Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy.

Beauvoir, Ernaux, and Me: On Age, Disability, and Dying Well.

Can the fraught relation between disability and aging ever become untangled? What is the place of the catastrophically disabled in a time when giving voice and being seen are significant lodestars of political activism? And what becomes of the caregivers, who often labor in silence, and who hope to work well enough just to get through another day? This essay draws on the memoirs of Simone de Beauvoir, Annie Ernaux, Amy Bloom, and my own experiences to show the complicated imbrications of age, disability, and caretaking. I attempt to demonstrate through these experiences that age and disability, which appear to be intimately woven together, are oftentimes misleadingly connected. I suggest that an ethic of vulnerability, rather, is a more useful heuristic that avoids collapsing the categories of age and disability together.

Nutrient-driven histone code determines exhausted CD8 T cell fates.

Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity.

SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections.

Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection.

Protocol for a multicentric, double-blind, randomised controlled trial of hyperbaric oxygen therapy (HBOT) versus sham for treating vaso-occlusive crisis (VOC) in sickle cell disease (SCD) in patients aged 8 years or older (HBOT-SCD study).

Introduction: Sickle cell disease (SCD) is one of the most common genetic diseases in the world, annually affecting approximately 310 000 births and causing >100 000 deaths. Vaso-occlusive crisis (VOC) is the most frequent complication of SCD, leading to bone pain, thoracic pain (acute chest syndrome) and/or abdominal spasms. It is the main cause of mortality in patients with SCD, reducing life expectancy.