Gene expression profile predicts response to pembrolizumab

Anti-PD-1 therapy with inhibitors such as pembrolizumab has proven beneficial for multiple types of cancers. Not all patients respond to PD-1 blockade; therefore, strategies to better predict individual response to anti-PD-1 would be of great clinical benefit. In this episode, Terri McClanahan and Jared Lunceford discuss their work, which has led to the identification of a gene expression profile that correlates with clinical response to pembrolizimab. Importantly, the presence of this T cell-inflamed gene expression profile in patients prior to treatment was shown to be indicative of response in multiple cohorts and cancer types.

Neuropeptide FF acts on adipose tissue macrophages

The accumulation of macrophages with a proinflammatory phenotype in adipose tissue is a driver of obesity-associated metabolic disease. While adipose tissue macrophages are found in the lean state, these cells have an alternatively activated (M2) phenotype. In this episode, Tamás Röszer and colleagues demonstrate that adipose tissue macrophages express a receptor for the appetite-reducing neuropeptide FF and that and that neuropeptide FF promotes M2 activation and proliferation. Additionally, obesity was associated with reduced levels of circulating neuropeptide FF. Together, the results of this study reveal an important role for neuropeptide FF in maintaining metabolically beneficial macrophages in adipose tissue.

Twenty fascinating conversations

In 2012, the JCI’s Editor in Chief Howard Rockman proposed a new series focusing on the careers of today’s most accomplished physician-scientists. Since then, Editor at Large Ushma Neill has interviewed scientists as part of the Conversations with Giants in Medicine series, including Laurie Glimcher, Huda Zoghbi, and Oliver Smithies. The interviews have revealed the diverse career paths, hidden talents, and sometimes quirky personalities of this inspirational group of researchers. To reflect on her experiences, she collected her favorite moments from the series in this highlight reel.

Best of Conversations with Giants in Medicine

JCI Editor at Large Ushma S. Neill shares some of the best moments from the series Conversations with Giants in Medicine, 2012–2017.

Lymphatic vessel valves require RASA1 for development and function

Ras GTPase activating proteins (RasGAPs) control the activation of Ras, a small GTP-binding protein that regulates signal transduction pathways involved in cell growth, survival, and differentiation. Inactivating mutations the RasGAP RASA1 cause a blood and lymphatic vessel (LV) disorder known as capillary malformation-arteriovenous malformation, though exactly how loss of RASA1 function contributes to LV leakage is unclear.

This week in the JCI, research led by Philip King at University of Michigan Medical School reports that LV development and function critically depends on RASA1 activity. Ablation of RASA1 in adult mice led to specific defects in lymphatic valves that impaired the efficiency of LV pumping. Valve closure tests revealed that RASA1-deficient lymphatic vessels failed to prevent back-leak across valves. Moreover, ablating RASA1 in embryos impaired LV valve development. Together, these findings support an essential role for RASA1 in both LV formation and maintenance. 

The accompanying video visualizes LV responses to increases in downstream pressure. In the top panel, as pressure increases, LV valves in wildtype mice rapidly close to prevent backflow. In the bottom panel, valve failure in RASA1-deficient mice results in backflow into the upstream regions of the LV.