Altered abiraterone metabolism in individuals with HSD3B1 variant

Prostate cancer is driven by stimulation of the androgen receptor (AR) with testosterone and the potent metabolite 5α-dihydrotestosterone; therefore, androgen deprivation, via medical or surgical castration, is the standard treatment for disease. Unfortunately, extragonadal androgen production often increases in response to castration. In particular, patients with a 1245A>C variant of HSD3B1, which encodes 3β-hydroxysteroid dehydrogenase-1(3βHSD1), exhibit rapid development of castration resistance. In this episode, Nima Sharifi and colleagues evaluated the effect of the HSD3B1(1245C) variant on metabolism of abiraterone, a drug used to block extragonadal androgens. Compared to those with HSD3B1(1245A), those with the mutation had increased levels of the metabolite 3-keto-5α-abiraterone, which has androgenic activity. These results support further investigation into the clinical consequences of increased 3-keto-5α-abiraterone in patients harboring HSD3B1(1245C).

JAK inhibitor treatment shows benefit for patients with interferonopathies

Patients with IFN-mediated autoinflammatory diseases, such as CANDLE and SAVI, present with a variety of severe manifestations, including fever and inflammatory organ damage, and have a high mortality rate. Many of these patients fail to respond to IL-1-blocking agents or other approved therapies for autoinflammatory disease.  In this episode, Gina A. Montealegre Sanchez, Raphaela Goldbach-Mansky, and colleagues present the results of compassionate use, dose-escalation study of the JAK1/2 inhibitor baricitinib in small cohort of patients with interferonopathies. Baricitinib treatment reduced clinical manifestations and inflammatory biomarkers in most patients with few adverse effects, supporting the use of JAK inhibitors for this subtype of autoinflammatory disease.

REV-ERBα controls the clock in the lung

There is a strong variation in pulmonary inflammation depending on the time of day. Airway epithelial cells have been shown to mediate rhythmic inflammatory responses, and loss of the central clock component BMAL1 in airway epithelium augments inflammation. It is not clear how BMAL1 regulates lung inflammation; however, REV-ERB transcription factors, have been proposed to regulate immune function downstream of BMAL1. In this episode, David Ray, Marie Pariollaud and colleagues provide evidence that REV-ERBα couples the pulmonary clock to innate immunity. Inflammatory stimuli were shown to promote REV-ERBα degradation, and complete lack of REV-ERBα further enhanced inflammation in the lungs in following inflammatory challenge. Together, these results identify REV-ERBα as a regulator of rhythmic inflammatory responses in the lung and provide rationale for further exploration of REV-ERBα as a target for inflammatory disease.

Immune tolerance-like pathway inhibits repair following white matter injury

White matter injury is associated with neurological dysfunction in a variety of conditions, ranging from cerebral palsy to vascular dementia. Oligodendrocyte progenitor cells (OPCs) are able to regenerate themselves and initiate a repair response following injury; however, the release of hyaluronic acid from the ECM following white matter injury impairs OPC maturation and remyelination. In this episode, Stephen Back and colleagues identify a bioactive hyaluronan fragment (bHAf) that selectively blocks OPC differentiation via activation of a noncanonical TLR4/AKT/FoxO3 signaling pathway. These results elucidate a mechanism by which white matter injury prevents repair and suggest that strategies to overcome this block in OPC maturation have potential for promoting regeneration after injury.

Vaginal epithelial shedding mediates ascending group B streptococcus infection

Group B streptococcus (GBS) is part of the normal vaginal flora of approximately 25% of healthy women. Unfortunately, GBS is associated with adverse pregnancy outcomes, due to in utero infection, and can cause serious infections in newborns, including pneumonia, sepsis, and meningitis. In this episode, Lakshmi Rajagopal and colleagues demonstrate that GBS promotes shedding of the vaginal epithelium, which in turn increases bacterial dissemination and ascending GBS infection. Importantly, prevention of epithelial exfoliation in murine models reduced ascending GBS infection and improved pregnancy outcomes.