In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The journal accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Cryptococcal meningitis (CM) is an opportunistic fungal infection that primarily affects immunocompromised individuals, particularly those with HIV/AIDS. In resource-limited countries, patients often receive antifungal drug fluconazole monotherapy; however, long-term outcomes, even at high doses, are poor. In this episode, Neil Stone and colleagues observed treatment response in a cohort of patients with HIV-associated CM given fluconazole alone or in combination with flucytosine. Patients treated with fluconazole monotherapy had an increase in resistant subpopulations in the CSF; however, combination prevented expansion of resistant populations. Fluconazole-resistant strains had high rates of aneuploidy characterized predominant diploidy of drug efflux pump-containing chromosome 1. Together, these results support combination therapy as a successful strategy for suppressing heteroresistance.
Group A streptococcus (GAS) is a common cause of life-threating necrotizing fasciitis and myositis. Necrotizing disease is relatively rare; however, it has a high rate of mortality, and affected limbs must often be amputated. In this episode, James Musser and colleagues use transposon-directed insertion-site sequencing (TraDIS) to identify GAS genes required for the development of necrotizing myositis in a nonhuman primate model. In particular, several bacterial transporters were determined to be required for infection, and thereby represent potential therapeutic targets for this devastating disease.
Activity-dependent neuroprotective protein (ADNP) is essential for brain formation, and mutations in the ADNP-encoding gene have been linked to an autism-like syndrome in children that is characterized by developmental delay along with intellectual and social disabilities. An 8-amino acid motif derived from ADNP (referred to as NAP) has been shown to be neuroprotective, via enhancing dendritic spine formation, in mice lacking ADNP. In this episode, Illana Gozes and colleagues characterize Adnp+/- mice as a model of ANDP syndrome. Adnp+/- animals had reduced dendritic spine density, developmental delays, impaired vocalizations, and motor dysfunction along with memory and social impairment. Administration of NAP partially reversed behavior and developmental defects and increased dendritic spine density. The results of this study support further exploration of NAP administration for treatment of ADNP syndrome.
Graft-versus-host-disease (GVHD) is a life-threatening complication of allogeneic BM transplantation that affects skin, liver, and the gastrointestinal (GI) tract. GI involvement is associated with the most severe form of disease and outcomes for these patients are poor. Treatments for GVHD are limited; therefore, a better understanding of markers of GI involvement have potential to improve treatment. In this episode, James Ferrara and colleagues identify the Paneth cell protein regenerating islet-derived 3α (REG3α) as a biomarker that is upregulated in sera of patients with GI GVHD. Moreover, using murine models, the authors determined that REG3α, which has well-known antimicrobial function, promotes intestinal stem cell survival; thereby, protecting the intestinal barrier. Together, these results indicate that strategies to increase REG3α should be explored for limiting GI GVHD.
Prostate cancer is an androgen-dependent disease; therefore, current approaches for treatment aim to disrupt androgen signaling. Unfortunately, this approach is rarely curative due to the selection of resistant clones and adaptation of stromal and endothelial cells to support tumor growth. In this episode, Neil Bhowmick and colleagues evaluated epigenetic alterations in prostate cancer-associated fibroblasts (CAFs) and determined that the Ras inhibitor RASAL3 is silenced in these cells, thereby driving macropinocytosis-mediated glutamine synthesis due to increased oncogenic Ras activity. The increase in stromal glutamine associated with neuroendocrine differentiation, and in prostate cancer patients, blood glutamine levels were elevated in patients that were resistant to androgen deprivation compared to those that were responsive. Together, these results suggest that strategies to prevent glutamine uptake be considered in conjunction with androgen deprivation.