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feasibility and safety of systemic raav9-hnaglu delivery for treating mucopolysaccharidosis iiib: toxicology, biodistribution, and immunological assessments in primates.no treatment is currently available for mucopolysaccharidosis (mps) iiib, a neuropathic lysosomal storage disease caused by autosomal recessive defect in α-n-acetylglucosaminidase (naglu). in anticipation of a clinical gene therapy treatment for mps iiib in humans, we tested the raav9-cmv-hnaglu vector administration to cynomolgus monkeys (n=8) at 1e13 vg/kg or 2e13 vg/kg via intravenous injection. no adverse events or detectable toxicity occurred over a 6-month period. gene delivery resulted in ...201424720466
investigation of ocular events associated with taprenepag isopropyl, a topical ep2 agonist in development for treatment of glaucoma.taprenepag isopropyl is an ep2 receptor agonist that is in development for the treatment of glaucoma. iritis, photophobia, and increased corneal thickness observed in a phase 2 clinical trial with taprenepag isopropyl were not previously observed in topical ocular toxicity studies in rabbits and dogs. in vivo studies using cynomolgus monkeys and in vitro models were used to elucidate the mechanisms underlying these ocular events.201424720348
effects of maternal exposure to thiamazole on behavioral development in infant cynomolgus monkeys.thiamazole, an anti-hyperthyroidism agent, was administered orally to pregnant cynomolgus monkeys at doses of 2.0 and 3.5 mg/kg per day from gd 120 to gd 150 to investigate effects on behavioral development of their infants. swelling of the throat region due to enlargement of the thyroid glands was observed at birth in thiamazole-treated infants, and it returned to normal around postnatal day (pnd) 30. at necropsy of infants at 12 months of age, thyroidal weight in the thiamazole groups was incr ...201324712473
targeting of acute myeloid leukemia in vitro and in vivo with an anti-cd123 mab engineered for optimal adcc.acute myeloid leukemia (aml) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. despite this heterogeneity, overexpression of the interleukin (il)-3 receptor α-chain (il-3 rα/cd123) on both the blast and leukemic stem cell (lsc) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target cd123 in aml patients. we report here the development of csl362, a monoclonal antibody t ...201424705479
respiratory mechanics: comparison of beagle dogs, göttingen minipigs and cynomolgus monkeys.when the no observed adverse effect level (noael) is determined by respiratory safety pharmacology, follow-up studies are warranted and may include airway resistance and compliance. respiratory mechanics in commonly used large animal species (beagle dogs, cynomolgus monkeys, and göttingen minipigs) were compared.201424704341
atypical yersinia pseudotuberculosis serotype o:3 isolated from hunted wild boars in italy.atypical yersinia pseudotuberculosis serotype o:3 was isolated from rectal contents of two wild boars hunted in italy within a regional wildlife management program. no outbreak of yersiniosis was reported in this area in the same period and no lesions were found by the veterinarian at post-mortem inspection. nevertheless, after histological examination, granulomatous lesions were detected in submandibular lymph nodes of one of the two wild boars. microbiological and bio molecular characterizatio ...201424698132
dose-dependent exposure and metabolism of gne-892, a β-secretase inhibitor, in monkeys: contributions by p450, ao, and p-gp.(r)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'h-spiro[imidazole-4,1'-naphthalen]-5(1h)-one (gne-892) is an orally administered inhibitor of β-secretase 1 (β-site amyloid precursor protein cleaving enzyme 1, bace1) that was developed as an intervention therapy against alzheimer's disease. a clinical microdosing strategy was being considered for de-risking the potential pharmacokinetic liabilities of gne-892. we tested whether dose-proportionality was observed in cynomolgus mon ...201524696325
effect of mhc haplotype on immune response upon experimental shivsf162p4cy infection of mauritian cynomolgus macaques.little is known about the effects of major histocompatibility complex (mhc) haplotypes on immunity to primate lentiviruses involving both acquired and innate immune responses. we present statistical evidence of the influence of mhc polymorphism on antiviral immunity of mauritian cynomolgus macaques (mcm) following simian/human immunodeficiency virus shivsf162p4cy infection, involving the production of pro- and anti-inflammatory cytokines and α-defensins, which may modulate acquired immune respon ...201424695530
genetic diversity, haplotypes and allele groups of duffy binding protein (pkdbpαii) of plasmodium knowlesi clinical isolates from peninsular malaysia.the monkey malaria parasite plasmodium knowlesi is now recognized as the fifth species of plasmodium that can cause human malaria. like the region ii of the duffy binding protein of p. vivax (pvdbpii), the region ii of the p. knowlesi duffy binding protein (pkdbpαii) plays an essential role in the parasite's invasion into the host's erythrocyte. numerous polymorphism studies have been carried out on pvdbpii, but none has been reported on pkdbpαii. in this study, the genetic diversity, haplotyes ...201424693997
usefulness of optical coherence tomography to detect central serous chorioretinopathy in monkeys.many systemic drugs can induce ocular toxicity and several ocular side-effects have been identified in clinical studies. however, it is difficult to detect ocular toxicity in preclinical studies because of the lack of appropriate evaluation methods. optical coherence tomography (oct) is useful because it can provide real-time images throughout a study period, whereas histopathology only provides images of sacrificed animals. using oct alongside histopathology, attempts were made to find effectiv ...201524677158
mhc polymorphism in caribbean african green monkeys.african green monkeys (agm) are among the most widely used nonhuman primate models used in various fields of medical research. one species of agm that originated from west africa, chlorocebus sabaeus, was introduced three centuries ago in the caribbean islands. we present here a systematic study of the major histocompatibility complex (mhc) polymorphism of caribbean agm which is currently frequently used as an animal model. we studied 54 animals originated from barbados (n=25) or saint kitts (n= ...201424676686
