Colon cancer death toll due to metastasis is expected to rise. Extracellular vesicles are signalling molecules which can regulate communication between cells and either inhibit or promote cancer metastasis. Extracellular vesicles from adipose mesenchymal stem cells of Macaca fascicularis were obtained from previous research. Various concentrations of extracellular vesicles (5 μg/mL, 10 μg/mL, and 20 μg/mL) were applied to colon cancer cell line WiDr in a transwell invasion assay. CXCR3 gene expression analysis was done using RT-qPCR. Application of extracellular vesicles successfully inhibited colon cancer invasion with decrease of number of invasive cells with increase in concentration. There was no statistical difference between cells treated with 10 μg/mL and 20 μg/mL of extracellular vesicles. Colon cancer cells treated with extracellular vesicles show upregulation of CXCR3A and CXCR3B gene expression compared to negative control. Extracellular vesicles inhibit colon cancer cell invasion through upregulation of CXCR3B expression.

Carbonic anhydrase IX (CAIX) is an important target for imaging clear cell renal cell carcinoma (ccRCC), but existing probes show high gastrointestinal uptake. Here, a sulfur(VI) fluoride exchange (SuFEx)-modified PET probe, [68Ga]Ga-SF-DPI-4452, was developed to improve biodistribution. In vitro studies showed slightly lower CAIX affinity than [68Ga]Ga-DPI-4452 (IC50:7.53 vs 4.60 nM) but higher internalization (23% vs 7%). In OS-RC-2 tumor-bearing mice, both tracers displayed specific and high tumor uptake at 1 h postinjection ([68Ga]Ga-SF-DPI-4452:10.68 ± 2.25%ID/g vs [68Ga]Ga-DPI-4452:9.83 ± 5.86%ID/g, P > 0.05). Notably, [68Ga]Ga-SF-DPI-4452 significantly reduced gastrointestinal uptake, resulting in markedly improved tumor-to-background contrast (e.g., tumor-to-stomach ratio: 32.69 ± 15.51 vs 1.21 ± 0.34, P < 0.05). Biodistribution studies in mice and PET/CT imaging in cynomolgus monkeys further confirmed reduced gastrointestinal accumulation. Overall, SuFEx modification preserves tumor targeting while minimizing off-target uptake, supporting its potential for CAIX-targeted imaging and radionuclide therapy.

The use of antibody-drug conjugates (ADCs) specific to human epidermal growth factor receptor 2 (HER2), such as ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (Enhertu, T-DXd), and trastuzumab duocarmazine (SYD985), to treat breast cancer patients has been associated with a variety of toxicities including corneal epithelial keratitis. The anatomic basis for ocular toxicities has not been established. Using immunohistochemistry, HER2 expression was identified in the human corneal, limbal and conjunctival epithelium of fetal and adult human eyes. We also identified HER2 expression in tissues from the Macaca fascicularis (monkey) to confirm a similar distribution of HER2 expression as found in humans and to support the use of this species as a toxicology model in preclinical testing of anti-HER2 ADCs. As in the human, expression of HER2 in monkey was limited to normal epithelium, as illustrated for the eye, kidney, and uterus. Incubation of normal human corneal epithelial cell lines with trastuzumab or T-DXd demonstrated the capacity for receptor-mediated endocytosis of HER2-targeted therapies by epithelia in the eye. Our findings of HER2 expression in normal human corneal epithelium suggest that the ocular adverse events associated with HER2-targeted ADCs may be driven, at least in part, by an on-target effect.

