Selected Grantee Publications
- Clear All
- 71 results found
- Pediatrics
- Women's Health
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Effects of Acute Femoral Head Ischemia on the Growth Plate and Metaphysis in a Piglet Model of Legg-Calvé-Perthes Disease
Armstrong et al., Osteoarthritis and Cartilage. 2023.
https://pubmed.ncbi.nlm.nih.gov/36696941/
Legg-Calvé-Perthes disease (LCPD) can lead to permanent deformity of the femoral head and premature osteoarthritis, but the underlying cause remains unknown. More work is needed to determine optimal treatment methods for LCPD. Using a piglet model for LCPD, researchers assessed the effects of acute femoral head ischemia on the proximal femoral growth plate and metaphysis. They reported that alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. These findings suggest that growth disruption may occur sooner after the onset of ischemia than researchers had hypothesized previously. Supported by ORIP (T32OD010993, K01OD021293), NIAMS, and NCATS.
Infection of the Maternal–Fetal Interface and Vertical Transmission Following Low-Dose Inoculation of Pregnant Rhesus Macaques (Macaca mulatta) with an African-Lineage Zika Virus
Koenig et al., PLOS ONE. 2023.
https://doi.org/10.1371/journal.pone.0284964
Researchers examined transmission of Zika virus to nonhuman primate fetuses during pregnancy. Even with a low dosage of inoculation of the dams, the investigators found that the Zika virus infected fetuses, despite the presence of a “placental fortress,” which normally protects fetuses during gestation. This transmission illustrates the high level of infectivity threat that Zika poses, which may increase if mosquitoes expand their global habitats. Understanding how Zika breaches the placental barrier will help researchers develop strategies to prevent fetal infection during pregnancy and thereby prevent adverse outcomes, such as brain malformation defects. Supported by ORIP (P51OD011106, S10OD023526), NIAID, NCI, and NIGMS.
Giardia Hinders Growth by Disrupting Nutrient Metabolism Independent of Inflammatory Enteropathy
Giallourou et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-38363-2
Giardia lamblia is one of the most common intestinal pathogens among children in low- and middle-income countries. Investigators performed translational investigations using the Malnutrition and Enteric Diseases (MAL-ED) male and female cohort, as well as mice of both sexes, to identify mechanistic pathways that might explain Giardia-induced effects on early childhood growth. They identified signatures in the urinary metabolome of young children, suggesting that host growth restriction during infection is mediated by dysregulated amino acid metabolism. Supported by ORIP (P40OD010995), NIAID, and NIDDK.
Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography
Coughlan et al., JAMA Neurology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37010830/
To understand the predominance (70%) of women among individuals with Alzheimer’s disease, the investigators studied regional tau and β-amyloid (Aβ) in relation to age at menopause and hormone therapy (HT) in postmenopausal women and age-matched men using positron emission tomography. The study demonstrated that females exhibited higher tau deposition compared with age-matched males, particularly in the setting of elevated Aβ; earlier age at menopause and late initiation of HT were associated with increased tau vulnerability. This study suggests female individuals with these conditions may be at higher risk of pathological burden. Supported by ORIP (S10OD025245), NIA, and NICHD.
The Incompetence of Mosquitoes—Can Zika Virus Be Adapted to Infect Culex tarsalis Cells?
Gallichotte et al., mSphere . 2023.
Zika virus (ZIKV) is transmitted between humans by Aedes aegypti mosquitoes. However, the 2015 to 2017 outbreak raised questions regarding the role of Culex species mosquitoes in transmission. Investigators attempted to adapt ZIKV to C. tarsalis by serially passaging the virus on cocultured A. aegypti and C. tarsalis cells to identify viral determinants of species specificity. Next-generation sequencing of cocultured virus passages revealed variants of interest that were engineered into nine recombinant viruses. None of these viruses showed increased infection of Culex cells or mosquitoes. Thus, although ZIKV might infect Culex mosquitoes occasionally, Aedes mosquitoes likely drive transmission and human risk. Supported by ORIP (T32OD010437) and NIAID.
Infant Rhesus Macaques Immunized Against SARS-CoV-2 Are Protected Against Heterologous Virus Challenge 1 Year Later
Milligan et al., Science Translational Medicine. 2023.
https://doi.org/10.1126/scitranslmed.add6383
The Moderna and Pfizer–BioNTech mRNA vaccines received emergency use authorization for infants 6 months and older in June 2022, but questions remain regarding the durability of vaccine efficacy against emerging variants in this age group. Using a two-dose vaccine regimen consisting of stabilized prefusion Washington-strain spike protein encoded by mRNA and encapsulated in lipid nanoparticles, the investigators immunized 2-month-old rhesus macaques of both sexes. They found that the immune responses persisted and protected from severe disease after heterologous challenge with the Delta variant 1 year later. The decay kinetics of vaccine-induced neutralizing antibody responses in the infant monkeys are comparable to those observed in adult humans and nonhuman primates. Supported by ORIP (P51OD011107), NIAID, and NCI.
Naturally Occurring Osteochondrosis Latens Lesions Identified by Quantitative and Morphological 10.5 T MRI in Pigs
Armstrong et al., Journal of Orthopaedic Research. 2023.
https://pubmed.ncbi.nlm.nih.gov/35716161/
Juvenile osteochondritis dissecans (JOCD) is a pediatric orthopedic disorder that is associated with pain and gait deficits. JOCD lesions form in the knee, elbow, and ankle joints and can progress to early-onset osteoarthritis. In this study, researchers used a noninvasive magnetic resonance imaging (MRI) method to identify naturally occurring lesions in intact knee and elbow joints of juvenile pigs. This work can be applied to noninvasive identification and monitoring of early JOCD lesions and determination of risk factors that contribute to their progression in children. Supported by ORIP (K01OD021293, T32OD010993), NIAMS, and NIBIB.
Impaired Placental Hemodynamics and Function in a Non-Human Primate Model of Gestational Protein Restriction
Lo et al., Scientific Reports. 2023.
https://www.nature.com/articles/s41598-023-28051-y
Maternal malnutrition is a global health epidemic that adversely affects fetal outcomes and results in long-term health complications in children. Investigators used a previously developed model in nonhuman primates for gestational protein restriction to study the impact of undernutrition, specifically protein deficiency, on placental function and pregnancy outcomes. The data demonstrate that a 50% protein-restricted diet reduces maternal placental perfusion, decreases fetal oxygen availability, and increases fetal mortality. These alterations in placental hemodynamics could partly explain human growth restriction and stillbirth seen with severe protein restriction in developing countries. Supported by ORIP (P51OD011092) and NICHD.
Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus–Infected Individuals
Vimali et al., Viral Immunology. 2023.
Researchers have previously observed that human pegivirus (HPgV) infection is associated with reduced progression of HIV. Investigators examined markers of HIV progression in male and female individuals with HIV and HPgV infection. They reported that HIV plasma viral load was lower in HPgV-seropositive individuals with HIV than in HPgV‑seronegative individuals with HIV. They also found that clinical markers of hepatic damage were significantly lower in HPgV-seropositive individuals with HIV. Future work could examine pathways through which HPgV influences HIV control, which might inform the development of new therapeutics. Supported by ORIP (P51OD011132) and NIAID.