preclinical characterization of amg 330, a cd3/cd33-bispecific t-cell-engaging antibody with potential for treatment of acute myelogenous leukemia.there is high demand for novel therapeutic options for patients with acute myelogenous leukemia (aml). one possible approach is the bispecific t-cell-engaging (bite, a registered trademark of amgen) antibody amg 330 with dual specificity for cd3 and the sialic acid-binding lectin cd33 (siglec-3), which is frequently expressed on the surface of aml blasts and leukemic stem cells. amg 330 binds with low nanomolar affinity to cd33 and cd3ε of both human and cynomolgus monkey origin. eleven human am ...201424674885
role of retinoic acid and fibroblast growth factor 2 in neural differentiation from cynomolgus monkey (macaca fascicularis) embryonic stem cells.retinoic acid is a widely used factor in both mouse and human embryonic stem cells. it suppresses differentiation to mesoderm and enhances differentiation to ectoderm. fibroblast growth factor 2 (fgf2) is widely used to induce differentiation to neurons in mice, yet in primates, including humans, it maintains embryonic stem cells in the undifferentiated state. in this study, we established an fgf2 low-dose-dependent embryonic stem cell line from cynomolgus monkeys and then analyzed neural differ ...201424674590
studies of the safety, pharmacokinetics and immunogenicity of repeated doses of intravenous staphylococcal protein a in cynomolgus monkeys.three good laboratory practice safety studies were performed with intravenous injections of highly purified staphylococcal protein a (spa) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. these studies established a no-observable-adverse-effect level (noael) for up to 12 weekly doses of spa, as well as toxicokinetic profiles for spa, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic re ...201424674306
development of new pcr primers by comparative genomics for the detection of helicobacter suis in gastric biopsy specimens.although the infection rate of helicobacter suis is significantly lower than that of helicobacter pylori, the h. suis infection is associated with a high rate of gastric mucosa-associated lymphoid tissue (malt) lymphoma. in addition, in vitro cultivation of h. suis remains difficult, and some h. suis-infected patients show negative results on the urea breath test (ubt).201424673878
surgical correction of an arteriovenous fistula in a ring-tailed lemur (lemur catta).a 10-y-old ovariohysterectomized ring-tailed lemur (lemur catta) was presented for exacerbation of respiratory signs. the lemur had a history of multiple examinations for various problems, including traumatic lacerations and recurrent perivulvar dermatitis. examination revealed abnormal lung sounds and a femoral arteriovenous fistula with a palpable thrill and auscultable bruit in the right inguinal area. a diagnosis of congestive heart failure was made on the basis of exam findings, radiography ...201424672831
early changes by (18)fluorodeoxyglucose positron emission tomography coregistered with computed tomography predict outcome after mycobacterium tuberculosis infection in cynomolgus macaques.cynomolgus macaques infected with low-dose mycobacterium tuberculosis develop both active tuberculosis and latent infection similar to those of humans, providing an opportunity to study the clinically silent early events in infection. (18)fluorodeoxyglucose radiotracer with positron emission tomography coregistered with computed tomography (fdg pet/ct) provides a noninvasive method to measure disease progression. we sought to determine temporal patterns of granuloma evolution that distinguished ...201424664509
strontium does not affect the intrinsic bone quality at tissue and bsu levels in iliac samples from macaca fascicularis monkeys.our purpose was to evaluate the impact of strontium ranelate (srran) on bone mineral quality at both tissue and bone structural unit (bsu) levels. thirty iliac bone samples (dehydrated then embedded) were taken from monkeys who received 0 (controls), 200, 500 or 1250 mg/kg/day of srran for 52 weeks and were sacrificed either at the end of administration (treated animals, n=16) or 10 weeks later (reverse animals, n=14). degree of mineralization (dmb), heterogeneity index of mineralization (hi), v ...201424662618
mate-guarding constrains feeding activity but not energetic status of wild male long-tailed macaques (macaca fascicularis).mate-guarding is an important determinant of male reproductive success in a number of species. little is known however about the constraints of this behaviour, e.g. the associated energetic costs. we investigated these costs in long-tailed macaques where alpha males mate guard females to a lesser extent than predicted by the priority of access model. the study was carried out during two mating periods on three wild groups living in the gunung leuser national park, indonesia. we combined behaviou ...201424659851
extending serum half-life of albumin by engineering neonatal fc receptor (fcrn) binding.a major challenge for the therapeutic use of many peptides and proteins is their short circulatory half-life. albumin has an extended serum half-life of 3 weeks because of its size and fcrn-mediated recycling that prevents intracellular degradation, properties shared with igg antibodies. engineering the strictly ph-dependent igg-fcrn interaction is known to extend igg half-life. however, this principle has not been extensively explored for albumin. we have engineered human albumin by introducing ...201424652290
age-related pharmacokinetic changes of acetaminophen, antipyrine, diazepam, diphenhydramine, and ofloxacin in male cynomolgus monkeys and beagle dogs.1. the pharmacokinetics of acetaminophen (marker of gastric emptying), antipyrine (marker of hepatic metabolic activity and total body water), diazepam (lipophilic and highly distributed), diphenhydramine (hepatic blood flow-limited and alpha-1 acid glycoprotein bound) and ofloxacin (renally eliminated) were evaluated in cynomolgus monkeys (3-18 years old) and beagle dogs (2-11 years old) as models in elderly persons. 2. gastric ph fluctuated with aging in monkeys and dogs. the concentration of ...201424650193
whole-genome sequencing of tibetan macaque (macaca thibetana) provides new insight into the macaque evolutionary history.macaques are the most widely distributed nonhuman primates and used as animal models in biomedical research. the availability of full-genome sequences from them would be essential to both biomedical and primate evolutionary studies. previous studies have reported whole-genome sequences from rhesus macaque (macaca mulatta) and cynomolgus macaque (m. fascicularis, ce), both of which belong to the fascicularis group. here, we present a 37-fold coverage genome sequence of the tibetan macaque (m. thi ...201424648498