The early organogenesis stage is a critical phase of embryogenesis that lays the foundation for organ development, and is characterized by dynamic and spatially organized transcriptional programs. However, limited spatial transcriptomic information has constrained our understanding of early primate organogenesis. Here we present a comprehensive three-dimensional (3D) spatial transcriptomic atlas of cynomolgus monkey embryos at Carnegie stages (CS) 9 and 10, capturing key morphogenetic events including cardiogenesis, gut tube regionalization, neurulation, axial mesendoderm patterning and early somitogenesis. Using high-resolution spatial transcriptomics and 3D reconstruction, we identify spatially defined lineage domains across germ layers and resolve regionally restricted gene expression, transcription factor activity, and signalling landscapes along major embryonic axes, exemplified by the emergence of dorsoventrally patterned spinal cord subpopulations during neurulation. Cross-species comparisons with human and mouse datasets reveal conserved and species-biased transcriptional programs. Together, this atlas provides a foundational reference for studying early primate development.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which results in cognitive decline and memory loss, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Despite numerous efforts to develop animal models of AD across various species to understand its pathological characteristics and underlying mechanisms, the model that accurately mimics the pathological phenotypes of AD remains elusive. In this study, we aimed to induce sporadic AD pathological progression in non-human primates (NHP) through the repeated administration of Aβ oligomers (AβO) via the CBCT-guided intra-cisterna manga (ICM) injection. Cynomolgus monkeys were administered AβO twice a week for four weeks, and then euthanized one week after the final injection. We found that AβO-injected NHP developed AD pathologies, including Aβ deposition, synaptic impairment, and neuroinflammation in the CA1 area of the hippocampus. Additionally, the levels of hyperphosphorylated tau were significantly increased in the cerebrospinal fluid (CSF) of AβO-injected NHP. Our results demonstrate that repeated AβO injection via the ICM route induces several early-stage AD-like neuropathological alterations, including intracellular Aβ accumulation, tau phosphorylation, and synaptic dysfunction. The present study indicates that repeated ICM administration of AβO could be good approach to reproduce a translational NHP model of AD, enabling the study of AD pathogenesis and pre-clinical testing of potential therapeutic candidates for AD.

Testing for preexisting anti-AAV immunity in non-human primates constitutes an essential part of screening procedures for nonclinical studies with gene therapy, which is customary performed using transduction inhibition (TI) assays. These assays cause high costs and a significant operational burden owing to their complexity and low throughput. However, broader implementation of more practical total antibody assays (TAb) is hindered by the lack of conclusive data demonstrating assays comparability in non-human primates. To determine whether TAb assays can serve as a viable alternative to TI assays for anti-AAV screening in monkeys, we conducted a comparative study for two AAV serotypes (AAV2 and AAV9), with tailored specificity control measures incorporated in both assay formats. Both the TI and TAb assays showed a high concordance in detection of preexisting anti-AAV immunity in cynomolgus monkey. The presented TAb assay offers a simple, cost- and time-saving alternative to TI assays for pre-study testing of non-human primates. The use of such TAb assays can thus result in concordant animal enrollment at lower cost and greater speed as compared to TI-based screening tests.

Reactivation of latent viruses after hematopoietic stem cell transplantation is a major cause of illness in transplant recipients, yet options for prevention and treatment remain limited. Progress has been hindered by the lack of animal models that accurately reflect human disease. In this study, we show that Mauritian cynomolgus macaques harbor multiple polyomaviruses that reactivate at high levels following transplantation and are associated with urinary tract disease, closely paralleling complications seen in humans. We define the genetic identity of these viruses and demonstrate that immunosuppression strongly enhances viral shedding and disease severity. By establishing clear similarities between viral reactivation in macaques and humans, this work validates the Mauritian cynomolgus macaque transplantation model as a powerful platform for studying virus-driven disease mechanisms and testing antiviral therapies and vaccines relevant to human transplantation.

The mammalian pineal gland maintains normal circadian rhythms and homeostasis by secreting melatonin. However, the lack of a single-cell-resolved regulatory map limits our understanding of how these neuroendocrine functions are orchestrated. Here, we constructed a multiomics atlas of the pineal gland from Macaca fascicularis by integrating snRNA-seq, snATAC-seq, and spatial transcriptomics. We identified pinealocytes as the predominant cell type, alongside six glial and vascular lineages. Chromatin accessibility analysis delineated cell-type-specific regions enriched for melatonin synthesis and phototransduction genes. Notably, we resolved a dual-layer regulatory architecture: While melatonin synthesis programs are robustly organized, circadian clock regulators exhibit a distinct, sparse spatial pattern. Coexpression networks further identified core modules and regulatory hubs-including CRX/OTX2, LHX4, and RORA-that integrate these circadian and light-responsive signals. Cell-cell communication analysis identified signaling axes, such as PTN-ALK/SDC2, RA-RORB, and NRG1-ERBB4, that potentially coordinate this spatial functional organization. Integrating genetic traits showed that sleep and neuropsychiatric risk variants preferentially map to these pineal regulatory modules. Specifically, sleep-associated loci converged on MEIS1-linked elements, while bipolar disorder-associated loci highlighted candidate genes of RDH12 and SDK2. Overall, this study reveals the cellular diversity and spatial regulatory logic of the primate pineal gland, providing a physiological foundation for investigating circadian and neuroendocrine regulation in healthy and disease models.

