[Abstract unavailable

Brain, Behavior, and Immunity xxx (xxxx) xxx-xxx 0889-1591/

The discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the outbreak of coronavirus disease 2019 are causing public health emergency. A handful of literatures have summarized its clinical and radiologic features, whereas therapies for COVID-19 are rather limited. In order to evaluate the efficacy of convalescent plasma therapy in COVID-19 patients, we did this timely descriptive study. 6 laboratory confirmed COVID-19 patients were enrolled and received the transfusion of ABO-compatible convalescent plasma.The efficacy of this intervention was determined by the alleviation of symptoms, changes in radiologic abnormalities and laboratory tests. No obvious adverse effect observed during the treatment. Transfusion of convalescent plasma led to a resolution of ground glass opacities (GGOs) and consolidation in patient #1, #2, #3, #4 and #6. In patient #1 and #5 who presented with SARS-CoV-2 in throat This article is protected by copyright. All rights reserved. Accepted Articleswab, convalescent plasma therapy elicited an elimination of virus. Serologic analysis indicated an immediate increase in anti-SARS-CoV-2 antibody titers in patient #2 and #3, but not in patient #1. This study indicates that convalescent plasma therapy is effective and specific for COVID-19. This intervention has a special significance for eliminating SARS-CoV-2 and is believed to be a promising state-of-art therapy during COVID-19 pandemic crisis.

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Protein arginine methyltransferase 5 (PRMT5) functions as a tumor initiator to regulate several cancer progressions, such as proliferation and apoptosis, by catalyzing the symmetrical dimethylation (me2s) of arginine residues within targeted molecules. However, the exact role of PRMT5-mediated metastasis in lung cancer is not fully understood. Here, we illustrated its potential effects in lung cancer metastasis in vivo and vitro. PRMT5 was frequently overexpressed in lung tumors, and its expression was positively related to tumor stages, lymphatic metastasis and poor outcome. In this model, PRMT5 repressed the transcription of the miR-99 family by symmetrical dimethylation of histone H4R3, which increased FGFR3 expression and in turn activated Erk1/2 and Akt, leading to cell growth and metastasis in lung cancer. Furthermore, loss of PRMT5 exerted anti-metastasis effects on lung cancer progression by blocking histone-modification of miR-99 family. Overall, this study provides new insights into the PRMT5/miR-99 family/FGFR3 axis in regulating lung cancer progression and identifies PRMT5 as a promising prognostic biomarker and therapeutic target.

Inhibition of EGFR and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathologic features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt-and MEK/ERK-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7a) leads to targeted therapy resistance via stabilization of antiapoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. ERK cooperated with GSKb to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt-and MEK/ERK-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy.

The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC.

Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non–small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2–Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227–39. ©2017 AACR.