withdrawal assessment following subchronic oral ketamine administration in cynomolgus macaques.recently there is increased regulatory interest in the assessment of physical dependence and withdrawal as part of the safety assessment for novel therapeutic entities. choosing appropriate and sensitive parameters to detect withdrawal syndromes, and relevant positive control comparator drugs that can be administered in the same manner as the test agent, are critical study design elements. pilot studies to determine the effects of oral ketamine in cynomolgus monkeys during, and following cessati ...201424648280
neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains.the neuroprotective effects of dexmedetomidine have been reported by many investigators; however its underlying mechanism to reduce neuronal injury during a prolonged anesthesia remains unclear. in this study, we investigated the neurotoxic effects of dexmedetomidine in fetal monkey brains. in the present study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys. twenty pregnant monkeys at appr ...201424646706
seeing the experimenter influences the response to pointing cues in long-tailed macaques.methodological variations in experimental conditions can strongly influence animals' performances in cognitive tests. specifically, the procedure of the so-called object-choice task has been controversially discussed; here, a human experimenter indicates the location of hidden food by pointing or gazing at one of two or more containers. whereas dogs usually succeed, results for nonhuman primates are ambiguous. in the standard version of the task the majority of subjects do not respond appropriat ...201424646501
recombinant human tripeptidyl peptidase-1 infusion to the monkey cns: safety, pharmacokinetics, and distribution.cln2 disease is caused by deficiency in tripeptidyl peptidase-1 (tpp1), leading to neurodegeneration and death. the safety, pharmacokinetics (pk), and cns distribution of recombinant human tpp1 (rhtpp1) were characterized following a single intracerebroventricular (icv) or intrathecal-lumbar (it-l) infusion to cynomolgus monkeys. animals received 0, 5, 14, or 20mg rhtpp1, icv, or 14 mg it-l, in artificial cerebrospinal fluid (acsf) vehicle. plasma and csf were collected for pk analysis. necropsi ...201424642058
perfusion method for intra-bone marrow collection and stem cell transplantation: a critical review.a bone marrow transplant is a procedure to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. bone marrow is the soft, fatty tissue inside our bones. bone marrow transplantation (bmt) is a powerful strategy for the treatment of leukemia, aplastic anemia, congenital immunodeficiency and autoimmune diseases. in humans, bone marrow cells (bmcs) have usually been collected by multiple bone marrow aspirations from the iliac crest. we have established a new "perfusion" metho ...201424641258
the adult macaque spinal cord central canal zone contains proliferative cells and closely resembles the human.the persistence of proliferative cells, which could correspond to progenitor populations or potential cells of origin for tumors, has been extensively studied in the adult mammalian forebrain, including human and nonhuman primates. proliferating cells have been found along the entire ventricular system, including around the central canal, of rodents, but little is known about the primate spinal cord. here we describe the central canal cellular composition of the old world primate macaca fascicul ...201424638933
the effects of bazedoxifene in the ovariectomized aged cynomolgus monkey.bazedoxifene (bza) is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. this preclinical study evaluated the efficacy and safety of bza in preventing ovariectomy (ovx)-induced bone loss in aged cynomolgus monkeys. animals (18 per group) underwent ovx and were administered bza (0.2, 0.5, 1, 5, or 25 mg/kg/day) or vehicle, or were sham-operated and administered vehicle, by daily oral gavage for 18 months. biochemi ...201524633538
poor memory performance in aged cynomolgus monkeys with hippocampal atrophy, depletion of amyloid beta 1-42 and accumulation of tau proteins in cerebrospinal fluid.due to their similarities in behavior and disease pathology to humans, non-human primate models are desirable to complement small animals as models for the study of age-related dementia.201524632970
primate ips cells as tools for evolutionary analyses.induced pluripotent stem cells (ipscs) are regarded as a central tool to understand human biology in health and disease. similarly, ipscs from non-human primates should be a central tool to understand human evolution, in particular for assessing the conservation of regulatory networks in ipsc models. here, we have generated human, gorilla, bonobo and cynomolgus monkey ipscs and assess their usefulness in such a framework. we show that these cells are well comparable in their differentiation pote ...201424631741
induction of protective immunity against h1n1 influenza a(h1n1)pdm09 with spray-dried and electron-beam sterilised vaccines in non-human primates.currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. to overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza a vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. we evaluated the efficacy of novel antigen stabilizing and protecting solutions (sps) to protect influenza a(h1n1) ...201424631078
human non-pigmented ciliary epithelium bradykinin b2-receptors: receptor localization, pharmacological characterization of intracellular ca(2+) mobilization, and prostaglandin secretion.to characterize the bradykinin (bk) receptor system in human non-pigmented ciliary epithelium (npce) using immunohistochemistry and functional cell-based techniques.201424624903
effect of soy isoflavones on thyroid hormones in intact and ovariectomized cynomolgus monkeys (macaca fascicularis).soy isoflavones are commonly used to alleviate menopause-related symptoms. postmenopausal women are at increased risk for hypothyroidism, and there are concerns that isoflavones may be detrimental to thyroid health. the aim of this study was to examine the effects of soy protein and isoflavones on thyroid function and the relationship between thyroid function and ovarian function.201424618766
hypothalamic kiss1 expression, gonadotrophin-releasing hormone and neurotransmitter innervation vary with stress and sensitivity in macaques.the present study examined the effect of short-term psychosocial and metabolic stress in a monkey model of stress-induced amenorrhaea on the hypothalamic-pituitary-gonadal axis. kiss1 expression was determined by in situ hybridisation in the infundibular arcuate nucleus. downstream of kiss1, gonadotrophin-releasing hormone (gnrh) axons in lateral areas rostral to the infundibular recess, serum luteinising hormone (lh) and serum oestradiol were measured by immunohistochemistry and radioimmunoassa ...201424617839
