This series showcases video summaries of new findings published in the Journal of Clinical Investigation. This format allows authors to to provide a personally guided tour of their results and makes the research more accessible to a broad readership. The JCI accepts videos from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Alcohol abuse is a major risk factor for morbidity and disability throughout the world, and treatment options are limited for this complex psychiatric condition. In this episode, Leandro Vendruscolo and colleagues demonstrate that administration of the glucocorticoid receptor antagonist mifepristone reduces alcohol intake in alcohol-dependent rats, but not in nondependent animals. Moreover, in a double-blinded study of 56 alcohol-dependent human subjects, mifepristone treatment substantially reduced alcohol craving and alcohol consumption compared to placebo. The results of this study support further evaluation of mifepristone as a therapeutic strategy for the treatment of alcoholism.
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by increased type I IFN and circulating apoptotic cell-derived autoantigens (AC-Ags), both of which drive autoantibody production by B cells. In this episode, John Mountz, Hui-Chen Hsu, and Hao Li describe a mechanism by which type 1 IFN prevents clearance of ACs by marginal zone macrophages (MZMs) in SLE. The authors found that in murine SLE models, type I IFN increased follicular translocation of MZ B cells in the spleen, which disrupted the interaction between these B cells and MZ macrophages (MZMs). The interaction between MZ B cells and MZMs was shown to activate the megakaryoblastic leukemia 1–mediated (MKL1-mediated) mechanosensing pathway, which was essential for MZMs to phagocytize ACs and thereby prevent follicular entry of AC-Ags. Moreover, these defects were also present in spleens from patients with SLE. The results of this study suggest that strategies to maintain this mechanosensing pathway may block follicular entry of AC-Ags and prevent the development of autoantibodies against these antigens.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening condition that results from the development of maternal antibodies that target and destroy fetal platelets. Intracranial hemorrhage (ICH) is the most serious complication of FNAIT and is thought to be the result of severe thrombocytopenia. In this episode, Heyu Ni and colleagues present evidence that the development of ICH in FNAIT specifically occurs as the result of maternal anti-platelet β3 integrins and not as the result of maternal antibodies against other platelet factors. In a murine model of anti–β3 integrin–mediated FNAIT, ICH was the result of impaired angiogenesis and was prevented by administration of intravenous immunoglobulin. The results of this study suggest that current platelet transfusion therapies for FNAIT should be reexamined and intravenous immunoglobulin be further explored to treat this disease.
The inherited disorder dyskeratosis congenita is characterized by short telomeres, mucocutaneous abnormalities, and bone marrow failure. The underlying genetic mutations are known in ~40% of cases and are found within genes associated with telomere maintenance and function. In this episode, Tom Vulliamy and Hemanth Tummala discuss their work, which identifies biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in three families with severe dyskeratosis congenita. These mutations inhibit the deadenylation activity of PARN, resulting in the downregulation of 4 genes involved in telomere maintenance and shortened telomeres. The results of this study establish a causative role for PARN in a severe form of dyskeratosis congenita.
Mutations in the RAS oncogene are present in almost 25% of all cancers. Direct targeting of RAS for limiting these cancers has been challenging; therefore, elucidation of the pathways downstream of RAS has potential to provide therapeutic targets. In this episode, David Virshup and Jit Kong Cheong discuss their work, which identifies the serine/threonine kinase casein kinase 1a (CK1a) as a key negative regulator of oncogenic RAS-induced autophagy. Combined pharmacological inhibition of both CK1a and autophagy attenuated the growth of RAS-driven tumor xenografts. The results of this study support further exploration of CK1a as a therapeutic target for oncogenic RAS-driven cancers.
Copyright © 2015 American Society for Clinical Investigation