Objective.An accurate forecast of longitudinal brain activity is essential for monitoring disease progression. While time-series forecasting has been applied to short-term electroencephalography (EEG) dynamics, the modeling of continuous, longitudinal signals remains largely unexplored. This study addresses this gap by validating an individualized time series forecasting framework based on a trigonometric, box-cox transformation with autoregressive moving average errors and trend and seasonal/periodic components (TBATS) model to predict slow-wave activity (SWA, 0.5-4 Hz) power in EEG collected from cynomolgus monkeys.Approach.We recorded continuous wireless telemetry EEG data from three cynomolgus monkeys for 12 consecutive days. The SWA power was aggregated into hourly bins. We implemented a TBATS model to forecast SWA dynamics and compared its root mean squared errors (RMSE) against a naïve model, Holt-Winters (HW) model, and seasonal autoregressive integrated moving average (SARIMA) model. We then assessed the model validity using residual autocorrelation to evaluate the independence of model residuals. We also applied an expanding window approach to calculate the minimum amount of training data required for accurate model performance.Main results.The TBATS model demonstrated high data efficiency by achieving stable forecasts with as few as 2 d of training data. TBATS demonstrated comparable out-of-sample RMSE values in comparison to SARIMA and HW benchmarks. In contrast to SARIMA and HW, TBATS was the only framework to consistently produce white-noise residuals, which indicated that it captured the latent temporal dynamics of the time series data.Significance.This study demonstrated the TBATS model as a robust and efficient tool for forecasting longitudinal EEG signals. By accurately modeling subject-specific temporal structure with minimal data requirements, this approach provided a practical method for establishing a personalized neural baseline, critical for tracking neurodegeneration or optimizing closed-loop therapies.

A >8-year two-generation study on the long-term effects of genetically modified maize (Zea mays) containing cry1Ab/cry2Aj and EPSPS genes on cardiac function and arrhythmia risk of cynomolgus macaques.

Coastal populations of long-tailed macaques (Macaca fascicularis) display remarkable behavioral flexibility in exploiting intertidal food resources. Tool-using groups in Thailand are known to crack marine shellfish with stones, yet the behavioral repertoire of non-tool-using populations remains poorly documented. Here, we present the first report of long-tailed macaques preying on aquatic hermit crabs without using tools, based on observations at Wat Takiap, Hua Hin District, Prachuap Khiri Khan Province, Thailand. During low tide, macaques were observed employing a sequence of substrate-assisted manipulations: repeatedly rubbing gastropod shells against rocks or concrete to thin and weaken the shell wall, followed by fracturing it with their teeth or by striking it against hard surfaces, and finally extracting and consuming the hermit crab's appendages. This behavior represents a novel, non-tool extractive technique for accessing encased prey-a strategy intermediate between manual shell handling and percussive tool use. Such manipulation indicates refined motor control and problem-solving in a foraging context where encased prey are abundant but challenging to access. Given the absence of long-term data, these observations provide a valuable record of a potential pre-emergent stage in the evolution of tool use. Continued longitudinal and comparative studies will be essential to determine whether such substrate-assisted behaviors may serve as precursors to habitual stone-tool use in coastal macaques.

To characterize sex-specific and offspring number-associated patterns of ocular aging in Macaca fascicularis. Comprehensive ophthalmic examinations were performed on 94 adult macaques (47 males, 47 females). Ocular biometry (lens thickness [LT], anterior chamber depth [ACD], axial length), nuclear lens density (NLD), macula retinal thickness, and retinal nerve fiber layer thickness (RNFLT) were assessed using IOLMaster and swept-source optical coherence tomography. Cataract and drusen were diagnosed using clinical imaging criteria. Sex-specific age associations were examined using correlation. Offspring number analyses included 16 females and 24 males with confirmed reproductive records. Females and males differed significantly in ocular dimensions, with females showing smaller eyes and thinner retinas. Cataract prevalence was significantly higher in females compared to males (19.2% vs. 4.3%, P = 0.0286), whereas drusen prevalence was similar between sexes (17.0% in females vs. 14.9% in males). Although NLD and LT increased and ACD decreased with age in both sexes, aging slopes were consistently steeper in females. Increasing offspring number was associated with significant reductions in RNFLT in females, independent of age, while lens-related parameters showed no significant association with offspring number in either sex. Female macaques exhibit accelerated lens aging and increased cataract susceptibility, mirroring patterns observed in human populations. Offspring number selectively contributes to neuroretinal thinning, suggesting a reproductive influence on retinal decline that is distinct from lens aging. These findings highlight the importance of considering sex and reproductive history in NHP-based ocular aging studies and provide biological insights relevant to human age-related eye disease.