characterization, biomarkers, and reversibility of a monoclonal antibody-induced immune complex disease in cynomolgus monkeys (macaca fascicularis).two 6-month repeat-dose toxicity studies in cynomolgus monkeys illustrated immune complex-mediated adverse findings in individual monkeys and identified parameters that potentially signal the onset of immune complex-mediated reactions following administration of rn6g, a monoclonal antibody (mab). in the first study, 3 monkeys exhibited nondose-dependent severe clinical signs accompanied by decreased erythrocytes with increased reticulocytes, neutrophilia, monocytosis, thrombocytopenia, coagulopa ...201424616262
trime7-cypa, an alternative splicing isoform of trimcyp in rhesus macaque, negatively modulates trim5α activity.the existence of innate, host-specific restriction factors is a major obstacle to the development of nonhuman primate models for aids studies, and trim5α is one of the most important of these restriction factors. in recent years, a trim5 chimeric gene that was retrotransposed by a cyclophilin a (cypa) cdna was identified in certain macaque species. the trim5α-cypa fusion protein, trimcyp, which was expressed in these monkeys, had lost its restriction ability toward hiv-1. we previously found tha ...201424613845
uterus allotransplantation in cynomolgus macaque: a preliminary experience with non-human primate models.uterine transplantation (utx) is a potential option for child-bearing in women with uterine infertility. recovery of uterine function after allogeneic utx in non-human primates has not been reported. the objective of this study is to establish the functional uterine transplant model in non-human primates.201424612366
the human glp-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates.increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. novo nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (glp-1) receptor agonists. in a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. such dose-relate ...201424608440
comparative nonclinical assessments of the proposed biosimilar pf-05280586 and rituximab (mabthera®).comparative nonclinical studies were conducted with the proposed biosimilar pf-05280586 and rituximab-eu (mabthera®). in side-by-side analyses, peptide maps and complement-dependent cytotoxicity assay results were similar. sexually-mature cynomolgus monkeys were administered pf-05280586 or rituximab-eu as a single dose of 0, 2, 10, or 20 mg/kg on day 1 and observed for 92 days (single-dose study) or as 5 weekly injections of 0 or 20 mg/kg and necropsied on day 30, the day after the 5th dose, or ...201424604381
depressive-like behavioral profiles in captive-bred single- and socially-housed rhesus and cynomolgus macaques: a species comparison.to unravel the causes of major depressive disorder (mdd), the third leading cause of disease burden around the world, ethological animal models have recently been proposed. our previous studies highlighted a depressive-like profile among single- and socially-housed farm-bred cynomolgus macaques. although phylogenetically close, cynomolgus and rhesus macaques, the two most commonly used macaque species in biomedical research, differ on several levels such as patterns of aggression, reconciliation ...201424600363
the mutual influences between depressed macaca fascicularis mothers and their infants.to assess the influence of infant rearing on the behavior of depressed adult female macaca fascicularis and the influence of depressed infant-rearing adult female macaca fascicularis on their infants in a free enclosure environment.201424599092
4β-hydroxycholesterol as an endogenous biomarker of cyp3a activity in cynomolgus monkeys.it has been proposed that in humans 4β-hydroxycholesterol is formed mainly by cyp3a-catalyzed metabolism of cholesterol and thus may serve as an endogenous marker for cyp3a activity. the cynomolgus monkey is widely used as one of the nonrodent preclinical safety species in pharmaceutical research. in the current study, the potential application of 4β-hydroxycholesterol as an endogenous biomarker of cyp3a in response to drug treatment was evaluated in cynomolgus monkeys. following multiple oral a ...201424595680
immunochemical detection of cytochrome p450 enzymes in small intestine microsomes of male and female untreated juvenile cynomolgus monkeys.the expression of small intestinal cytochromes p450 (p450s) has not been systematically measured in cynomolgus monkeys, which are widely used in preclinical drug studies to predict pharmacokinetics and toxicity in humans: therefore, p450 content of small intestine was quantified in 35 cynomolgus monkeys by immunoblotting using 11 selective antibodies. cyp2d, cyp2j2, cyp3a4 and cyp3a5 were detected in all 35 animals, while cyp1a and cyp2c9/19 were detected in 31 and 17 animals, respectively. cyp2 ...201424593267
protection against filovirus diseases by a novel broad-spectrum nucleoside analogue bcx4430.filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). licensed therapeutic or vaccine products are not available to treat filovirus diseases. candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. here we show t ...201424590073
what is your diagnosis? fecal smear stained with lugol's solution and giemsa from a cynomolgus macaque (macaca fascicularis) presenting with liquid diarrhea. 201424588697
anesthetic effect of a combination of medetomidine-midazolam-butorphanol in cynomolgus monkeys (macaca fascicularis).the anesthetic effect of a combination of medetomidine, midazolam and butorphanol (me-mi-bu) was evaluated in healthy cynomolgus monkeys. the me-mi-bu combination was intramuscularly administered as follows: dose 1, me 0.015 mg/kg-mi 0.1 mg/kg-bu 0.15 mg/kg; dose 2, me 0.02 mg/kg-mi 0.15 mg/kg-bu 0.2 mg/kg; and dose 3, me 0.04 mg/kg-mi 0.3 mg/kg-bu 0.4 mg/kg. the combination rapidly induced immobilization, and lateral recumbency was reached within 15 min. the duration of anesthesia for each dose ...201424584083
generation of a universal cd4 memory t cell recall peptide effective in humans, mice and non-human primates.cd4t cells play a key role in humoral immunity by providing help to b cells, enabling effective antibody class switching and affinity maturation. some vaccines may generate a poor response due to a lack of effective mhc class ii epitopes, resulting in ineffective helper t cell activation and recall and consequently poor humoral immunity. it may be beneficial to provide a cd4t cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen. such a t cell helper peptide ...201424583006
