interferon

RETRACTION: Salvianolic Acid B-Induced MicroRNA-152 Inhibits Liver Fibrosis by Attenuating DNMT1-Mediated Patched1 Methylation.

F. Yu, Z. Lu, B. Chen, X. Wu, P. Dong, and J. Zheng, "Salvianolic Acid B-Induced MicroRNA-152 Inhibits Liver Fibrosis by Attenuating DNMT1-Mediated Patched1 Methylation," Journal of Cellular and Molecular Medicine 19, no. 11 (2015): 2617-2632, https://doi.org/10.1111/jcmm.12655. The above article, published online on 10 August 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties. Specifically, the GAPDH blot shown in Figure 1D was found to have been later published elsewhere by the same author group but presented in a different scientific context. Further investigation by the publisher identified additional concerns, namely that the GAPDH bands in Figures 3C and 5B had been previously published by a different author group in a different scientific context. The clarification and materials provided by the authors were insufficient to address these concerns, and the authors did not supply the original data underlying the study upon request. Accordingly, the article has been retracted, as the editors consider its conclusions to be invalid. The authors have been informed of the retraction decision but were not available for final confirmation.

Complement activation linked to type II interferon signaling in Still disease.

Huijsmans Freya M C H FMCH, Thalheim Tabea T, Bodelón Alejandra A, Rogani Greta G et al.

Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. While complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD. Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n=15), non-systemic juvenile idiopathic arthritis (JIA, n=8), and SD patients at onset (n=19), remission (n=18), and macrophage activation syndrome (n=2). Whole-blood NanoString analysis of complement and interferon-related gene expression was conducted in SD (active n=41, inactive n=33) and JIA patients (n>600). Complement products and inflammatory mediators were measured by Luminex and ELISA. Functional complement activity was evaluated in SD (active n=30, inactive n=67) and JIA sera (n=12). In vitro assays examined monocytic C1q induction and complement-mediated CD8+ T cell activation. Transcriptomic analysis of monocytes from SD patients at onset revealed enrichment of the complement cascade compared to patients in remission (Padj=3.7×10-36), ranking among the top ten upregulated pathways. Classical complement genes (C1QB/C1QC) were markedly upregulated in onset SD compared to remission SD and JIA patients. Active SD patients showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with interferon-related markers, including IL-18, CXCL9 and CXCL10. Recombinant IFN-γ induced monocytic C1q, while C1q enhanced IFN-γ production by CD8+ T cells, supporting a feed-forward loop. SD is characterized by complement activation with marked upregulation of C1q, which is closely linked to IFN-γ/type-II signaling.

Combination treatment with intravesical interferon-alpha gene therapy and an oral pan-ErbB receptor family blocker improves survival in mice with bladder cancer.

Sood Akshay A, Martini Alberto A, Genitiano Paulo P, Rauf Mikael M et al.

Intravesical interferon-alpha (IFNα) gene therapy is approved by the FDA for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Identifying resistance mechanisms and deploying targeted combination treatment strategies is a rational approach to improving treatment responses. We identified the ErbB pathway as a resistance mechanism to IFNα gene therapy, and we hypothesized that combination treatment with an ErbB pathway blocker and IFN-α could improve outcomes in resistant tumors. Murine bladder cancer cells were treated in vitro with lentiviral IFNα (LV-IFNα) gene therapy, with/without afatinib (Afa), a pan-ErbB inhibitor, and cell viability and migration assays were performed. In vivo studies were conducted in a syngeneic MB49 orthotopic murine bladder cancer model, and mice were randomized into five treatment groups and treated with single treatments: Ctrl (vehicle), LV-Ctrl, LV-IFNα, and combination treatments with LV-Ctrl/Afa or LV-IFNα/Afa. Combination therapy with LV-IFNα/Afa significantly reduced MB49 cell viability in vitro compared to all other treatment conditions. This additive effect on cell viability appeared to be driven by a combination of early-cytostatic and late-cytolytic effects. The combination treatment also markedly inhibited cell migration. Finally, the in vivo studies demonstrated improved overall survival (OS) with LV-IFNα/Afa (median OS was 49 days in the LV-IFNα/Afa group vs. 15, 14, 29, and 26 days in Ctrl, LV-Ctrl, LV-IFNα, and LV-Ctrl/Afa groups, respectively; log-rank p < 0.001). Our findings suggest that the ErbB pathway may serve as a clinically actionable resistance mechanism to intravesical IFNα gene therapy and, when targeted concurrently, it may improve treatment efficacy.

Successful Therapy of CNS Tuberculosis With Granulomatous Inflammation in Immunodeficiency.

Cagdas Deniz D, Gocmen Rahsan R, Sonmez Gamze G, Akarsu Aysegul A et al.

Central nervous system (CNS) tuberculosis (TB) carries high mortality and neurologic sequelae, especially when unrecognized inborn errors of immunity are present. We report a young woman with refractory TB meningitis, multiple intracranial tuberculomas, hydrocephalus, and intracranial hypertension despite 10 months of standard anti-TB therapy and corticosteroids. Severe vomiting led to poor adherence and severe weight loss. As immunologic evaluation suggested atypical combined immunodeficiency (CID); monthly intravenous immunoglobulin (IVIG) was started. Neurosurgery did not give indication for shunt surgery. Given the severity and presumed impaired antimycobacterial immunity, adjuvant interferon-γ (IFN-γ; 50 µg/m² 3 times weekly) was added to therapy with steroids. Vomiting resolved, weight improved, and treatment was tolerated. Serial magnetic resonance imaging showed reduction in leptomeningeal enhancement and tuberculoma burden without surgery; no neurologic sequelae developed. Next-generation sequencing identified a homozygous NHEJ1 variant, not confirmed by Sanger, but findings supported CID. In refractory CNS-TB with suspected immunodeficiency, IFN-γ, steroids, IVIG in addition to anti-TB therapy may improve outcomes and avoid neurosurgical intervention. Early immunological evaluation and host-directed therapy should be considered.