset is a new world monkey widely used in biomedical studies. however, efficient methods that could generate ips cells from a variety of cells have not been established. here, we report that marmoset cells are efficiently ...201931099158
revised recommendations for health monitoring of non-human primate colonies (2018): felasa working group report.the genetic and biological similarity between non-human primates and humans has ensured the continued use of primates in biomedical research where other species cannot be used. health-monitoring programmes for non-human primates provide an approach to monitor and control both endemic and incoming agents that may cause zoonotic and anthroponotic disease or interfere with research outcomes. in 1999 felasa recommendations were published which aimed to provide a harmonized approach to health monitor ...201931068070
high susceptibility, viral dynamics and persistence of south american zika virus in new world monkey species.south american zika virus (zikv) recently emerged as a novel human pathogen, linked with neurological disorders. however, comparative zikv infectivity studies in new world primates are lacking. two members of the callitrichidae family, common marmosets (callithrix jacchus) and red-bellied tamarins (saguinus labiatus), were highly susceptible to sub-cutaneous challenge with the puerto rico-origin zikvprvabc59 strain. both exhibited rapid, high, acute viraemia with early neuroinvasion (3 days) in ...201931601848
primary infection with dengue or zika virus does not affect the severity of heterologous secondary infection in macaques.zika virus (zikv) and dengue virus (denv) are genetically and antigenically related flaviviruses that now co-circulate in much of the tropical and subtropical world. the rapid emergence of zikv in the americas in 2015 and 2016, and its recent associations with guillain-barré syndrome, birth defects, and fetal loss have led to the hypothesis that denv infection induces cross-reactive antibodies that influence the severity of secondary zikv infections. it has also been proposed that pre-existing z ...201931369649
little evidence of zika virus infection in wild long-tailed macaques, peninsular malaysia.we tested a sample of 234 wild long-tailed macaques (macaca fascicularis) trapped in peninsular malaysia in 2009, 2010, and 2016 for zika virus rna and antibodies. none were positive for rna, and only 1.3% were seropositive for neutralizing antibodies. long-tailed macaques are unlikely to be reservoirs for zika virus in malaysia.201930666941
reference values of hematological and biochemical parameters in young-adult cynomolgus monkey (macaca fascicularis) and rhesus monkey (macaca mulatta) anesthetized with ketamine hydrochloride.nonhuman primate models are valuable in biomedical research. however, reference data for clinical pathology parameters in cynomolgus and rhesus monkeys are limited. in the present study, we established hematologic and biochemical reference intervals for healthy cynomolgus and rhesus monkeys anesthetized with ketamine hydrochloride. a total of 142 cynomolgus monkeys (28 males and 114 females) and 42 rhesus monkeys (22 males and 20 females) were selected and analyzed in order to examine reference ...201932257895
preclinical studies on the toxicology, pharmacokinetics and safety of k1-70tm a human monoclonal autoantibody to the tsh receptor with tsh antagonist activity.the human monoclonal autoantibody k1-70™ binds to the tsh receptor (tshr) with high affinity and blocks tshr cyclic amp stimulation by tsh and thyroid stimulating autoantibodies.201932257067
design and characterization of mp0250, a tri-specific anti-hgf/anti-vegf darpin® drug candidate.mp0250 is a multi-domain drug candidate currently being tested in clinical trials for the treatment of cancer. it comprises one anti-vascular endothelial growth factor-a (vegf-a), one anti-hepatocyte growth factor (hgf), and two anti-human serum albumin (hsa) darpin® domains within a single polypeptide chain. while there is first clinical validation of a single-domain darpin® drug candidate, little is known about darpin® drug candidates comprising multiple domains. here, we show that mp0250 can ...201929035637
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
disposition and metabolism of [14c]lemborexant, a novel dual orexin receptor antagonist, in rats and monkeys.the disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [14c]lemborexant in sprague-dawley rats (10 mg/kg) and cynomolgus monkeys (3 mg/kg). in both species, [14c]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83-1.8 h, and decreased with elimination half-life of 110 h. the radioactivity administered was ...201929806508
unprecedented symbiont eukaryote diversity is governed by internal trophic webs in a wild non-human primate.research on host-associated microbiomes has highlighted major divisions between the role of eukaryotes in free-living and symbiont systems. these trends call into question the relevance of macroecological processes to host-associated systems and the relative importance of parasitism, commensalism, and mutualism as evolutionary patterns across the domains of life. however, it is unclear as to whether these apparent differences reflect biological realities or methodologies in community characteriz ...201829803114
effects of acute and chronic methamphetamine administration on cynomolgus monkey hippocampus structure and cellular transcriptome.methamphetamine (ma), a psychostimulant abused worldwide, gives rise to neurotoxicity in the hippocampus, resulting in cognitive impairments and hippocampal volume reduction. the cellular and molecular mechanisms associated with hippocampal impairments due to ma remain unknown. the aim of this study was to investigate the effects of ma on structural alterations and gene expressions in the hippocampus. we analyzed the pattern of volumetric changes in the hippocampus using magnetic resonance imagi ...201829802913
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
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
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
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
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
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
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
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
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
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
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
polymyxin derivatives nab739 and nab815 are more effective than polymyxin b in murine escherichia coli pyelonephritis.extremely multiresistant strains of enterobacteriaceae, such as those of escherichia coli and klebsiella pneumoniae, are emerging and spreading at a worrisome speed. polymyxins (polymyxin b, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. we have previously developed polymyxin derivatives nab739 and nab815 that are better tolerated in cynomolgus monkeys than polymyxin b and are, in contra ...201829149329
cat-02-106, a site-specifically conjugated anti-cd22 antibody bearing an mdr1-resistant maytansine payload yields excellent efficacy and safety in preclinical models.hematologically derived tumors make up ∼10% of all newly diagnosed cancer cases in the united states. of these, the non-hodgkin lymphoma (nhl) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of ...201829142069
a safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques.plague has led to millions of deaths in history and outbreaks continue to the present day. the efficacy limitations and safety concerns of the existing killed whole cell and live-attenuated vaccines call for the development of new vaccines. in this study, we evaluated the immunogenicity and safety of a novel subunit plague vaccine, comprising native f1 antigen and recombinant v antigen. the cynomolgus macaques in low- and high-dose vaccine groups were vaccinated at weeks 0, 2, 4 and 6, at dose l ...201829134676
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
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