age-associated changes of cerebrospinal fluid amyloid-β and tau in cynomolgus monkeys.nonhuman primates (nhps) are useful for the study of age-associated changes in the brain as a model that is biologically closely related to humans. for example, with age, all nhps analyzed to date, develop β-amyloid (aβ) plaques as seen in humans. nevertheless, it is still unclear if nhps have human-like age-associated changes in aβ and tau protein in cerebrospinal fluid. the present study was an attempt to specifically address these issues. cerebrospinal fluid levels of aβ and phosphorylated ta ...201424581480
study of mhc class ii region polymorphism in the filipino cynomolgus macaque population.the cynomolgus macaque (macaca fascicularis) is currently used as an animal model in various fields of immunology especially in the development of innovative vaccines for the prevention and treatment of infectious diseases. the polymorphism of the major histocompatibility complex (mhc) influences the development of adaptive immune responses and it is crucial to characterize the polymorphism of cynomolgus mhc genes. we present here a systematic study of the mhc class ii haplotypes in the filipino ...201424569954
pharmacokinetics of an anti-tfpi monoclonal antibody (concizumab) blocking the tfpi interaction with the active site of fxa in cynomolgus monkeys after iv and sc administration.concizumab (mab 2021) is a monoclonal igg4 antibody (mab) that binds to the kunitz-type protease inhibitor (kpi) 2 domain of tfpi thereby blocking the interaction of this domain with the active site of fxa. the objective of the present study was to characterize the pharmacokinetics of concizumab in cynomolgus monkeys after intravenous (iv) and subcutaneous (sc) administration.201424568891
correlation between presence of trypanosoma cruzi dna in heart tissue of baboons and cynomolgus monkeys, and lymphocytic myocarditis.trypanosoma cruzi, the causative agent of chagas' disease, preferentially infects cardiac and digestive tissues. baboons living in texas (papio hamadryas) and cynomolgus monkeys (macaca fascicularis) have been reported to be infected naturally with t. cruzi. in this study, we retrospectively reviewed cases of animals that were diagnosed with lymphocytic myocarditis and used a polymerase chain reaction (pcr)-based method (s36/s35 primer set) to amplify t. cruzi dna from archived frozen and formal ...201424567317
dynein dysfunction disrupts β-amyloid clearance in astrocytes through endocytic disturbances.we showed previously that aging attenuates the interaction between dynein-dynactin complexes in cynomolgus monkey brain and that dynein dysfunction reproduces age-dependent endocytic disturbances, resulting in intracellular β-amyloid (aβ) accumulation, synaptic vesicle transport deficits, and neuritic swelling. it remains unclear whether such endocytic disturbances also occur in glial cells. here, we show that endocytic pathology, such as intracellular accumulation of enlarged endosomes, occurs ...201424556945
differences in aerosolization of rift valley fever virus resulting from choice of inhalation exposure chamber: implications for animal challenge studies.the aerosol characteristics of rift valley fever virus (rvfv) were evaluated to achieve reproducible infection of experimental animals with aerosolized rvfv suitable for animal efficacy studies. spray factor (sf), the ratio between the concentrations of the aerosolized agent to the agent in the aerosol generator, is used to compare performance differences between aerosol exposures. sf indicates the efficiency of the aerosolization process; a higher sf means a lower nebulizer concentration is nee ...201424532259
the eosinophil surface receptor epidermal growth factor-like module containing mucin-like hormone receptor 1 (emr1): a novel therapeutic target for eosinophilic disorders.although several novel agents are currently in clinical trials for eosinophilic disorders, none has demonstrated efficacy in reducing blood and tissue eosinophilia in all subjects. additional approaches are clearly needed.201424530099
talen-mediated gene mutagenesis in rhesus and cynomolgus monkeys.recent advances in gene editing technology have introduced the potential for application of mutagenesis approaches in nonhuman primates to model human development and disease. here we report successful talen-mediated mutagenesis of an x-linked, rett syndrome (rtt) gene, methyl-cpg binding protein 2 (mecp2), in both rhesus and cynomolgus monkeys. microinjection of mecp2-targeting talen plasmids into rhesus and cynomolgus zygotes leads to effective gene editing of mecp2 with no detected off-target ...201424529597
granulomatous nephritis consistent with malakoplakia in a cynomolgus monkey.malakoplakia is a rare form of chronic granulomatous inflammation in mammals, and usually affects the urinary tract in humans. in this report, we present a case of granulomatous nephritis consistent with malakoplakia in a 4-year-old male cynomolgus monkey. gross examination showed that the kidney was markedly enlarged and adhered to the surrounding organs. histology showed that there was diffuse interstitial infiltration of histiocytes with abundant foamy eosinophilic cytoplasm resembling von ha ...201324526815
effects of equol on gene expression in female cynomolgus monkey iliac arteries.to examine effects of equol, the soy phytoestrogen metabolite, on gene expression in the monkey iliac artery.201424525253
allogeneic lymphocyte transfer in mhc-identical siblings and mhc-identical unrelated mauritian cynomolgus macaques.the detailed study of immune effector mechanisms in primate models of infectious disease has been limited by the inability to adoptively transfer lymphocytes from vaccinated animals into naïve immunocompetent recipients. recent advances in our understanding of the major histocompatibility complex diversity of mauritian cynomolgus macaques enabled the establishment of a breeding program to generate major histocompatibility complex (mhc)-identical animals. the current study utilised this resource ...201424523927
implementation of a simplified method of islet isolation for allogeneic islet transplantation in cynomolgus monkeys.the present study describes a simple and cost-effective islet isolation procedure. using this method, allogeneic islets reverse diabetes in cynomolgus monkeys.201424518500
generation and activity of a humanized monoclonal antibody that selectively neutralizes the epidermal growth factor receptor ligands transforming growth factor-α and epiregulin.at least seven distinct epidermal growth factor (egf) ligands bind to and activate the egf receptor (egfr). this activation plays an important role in the embryo and in the maintenance of adult tissues. importantly, pharmacologic egfr inhibition also plays a critical role in the pathophysiology of diverse disease states, especially cancer. the roles of specific egfr ligands are poorly defined in these disease states. accumulating evidence suggests a role for transforming growth factor α (tgfα) i ...201424518034