The purpose of this study was to establish a database of spontaneous ocular lesions in various laboratory animal species and to facilitate the evaluation of study findings in a preclinical toxicity study. Ophthalmologic examination (OE) records for laboratory animals before experiments from 2008 to 2023 were collected from the Provantis system at WuXi AppTec (Suzhou, China), including 23,388 CD-1 mice, 1,838 C57BL/6J mice, 193,076 Sprague-Dawley (SD) rats, 2,295 Wistar rats, 1,875 New Zealand White (NZW) rabbits, 1,794 Dutch belted (DB) rabbits, 32,919 Beagle dogs, 1,153 Bama minipigs, 23,706 cynomolgus monkeys, and 310 rhesus monkeys. These raw data were analyzed using the Fisher exact test. The most apparent features were as follows. SD and Wistar rats showed significantly higher incidences of corneal opacity (72.50% and 77.63%) compared with the other species, as well as persistent hyaloid artery (7.93%) and persistent pupillary membrane (2.75%); C57BL/6J mice had a significantly higher incidence of lens opacity (75.57%) compared with the other species; CD-1mice had more eccentric pupils (6.97%); rabbits were observed with more vitreous opacity and conjunctival hyperemia (12.88% and 1.88%); nontapetal redness was observed in dogs (2.83%); Bama minipigs showed higher incidences in ocular discharge, lens pigmentation, and esotropia (2.78%, 3.14%, and 2.25%); and leopard fundus was mostly found in monkeys (10.32%). The discrepancies between our results and relevant literature may be attributed to variations in genetic background, ingredients of diet, study sample size, and examination records. This study underlines the importance of establishing an in-house spontaneous lesion database.

Safety evaluation of repeated intra-articular injections of human adipose-derived mesenchymal stem cells in cynomolgus monkeys.

Tuberculosis outbreaks in nonhuman primate (NHP) colonies can result in disastrous financial, scientific, animal welfare, and public health outcomes. Tuberculin skin testing (TST) has been the standard diagnostic method for identifying Mycobacterium tuberculosis (Mtb) infection in NHPs but has limited sensitivity and specificity. In humans, Mtb-specific interferon-γ release assays (IGRAs) have become the preferred diagnostic method, overcoming significant limitations of the TST. We compared the diagnostic qualities of the TST and IGRA in a cohort of 673 rhesus and cynomolgus macaques with experimental Mtb infection. Serial TST and IGRA data were curated retrospectively for animals before and after Mtb infection and temporally matched to assess sensitivity, specificity, and agreement between the 2 tests. The overall sensitivity of the IGRA was 0.84 compared with 0.49 sensitivity of the TST test in detecting Mtb infection. Specificity of the IGRA and the TST was 0.83 and 1.0, respectively, with an overall agreement rate of 72% between the 2 tests. Sensitivity peaked at 3-5 weeks postinfection for TST and 5-7 weeks for IGRA. Data from a second cohort of animals (n = 227) that were not experimentally infected with Mtb, but for whom testing was done for screening and investigational purposes, demonstrated an agreement rate of 96%. To our knowledge, this is the largest reported comparison of TST and IGRA testing in NHPs. Although IGRAs are more labor intensive than TSTs, our data suggest that IGRAs have better diagnostic accuracy in detecting Mtb infection. Our data also suggest that the threshold for a positive TST could be lowered to improve sensitivity.

Animal models illuminate dengue immunopathogenesis to guide vaccine and therapeutic developments.

