Selected Grantee Publications
- 470 results found
Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines
Vasilatis et al., International Journal of Molecular Sciences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39201315
Prostate cancer (PCa) ranks second worldwide in cancer-related mortality, but only a few animal models exhibit naturally occurring PCa that recapitulates the symptoms of the disease. Neutered dogs have an increased risk of PCa and often lack androgen receptor (AR) signaling, which is involved in upregulating tumorigenesis but can also suppress aggressive cell growth. In this study, researchers sought to understand more about the role of AR signaling in canine PCa initiation and progression by restoring AR in canine PCa cell lines and treating them with dihydrotestosterone. One cell line exhibited AR-mediated tumor suppression; one cell line showed altered proliferation (but not migration or invasion); and a third cell line exhibited AR-mediated alterations in migration and invasion (but not proliferation). The study highlights the heterogeneous nature of PCa in dogs and humans but suggests that AR signaling might have therapeutic potential under certain conditions. Supported by ORIP (T32OD011147).
Cold Atmospheric Plasma Inactivates Aspergillus flavus and Fusarium keratoplasticum Biofilms and Conidia In Vitro
Roberts et al., Journal of Medical Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38985505
Fungal keratitis (FK) is a severe corneal disease associated with significant morbidity and vision loss that is caused by Aspergillus flavus and Fusarium keratoplasticum. Cold atmospheric plasma (CAP) is a novel nonpharmacologic antimicrobial intervention that has demonstrated potential as a broad-spectrum antifungal treatment. Researchers in this study assessed the efficacy of CAP against clinical FK isolates of A. flavus and F. keratoplasticum grown in vitro. CAP exhibited strong time-dependent inactivation of both fungal species, achieving complete metabolic activity inhibition within 10 minutes of treatment. These results indicate that CAP is an effective broad-spectrum antifungal and a potential treatment strategy for FK. Supported by ORIP (T35OD011070).
Sex-Specific Cardiac Remodeling in Aged Rats After Adolescent Chronic Stress: Associations with Endocrine and Metabolic Factors
Dearing et al., Biology of Sex Differences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39180122
Cardiovascular disease is a leading cause of death in the world. The potential effects of chronic stress on the development and progression of cardiovascular disease in the aged heart are unknown. In this study, researchers investigated sex- and stress-specific effects on left ventricular hypertrophy (LVH) after aging. Male and female rats were exposed to chronic stress during adolescence and then challenged with a swim test and a glucose tolerance test before and after aging 15 months. As a group, female rats showed increased LVH in response to early life stress. Male rats showed individual differences in vulnerability. These results indicate that sex and stress history can interact to determine susceptibility to cardiovascular risks. Supported by ORIP (F30OD032120, T35OD015130) and NHLBI.
Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy
Cook et al., Movement Disorders. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177409/
A newly recognized progressive neurodegenerative disorder in Miniature American Shepherd (MAS) dogs affects gait in young adult dogs and is characterized by pelvic limb weakness and ataxia. The authors of this study used genetic analysis to map the underlying cause of the disorder, a single base-pair deletion in the ring finger protein 170 (RNF170) gene that was predicted to cause early truncation of the RNF170 protein. RNF170 variants previously were identified in human patients with spastic paraplegia-85 (SPG85) who exhibit similar clinical and pathological phenotypes to RNF170-mutant dogs. SPG85 belongs to a group of inherited neurodegenerative disorders collectively referred to as neuroaxonal dystrophy (NAD). The authors of this paper propose that RNF170-mutant MAS dogs serve as a large animal model to study underlying mechanisms and therapeutics for NAD. Supported by ORIP (K01OD027051).
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice
Szalanczy et al., Radiation Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38772553
Radiation damages adipose progenitor cells and increases liver fibrosis, leading to the development of metabolic-associated fatty liver disease (MAFLD) and insulin resistance. As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize and mitigate the delayed effects of radiation exposure. Some of these effects are mediated by TGFβ pathway signaling, which increases in response to radiation exposure and causes fibrosis. In this study, IPW-5371—a small-molecule inhibitor of a TGFβ receptor called activin receptor-like kinase 5 (ALK5)—was shown to protect mice from the effects of sublethal whole-body irradiation and chronic consumption of a Western diet. Mice treated with IPW-5371 exhibited lower fibrosis and fat accumulation in the liver, were more responsive to insulin, and had lower circulating triglycerides and better muscle endurance. IPW-5371 is a promising treatment for mitigating the metabolic effects of radiation exposure and preventing MAFLD. Supported by ORIP (T35OD010946, T32OD010957).
Modeling Resistance to the Broadly Neutralizing Antibody PGT121 in People Living With HIV-1
Cassidy et al., PLOS Computational Biology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551976/
PGT121 is a broadly neutralizing antibody that demonstrated potent antiviral activity in an early clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants (sex unspecified), and the rebound viruses were entirely resistant to PGT121-mediated neutralization. However, two participants experienced long-term antiretroviral therapy–free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Mathematical models showed the importance of the relative fitness difference between PGT121-sensitive and -resistant subpopulations prior to treatment. Researchers identified the treatment-induced competitive advantage of a resistant population as a primary driver of resistance and emphasized the high neutralization ability of PGT121 in both participants who exhibited long-term viral control. Supported by ORIP (R01OD011095) and NIAID.
Anti–PD-1 Chimeric Antigen Receptor T Cells Efficiently Target SIV-Infected CD4+ T Cells in Germinal Centers
Eichholtz et al., The Journal of Clinical Investigation. 2024.
https://pubmed.ncbi.nlm.nih.gov/38557496/
Researchers conducted adoptive transfer of anti–programmed cell death protein 1 (PD-1) chimeric antigen receptor (CAR) T cells in simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes on antiretroviral therapy (ART). In some macaques, anti–PD-1 CAR T cells expanded and persisted concomitant with the depletion of PD-1+ memory T cells—including lymph node CD4+ follicular helper T cells—associated with depletion of SIV RNA from the germinal center. Following CAR T infusion and ART interruption, SIV replication increased in extrafollicular portions of lymph nodes, plasma viremia was higher, and disease progression accelerated, indicating that anti–PD-1 CAR T cells depleted PD-1+ T cells and eradicated SIV from this immunological sanctuary. Supported by ORIP (U42OD011123, U42OD010426, P51OD010425, P51OD011092), NCI, NIAID, and NIDDK.
Early Antiretroviral Therapy in SIV-Infected Rhesus Macaques Reveals a Multiphasic, Saturable Dynamic Accumulation of the Rebound Competent Viral Reservoir
Keele et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38593120/
Researchers studied the dynamics of rebound-competent viral reservoir (RCVR) establishment in male and female rhesus macaques and assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of antiretroviral therapy (ART) after 1 year. All rhesus macaques rebounded between 7 and 16 days after ART, with 3 to 28 rebound lineages. Calculated reactivation rates per pre-ART plasma viral load were consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks after infection. The data highlight the heterogeneity of the RCVR between rhesus macaques, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection. Supported by ORIP (P51OD011092), NCI, and NIAID.
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.