lip salivary-gland hamartoma in a cynomolgus macaque (macaca fascicularis).an incidental, asymptomatic, well-circumscribed, solitary, submucosal nodular mass was detected on the mucosal surface of the inner lower lip in a female cynomolgus macaque (age, approximately 2.4 y) during a juvenile chronic toxicology study. grossly, the nodule was soft with brown to tan discoloration and measured approximately 4 mm in diameter. microscopically, the nodule was covered by normal stratified squamous epithelium and composed of well-circumscribed irregular lobules containing hyper ...201424512964
application of canaloplasty in glaucoma gene therapy: where are we?schlemm's canal (sc) inner wall is adjacent to the juxtacanalicular trabecular meshwork (tm) over their entire circumference. we seek to transfer reporter and therapeutic genes to these outflow-modulating tissues via canaloplasty surgery in live monkeys.201724512297
persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures.malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of plasmodium vivax and plasmodium ovale, hinder global efforts to control and eliminate malaria. as primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally macaca rhesus and macac ...201424509527
mandibular reconstruction with a bioactive-coated cementless ti6al4v modular endoprosthesis in macaca fascicularis.the titanium mandibular modular endoprosthesis fixed with polymethylmethacrylate cement in the medullary space of the mandible has been introduced in previous studies. however, the internal parts of these devices have been found to be prone to loosening and wound dehiscence. the current study introduces a newly designed bioactive-coated cementless modular mandibular endoprosthesis, which was used for reconstruction in macaca fascicularis. the devices were coated with hydroxyapatite (ha) and hydr ...201424507820
a single-cell and feeder-free culture system for monkey embryonic stem cells.primate pluripotent stem cells (pscs), including embryonic stem cells (escs) and induced pluripotent stem cells (ipscs), hold great potential for research and application in regenerative medicine and drug discovery. to maximize primate psc potential, a practical system is required for generating desired functional cells and reproducible differentiation techniques. much progress regarding their culture systems has been reported to date; however, better methods would still be required for their pr ...201424505480
evidence for a role for interleukin-17, th17 cells and iron homeostasis in protective immunity against tuberculosis in cynomolgus macaques.tuberculosis (tb) remains a major global public health problem. the only vaccine, bcg, gives variable protection, especially in adults, so several new vaccines are in clinical trials. there are no correlates of protective immunity to tb; therefore vaccines progress through lengthy and expensive pre-clinical assessments and human trials. correlates of protection could act as early end-points during clinical trials, accelerating vaccine development and reducing costs. a genome-wide microarray was ...201424505407
neutrophil isolation from nonhuman species.the development of new advances in the understanding of neutrophil biochemistry requires effective procedures for isolating purified neutrophil populations. although methods for human neutrophil isolation are now standard, similar procedures for isolating neutrophils from many of the nonhuman species used to model human diseases are not as well developed. since neutrophils are reactive cells, the method of isolation is extremely important to avoid isolation technique-induced alterations in cell ...201424504944
novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action.the design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. these molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [leu(14)]exenatide-abd is an 88 residue peptide amide incorporating an albumin binding domain (abd) scaffold. [leu(14)]exenatide-abp is a 53 residue peptide incorporating a short albumin binding peptide (abp). [leu(14)]exenat ...201424503632
measles vaccination of nonhuman primates provides partial protection against infection with canine distemper virus.measles virus (mv) is being considered for global eradication, which would likely reduce compliance with mv vaccination. as a result, children will grow up without mv-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (cdv). natural cdv infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that cdv can cause disease in primates. we studied the virulence and tropi ...201424501402
tamoxifen-dna adduct formation in monkey and human reproductive organs.the estrogen analog tamoxifen (tam), used for adjuvant therapy of breast cancer, induces endometrial and uterine tumors in breast cancer patients. proliferation stimulus of the uterine endometrium is likely involved in tumor induction, but genotoxicity may also play a role. formation of tam-dna adducts in human tissues has been reported but remains controversial. to address this issue, we examined tam-dna adducts in uteri from two species of monkeys, erythrocebus patas (patas) and macaca fascicu ...201424501327
cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet.we sought to elucidate the impact of diet, cyanide or cyanate exposure on mammalian cyanide detoxification capabilities (cdc). male rats (~8 weeks old) (n=52) on 75% sulfur amino acid (saa)-deficient diet were treated with nacn (2.5mg/kg bw) or naocn (50mg/kg bw) for 6 weeks. macaca fascicularis monkeys (~12 years old) (n=12) were exclusively fed cassava for 5 weeks. cdc was assessed in plasma, or spinal cord, or brain. in rats, nacn induced seizures under saa-restricted diet whereas naocn induc ...201424500607
plasmacytoid dendritic cell dynamics tune interferon-alfa production in siv-infected cynomolgus macaques.ifn-i production is a characteristic of hiv/siv primary infections. however, acute ifn-i plasma concentrations rapidly decline thereafter. plasmacytoid dendritic cells (pdc) are key players in this production but primary infection is associated with decreased responsiveness of pdc to tlr 7 and 9 triggering. ifnα production during primary siv infection contrasts with increased pdc death, renewal and dysfunction. we investigated the contribution of pdc dynamics to both acute ifnα production and th ...201424497833
bayesian analysis of perfusion-weighted imaging to predict infarct volume: comparison with singular value decomposition.we compared the performances of a bayesian estimation method and oscillation index singular value decomposition (osvd) deconvolution for predicting final infarction using data previously obtained from 10 cynomolgus monkeys with permanent unilateral middle cerebral artery (mca) occlusion.201424492744
