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.
Chronic itch is a common symptom and complaint for many dermatological patients. While some patients find relief with antihistamines, many do not, and the underlying pathways responsible for itch are poorly understood. In this episode, Martin Steinhoff details the identification of endothelin–converting enzyme 1 (ECE-1) as a key regulator of endothelin (ET-1), which evokes a histamine-independent pruritus through activation of ERK1/2. In murine itch models, scratching behavior was enhanced by pharmacological inhibition of ECE-1 and ameliorated by administration of an ERK1/2 inhibitor. Furthermore, this ECE-1/ER-1/ERK1/2 axis was upregulated in patients with prurigo nodularis, suggesting that this pathway has potential as a therapeutic target to relieve chronic itch.
Broadly neutralizing antibodies (BnAbs) represent a promising strategy for targeting rapidly mutating viruses, such as HIV-1. BnAbs recognize conserved epitopes and display unique characteristics that suggest that their development may be limited by immune tolerance. In this episode, Baton Haynes discusses the identification and characterization of a BnAb in an HIV-1-infected individual that developed the autoimmune disease systemic lupus erythematosus. The BnAb targeted both the HIV-1 envelope and human antigens, including dsDNA, supporting the hypothesis that lax immune control allows for maturation and production of BnAbs.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly forms of cancer, primarily due to the resistance of PDAC tumors to current therapeutic strategies. Several lines of evidence suggest that ineffective delivery of chemotherapy agents to tumor cells in the pancreas contributes to PDAC-associated treatment resistance. In this episode, Eugene Koay and Jason Fleming discuss the results of their clinical study that links pancreatic transport properties collected from PDAC patient CT scans with survival and response to the chemotherapy agent gemcitabine.
Familial Alzheimer's disease (FAD) is an early on-set, hereditary form of neurological disease with variable pathophysiology that is often associated with loss of cerebellar function and amyloid plaque formation. Diego Sepulveda-Falla and colleagues investigated how a particular PS1 mutation (PS1-E280A), present in large Columbian kindred of FAD patients, promotes disease. Postmortem evaluation of cerebellar tissue from patients revealed that PS1-E280A is associated with Purkinje cell loss, an abundance of abnormal mitochondria and loss of calcium transport proteins. Furthermore, cell culture and murine models of PS1-E280A FAD revealed that PS1alterations disrupt calcium homeostasis and mitochondrial transport within cerebellar neurons, resulting in increased amyloid plaque formation and cerebellar dysfunction.
Vitamin A and its active metabolite retinoic acid (RA) are essential for lung formation, though it is not clear if prenatal vitamin A deficiency influences postnatal lung development and function. In this episode, Wellington Cardoso provides evidence that prenatal disruption of RA signaling results in aberrant, overly differentiated smooth muscle in airways. RA deficiency-associated defects persisted, regardless of the adult vitamin A status, and manifested in airway hyperresponsiveness and structural changes in the bronchial smooth muscle. The study indicates that RA signaling in the developing lung prevents excessive smooth muscle formation.