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- Women's Health
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.
Maternal Western-Style Diet Reduces Social Engagement and Increases Idiosyncratic Behavior in Japanese Macaque Offspring
Mitchell et al., Brain, Behavior, and Immunity. 2022.
https://www.doi.org/10.1016/j.bbi.2022.07.004
Evidence points to an association between maternal obesity and risk of early-emerging neurodevelopmental disorders in offspring, yet few preclinical studies have tested for associations between maternal Western-style diet (mWSD) and offspring behavior. Using Japanese macaques, researchers found that mWSD offspring exhibited less proximity to peers and initiated fewer affiliative social behaviors. These outcomes appear to be mediated by increased maternal interleukin-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin. These findings suggest specific prevention and intervention targets for early-emerging neurodevelopmental disorder in humans. Supported by ORIP (P51OD011092), NIMH, and NICHD.
X Chromosome Agents of Sexual Differentiation
Arnold et al., Nature Reviews Endocrinology. 2022.
https://www.doi.org/10.1038/s41574-022-00697-0
Many diseases affect one sex disproportionately. A major goal of biomedical research is to understand which sex-biasing factors influence disease severity and to develop therapeutic strategies to target these factors. Two groups of such agents are sex chromosome genes and gonadal hormones. Researchers use the “four core genotypes” model to enable comparisons among animals with different sex chromosomes but the same type of sex hormones, which allows investigators to distinguish disease mechanisms influenced by the sex chromosomes. Supported by ORIP (R01OD030496, R21OD026560), NICHD, NIDDK, and NHLBI.
Stromal P53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner
Wu et al., Molecular Cancer Research. 2022.
https://www.doi.org/10.1158/1541-7786.MCR-21-0960
Loss of stromal p53 function drives tumor progression in breast cancer, but the exact mechanisms have been relatively unexplored. Using mouse models, researchers demonstrated that loss of cancer-associated fibroblast (CAF) p53 enhances carcinoma formation driven by oncogenic KRAS G12D, but not ERBB2, in mammary epithelia. These results corresponded with increased tumor cell proliferation and DNA damage, as well as decreased apoptosis, in the KRAS G12D model. Furthermore, a gene cluster associated with CAF p53 deficiency was found to associate negatively with survival in microarray and heat map analyses. These data indicate that stromal p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately affects patient survival. Supported by ORIP (K01OD026527) and NCI.
Common and Divergent Features of T Cells From Blood, Gut, and Genital Tract of Antiretroviral Therapy–Treated HIV+ Women
Xie et al., Journal of Immunology. 2022.
https://www.doi.org/10.4049/jimmunol.2101102
T cells residing in mucosal tissues play important roles in homeostasis and defense against microbial pathogens, but how organ system environments affect the properties of resident T cells is relatively unknown. Researchers phenotyped T cells in the gut and reproductive tract using blood and tissue samples from women with HIV who have achieved viral suppression via antiretroviral therapy. The T cells exhibited differing expression of CD69 and CD103 markers, whereas resident memory CD8+ T cells from the female reproductive tract expressed PD1 preferentially. Additionally, CXCR4+ T inflammatory mucosal cells expressed multiple chemokine receptors differentially. These results suggest that T cells take on distinct properties in different mucosal sites, which allows them to tailor activities to their surrounding milieu. This study offers important insights for reproductive medicine in women. Supported by ORIP (S10OD018040), NHLBI, NIAID, and NIDDK.
Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy
Zhang et al., Cancer Research. 2022.
https://pubmed.ncbi.nlm.nih.gov/34965933/
Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T cell viral immunity against tumor cells. Investigators developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Based on functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus in ovarian cancer patients, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. The streamlined and systemic approach includes assessing APEC function in vivo using a new zebrafish xenograft platform that facilitates high-resolution single-cell imaging to assess therapy responses and then validating top candidates using traditional mouse xenograft studies and primary patient samples. This study develops a high-throughput preclinical platform to identify patient-specific antibody-peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma. Supported by ORIP (R24OD016761).
Deciphering the Role of Mucosal Immune Responses and the Cervicovaginal Microbiome in Resistance to HIV Infection in HIV-Exposed Seronegative Women
Ponnan et al., Microbiology Spectrum. 2021.
https://journals.asm.org/doi/10.1128/Spectrum.00470-21
Identifying correlates of protection in HIV-exposed seronegative (HESN) individuals requires identification of HIV-specific local immune responses. Researchers performed a comprehensive investigation of the vaginal mucosa and cervicovaginal microbiome in HESN women. They found elevated antiviral cytokines, soluble immunoglobulins, activated NK cells, CXCR5+ CD8+ T cells, and T follicular helper cells in HESN women compared to HIV-unexposed healthy women. They also found greater bacterial diversity and increased abundance of Gardnerella species in the mucosa of HESN women. These findings suggest that the genital tract of HESN women contains innate immune factors, antiviral mediators, and T cell subsets that protect against HIV. Supported by ORIP (P51OD011132) and NIAID.
Effects of Early Daily Alcohol Exposure on Placental Function and Fetal Growth in a Rhesus Macaque Model
Lo et al., American Journal of Obstetrics and Gynecology. 2021.
https://www.sciencedirect.com/science/article/pii/S0002937821008309?via%3Dihub=
In a rhesus macaque model for chronic prenatal alcohol exposure, daily consumption during early pregnancy significantly diminished placental perfusion at mid to late gestation and significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy. These findings were associated with the presence of microscopic placental infarctions. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury that persisted throughout pregnancy. Supported by ORIP (P51OD011092), NICHD, and NIAAA.
Sexual Dimorphic Impact of Adult-Onset Somatopause on Life Span and Age-Induced Osteoarthritis
Poudel et al., Aging Cell. 2021.
https://pubmed.ncbi.nlm.nih.gov/?term=Poudel%20SB&cauthor_id=34240807
Osteoarthritis (OA) is a major cause of disability worldwide. In humans, the age-associated decline in growth hormone (GH) levels was hypothesized to play a role in the etiology of OA. Investigators studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity in aged mice. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice. In conclusion, while their life span increased, AOiGHD female mice’s health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity. Supported by ORIP (S10OD010751) and others.