effects of altered fcγr binding on antibody pharmacokinetics in cynomolgus monkeys.antibody interactions with fcγ receptors (fcγrs), like fcγriiia, play a critical role in mediating antibody effector functions and thereby contribute significantly to the biologic and therapeutic activity of antibodies. over the past decade, considerable work has been directed towards production of antibodies with altered binding affinity to fcγrs and evaluation of how the alterations modulate their therapeutic activity. this has been achieved by altering glycosylation status at n297 or by engin ...201524492343
development of neutralizing scfv-fc against botulinum neurotoxin a light chain from a macaque immune library.botulinum toxins (bonts) are among the most toxic substances on earth, with serotype a toxin being the most toxic substance known. they are responsible for human botulism, a disease characterized by flaccid muscle paralysis that occurs naturally through food poisoning or the colonization of the gastrointestinal tract by bont-producing clostridia. bont has been classified as a category a agent by the centers for disease control, and it is one of six agents with the highest potential risk of use a ...201424492304
comparative reactivity of human ige to cynomolgus monkey and human effector cells and effects on ige effector cell potency.due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. ige therapeutics in development depend upon engagement with the fcεri and fcεrii receptors on immune effector cells for their function. only limited knowledge of the primate ige immune system is available to inform the choice of models for mechanistic and safety evaluations.201724492303
argx-110, a highly potent antibody targeting cd70, eliminates tumors via both enhanced adcc and immune checkpoint blockade.overexpression of cd70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. here, we describe argx-110, a defucosylated igg1 monoclonal antibody (mab) that selectively targets and neutralizes cd70, the ligand of cd27.   argx-110 was generated by immunization of outbred llamas. the antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assa ...201724492296
preclinical evaluation of 89zr-labeled anti-cd44 monoclonal antibody rg7356 in mice and cynomolgus monkeys: prelude to phase 1 clinical studies.rg7356 is a humanized antibody targeting the constant region of cd44. rg7356 was radiolabeled with (89)zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study of its biodistribution and the role of cd44 expression on rg7356 uptake.   studies with (89)zr-rg7356 were performed in mice bearing tumor xenografts that differ in the level of cd44 expression (cd44(+) or cd44(-)) and rg7356 responsiveness (resp or non-resp): mda-mb-231 (cd44(+), resp), ...201624492295
discordant biological and toxicological species responses to tlr3 activation.toll-like receptors (tlrs) are highly conserved type 1 membrane proteins that initiate a multiplicity of transient gene transcriptions, resulting in innate and adaptive immune responses. these essential immune responses are triggered by common tlr pattern recognition receptors of microbial products expressed through the cytoplasmic carboxy-terminal toll/il-1 domain. toll/il-1 adapter protein cascades are induced by an activated toll/il-1 to induce transient transcription responses. all tlrs, wit ...201424486326
generation of gene-modified cynomolgus monkey via cas9/rna-mediated gene targeting in one-cell embryos.monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. here, we first applied the crispr/cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. by coinjection of cas9 mrna and sgrnas into one-cell-stage embryos, we succes ...201424486104
development and three-dimensional morphology of the zygomaticotemporal suture in primate skulls.cranial sutures are an essential part of the growing skull, allowing bones to increase in size during growth, with their morphology widely believed to be dictated by the forces and displacements that they experience. the zygomaticotemporal suture in primates is located in the relatively weak zygomatic arch, and externally it appears a very simple connection. however, large forces are almost certainly transmitted across this suture, suggesting that it requires some level of stability while also a ...201424481002
functional characterization of cynomolgus monkey udp-glucuronosyltransferase 1a9.udp-glucuronosyltransferase 1a9 (ugt1a9) contributes to the glucuronidation of numerous drugs. cynomolgus monkeys are regarded as experimental animals similar to humans in studies on safety evaluation and biotransformation for drug development. in this study, the similarities and differences in the enzymatic properties of ugt1a9 between humans and cynomolgus monkeys were precisely identified. ugt1a9 cdnas of humans (humugt1a9) and cynomolgus monkeys (monugt1a9) were cloned, and the corresponding ...201424470170
effect of depression and sertraline treatment on cardiac function in female nonhuman primates.depression is a proposed risk factor for heart failure based largely on epidemiological data; few experimental data addressing this hypothesis are available.201424470133
divergence and diversity of ulbp2 genes in rhesus and cynomolgus macaques.non-human primates such as rhesus macaque and cynomolgus macaque are important animals for medical research fields and they are classified as old world monkey, in which genome structure is characterized by gene duplications. in the present study, we investigated polymorphisms in two genes for ulbp2 molecules that are ligands for nkg2d. a total of 15 and 11 ulbp2.1 alleles and 11 and 10 ulbp2.2 alleles were identified in rhesus macaques and cynomolgus macaques, respectively. nucleotide sequences ...201424469065
development of a rectal sexually transmitted infection--hiv coinfection model utilizing chlamydia trachomatis and shivsf162p3.rectal sexually transmitted infections (stis) may increase hiv susceptibility in men who have sex with men (msm), and chlamydia trachomatis is prevalent among hiv-positive msm. to study stis and hiv infection in msm, we first evaluated whether cynomolgus macaques can sustain both c. trachomatis and shivsf162p3 infections.201424460742
different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes.since there is evidence that the fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept on monkey eyes were investigated.201424457369