Sarcopenia is the decline in skeletal muscle mass and function with age and is observed in both humans and non-human primates. Sarcopenia progression in humans is highly correlated with various pathologies and mortality risks independent of other risk factors. Laboratory-housed non-human primates that do not engage in adequate physical activity are at higher risk of developing sarcopenia. We devised a simple behavioral task to enhance environmental enrichment and increase physical fitness. An aperture allowed vertical movement between two vertically mounted cages. Despite this arrangement, male cynomolgus macaques (approximately 13 years old) still spent the majority of time in the upper cage and were not very active. Therefore, we implemented a new behavioral method using sweetened liquid as a reinforcer. Monkeys could initiate each trial by pressing the touch screen in the upper cage which would light a large red button placed in the lower cage. Pressing the button resulted in immediate delivery of juice in the upper cage for 5 s; thus, the monkey was encouraged to rapidly ascend to the top cage to drink as much of the liquid reinforcer as possible. Increases in exercise behavior (measured via operant testing apparatus and real-time monitoring) and activity (measured via actigraphy monitors) suggest that this highly adaptable method successfully increases strenuous exercise and species-typical climbing behavior, and can potentially provide a novel means of measuring and promoting physical and psychological well-being, as well as potentially attenuating sarcopenia in laboratory-housed primates.

Establishment of ischemia-reperfusion model in male cynomolgus macaques and effects of piceatannol-3'-O-β-D-glucopyranoside injection intervention.

A significant population of chronic stroke patients urgently requires more effective therapies because of functional plateaus and limited intervention options. Intermittent theta-burst stimulation (iTBS) has been increasingly adopted in chronic-phase ischemic stroke management. However, the efficacy decreases over time. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for chronic stroke management through multiple mechanisms. Whether combined MSC transplantation and iTBS confers superior synergistic efficacy warrants further investigation. In this study, human umbilical cord-derived MSCs were stereotactically injected into the penumbra of the brain parenchyma adjacent to infarct sites in cynomolgus monkeys with chronic-stage middle cerebral artery occlusion (MCAO)-induced ischemic stroke. iTBS commenced at 1 week post-transplantation (5 sessions/week until week 17). Behavioral tests, electrophysiological recordings, functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), and plasma proteomic analysis were conducted longitudinally, with terminal histological and spatial proteomic analysis at week 17. The results indicated that combined MSC/iTBS therapy enhanced motor function, reduced cortical excitation thresholds, shortened motor-evoked potential (MEP) latency, increased neural activity intensity/synchronization, strengthened functional connectivity, and optimized motor cortex metabolism. In addition to the commonly attributed therapeutic mechanisms of MSCs and iTBS, the combined therapy additionally triggered neurogenesis and stem cell chemotaxis, which was potentially mediated by iTBS-enhanced CXCL12 secretion from MSCs. Therefore, MSC/iTBS combination therapy can effectively treat chronic stroke through multiple mechanisms, particularly involving the activation of endogenous neural stem cells (NSCs), representing a promising interdisciplinary treatment strategy.

Purpose:To develop and verify a physiologically based pharmacokinetic (PBPK) modeling strategy for mithramycin (MTM) and its analog, MTMSA-Trp, with the aim of projecting first-in-human plasma pharmacokinetics and supporting the translational development of MTMSA-Trp for Ewing sarcoma treatment.Methods:PBPK models were created in GastroPlus® using a middle-out approach, incorporating preclinical pharmacokinetic data from mice, rats, and cynomolgus monkeys. Human clearance was estimated through three methods: an additional clearance approach, allometric scaling, and single-species scaling from monkeys. The model was evaluated using clinical MTM plasma PK data and then employed to project human MTMSA-Trp plasma PK, with tissue predictions considered exploratory.Results:The additional clearance approach provided the most accurate prediction of human MTM plasma PK. Across all clearance prediction methods, MTMSA-Trp was predicted to achieve 8- to 15-fold higher human plasma exposure than MTM at the same dose. Model-derived liver exposures were 2- to 4-fold higher, with a lower predicted liver partition for MTMSA-Trp; however, these tissue predictions remained sensitive to distribution assumptions. Parameter sensitivity analysis identified the blood-to-plasma ratio as the most influential parameter among those examined.Conclusion:PBPK modeling supports the projection that MTMSA-Trp will achieve substantially higher plasma exposure than MTM in humans. This empirically developed workflow may inform translational efforts for the first-in-human development of MTMSA-Trp.