Zhao, Y. D. | Search bioRxiv

bioRxiv2024

From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis

BackgroundMyocarditis leads to dilated cardiomyopathy (DCM) with one-third failing to recover normal ejection fraction (EF50%), and there is a critical need for prognostic biomarkers to assess risk of nonrecovery. Cardiac myosin (CM) autoantibodies (AAbs) cross-reactive with the {beta}-adrenergic receptor ({beta}AR) are associated with myocarditis/DCM, but their potential for prognosis and functional relevance is not fully understood. MethodsCM AAbs and myocarditis-derived human monoclonal antibodies (mAbs) were investigated to define pathogenic mechanisms and CM epitopes of nonrecovery. Myocarditis patients who do not recover ejection fraction (EF<50%) by one year were studied in a longitudinal (n=41) cohort. Sera IgG and human mAbs were investigated for autoreactivity with CM and CM peptides by ELISA, protein kinase A (PKA) activation, and transcriptomic analysis in H9c2 heart cell line. ResultsCM AAbs were significantly elevated in nonrecovered compared to recovered patients and correlated with reduced EF (<50%). CM epitopes specific to nonrecovery were identified. Transcriptomic analysis revealed serum IgG and mAb 2C.4 induced fibrosis/apoptosis pathways in vitro similar to isoproterenol treated cells. Sera IgG and 2C.4 activated PKA in an IgG and {beta}AR-dependent manner. Endomyocardial biopsies from myocarditis/DCM revealed IgG+ trichrome+ tissues. ConclusionsCM AAbs were significantly elevated in nonrecovered patients, suggesting novel prognostic relevance. CM AAbs correlated with lower EF, and Ab-induced fibrosis/apoptosis pathways suggested a role for CM AAbs in patients who do not recover and develop irreversible heart failure. Homology between CM and {beta}ARs supports mechanisms related to cross-reactivity of CM AAbs with the {beta}AR, a potential AAb target in nonrecovery.

immunology↗

bioRxiv2018

A Tumor Suppressor-Regulated Cell Cycle Derived Gene Signature Is Prognostic Of Recurrence Risk In Prostate Cancer

BackgroundThe clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.\n\nMethodsWe used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analysis were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SIgCheck software.\n\nResultsLow levels of Tmeff2 mRNA significantly (p<0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9[≤]HR[≥]4.1; p[≤]0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96[≤]HR[≥]4.28; p[≤]0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017).\n\nConclusionsThis study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.

cancer biology↗