non-clinical pharmacokinetic/pharmacodynamic and early clinical studies supporting development of a novel subcutaneous formulation for the monoclonal antibody rituximab.this overview article describes the non-clinical pharmacology, pharmacokinetic and clinical dose-finding programs supporting the development of a novel subcutaneous formulation for rituximab, a monoclonal antibody that selectively targets cd20-positive b-lymphocytes. the subcutaneous route of administration is expected to improve convenience for patients and to reduce healthcare professional resource use compared with conventional intravenous infusion. various non-clinical and clinical studies w ...201424452524
vascular origin of vildagliptin-induced skin effects in cynomolgus monkeys: pathomechanistic role of peripheral sympathetic system and neuropeptide y.the purpose of this article is to characterize skin lesions in cynomolgus monkeys following vildagliptin (dipeptidyl peptidase-4 inhibitor) treatment. oral vildagliptin administration caused dose-dependent and reversible blister formation, peeling and flaking skin, erosions, ulcerations, scabs, and sores involving the extremities at ≥5 mg/kg/day and necrosis of the tail and the pinnae at ≥80 mg/kg/day after 3 weeks of treatment. at the affected sites, the media and the endothelium of dermal arte ...201424448599
pet imaging of ischemia-induced impairment of mitochondrial complex i function in monkey brain.to assess the capability of (18)f-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2h-pyridazin-3-one ((18)f-bcpp-ef), a novel positron emission tomography (pet) probe for mitochondrial complex i (mc-i) activity, as a specific marker of ischemia-induced neuronal death without being disturbed by inflammation, translational research was conducted using an animal pet in ischemic brains of cynomolgus monkeys (macaca fascicularis). focal ischemia was induced by the right mi ...201424447952
plasma antibody profiles in non-human primate tuberculosis.tuberculosis (tb) in non-human primates (nhps) is highly contagious, requiring efficient identification of animals infected with mycobacterium tuberculosis. tuberculin skin test is usually used but lacks desirable sensitivity/specificity and efficiency.201424446897
altered expression of glial and synaptic markers in the anterior hippocampus of behaviorally depressed female monkeys.the anterior hippocampus is associated with emotional functioning and hippocampal volume is reduced in depression. we reported reduced neuropil volume and number of glia in the dentate gyrus (dg) and cornu ammonis (ca)1 of the anterior hippocampus in behaviorally depressed adult female cynomolgus macaques. to determine the biochemical correlates of morphometric and behavioral differences between behaviorally depressed and nondepressed adult female monkeys, glial and synaptic transcripts and prot ...201424440617
discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel gpr119 agonists.we describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of gpr119. previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) gpr119 making evaluation of the target in preclinical models difficult. replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline c-n bond and gave compounds with increased effica ...201424440299
a large-scale snp-based genomic admixture analysis of the captive rhesus macaque colony at the california national primate research center.some breeding facilities in the united states have crossbred chinese and indian rhesus macaque (macaca mulatta) founders either purposefully or inadvertently. genetic variation that reflects geographic origins among research subjects has the potential to influence experimental outcomes. the use of animals from different geographic regions, their hybrids, and animals of varying degrees of kinship in an experiment can obscure treatment effects under study because high interanimal genetic variance ...201224436199
digoxin-induced reversible dysfunction of the cone photoreceptors in monkeys.to investigate functional alteration of the retina induced by digoxin in monkeys.201424436189
species difference in glucuronidation formation kinetics with a selective mtor inhibitor.the mammalian target of rapamycin (mtor) is a protein kinase that shows key involvement in age-related disease and promises to be a target for treatment of cancer. in the present study, the elimination of potent atp-competitive mtor inhibitor 3-(6-amino-2-methylpyrimidin-4-yl)-n-(1h-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine (compound 1) is studied in bile duct-cannulated rats, and the metabolism of compound 1 in liver microsomes is compared across species. compound 1 was shown to undergo exte ...201424423753
production of cxc and cc chemokines by human antigen-presenting cells in response to lassa virus or closely related immunogenic viruses, and in cynomolgus monkeys with lassa fever.the pathogenesis of lassa fever (lf), a hemorrhagic fever endemic to west africa, remains unclear. we previously compared lassa virus (lasv) with its genetically close, but nonpathogenic homolog mopeia virus (mopv) and demonstrated that the strong activation of antigen-presenting cells (apc), including type i ifn production, observed in response to mopv probably plays a crucial role in controlling infection. we show here that human macrophages (mp) produce large amounts of cc and cxc chemokines ...201424421914
normal thoracic radiographic appearance of the cynomolgus monkey (macaca fascicularis).the cynomolgus monkey (macaca fascicularis) has been increasingly used as a non-human primate model in biomedical research. as establishing baseline thoracic radiography for the cynomolgus monkey is essential, we tested the hypothesis that age and sex may affect the thoracic radiography parameters of this species.201424416248
genetic polymorphism and zoonotic potential of enterocytozoon bieneusi from nonhuman primates in china.enterocytozoon bieneusi is an important zoonotic pathogen. to assess the human-infective potential of e. bieneusi in nonhuman primates (nhps), we examined the prevalence and genotype distribution of e. bieneusi in 23 nhp species by pcr and sequence analysis of the ribosomal internal transcribed spacer (its). a total of 1,386 fecal specimens from nhps from five provinces in china were examined, and e. bieneusi was detected in 158 (11.4%) specimens from five nhp species, including cynomolgus monke ...201424413605
effects of weekly blood collection in male and female cynomolgus macaques (macaca fascicularis).this study was designed to evaluate the maximal amount of blood that can be safely collected in healthy, adult male and female cynomolgus macaques for 4 consecutive weeks with minimal effect on animal wellbeing. general guidelines for blood collection volumes in laboratory animals are not species-specific, and currently there are few evaluations of blood collection in macaques. in this study, blood was removed at 7.5%, 10%, 12.5%, 15%, or 17.5% of total blood volume (tbv) for 4 consecutive weeks ...201424411784
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