Our understanding of the quality and duration of immunity to COVID-19 following natural infection remains important area of public health research. The long-term kinetics of IgG antibodies to the spike and nucleocapsid (N) proteins of the SARS-CoV-2 virus are of particular interest as easily measurable potential indirect markers of both previous infection and resistance to reinfection. Previous studies in hospitalized patients have found that anti-N IgG levels decline over time. We undertook this study to characterize the kinetics of anti-N IgG in a longitudinal cohort of health care workers in an acute hospital setting. All HCWs who were either employed or part of the medical staff at six acute-care hospitals in Phoenix, AZ in June 2019 were invited to participate in a long-term study of the impact of the COVID-19 pandemic on HCWs. A cohort of 1358 HCWs provided informed consent, filled out a questionnaire regarding their health care role and potential COVID-19 symptoms, and had blood drawn between June 15 th and August 15 th, 2020 (Draw 1). The questionnaire and blood draws were repeated in October 2020 (Draw 2), January 2021 (Draw 3), and April 2021. SARS-CoV-2 anti-N IgG was measured using the Abbott Architect platform, using a signal to cutoff ratio (S/Co) greater than 1.4 as a positive result. A participant's first positive result was treated as Time 0. Anti-N IgG S/Co values at each time point were summarized as mean, median, and inter-quartile range, and differences over time were tested using the Friedman's test. 290 participants (21.4%) had at least one positive IgG, with a median S/Co of 4.96, IQR 2.37-6.67. The Month 3 median S/Co was 2.32, IQR 1.34-4.22, Month 6 median was 0.96, IQR 0.51-2.05, and Month 9 median was 0.60, IQR 0.26-1.29 (See Figure). Freidman's test for differences was significant at p<0.0001 at all time points. No participant was hospitalized for their acute COVID-19 illness. 68/244 participants (27.4%) were seronegative at 3 months, 81/126 (64.3%) at six months, and 65/84 (77.4%) at nine months. In a cohort of health care workers with mild to moderate COVID-19, anti-N IgG levels steadily decreased over 9 months from the initial positive IgG. The high rates of conversion to seronegative over a relatively short time frame illustrate why antibody-based testing must be interpreted cautiously when used as a definitive marker of prior COVID infection.
Supplementary Data from Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer
Supplementary Data from Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer
Supplementary Data from Targeting the Ubiquitin–Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer
<p>A Netrin-UNC5-ITGAV/B5 pathway mediates YAP-induced cytostasis. <b>A–D,</b> A netrin blocking antibody (α-NTN) or trapping reagent (UNC5-Fc) alleviates YAP-induced cytostasis in YAP<sup>off</sup> cell lines. Cell lines and tumor types are indicated in each. Y79 cells expressed wild type YAP, whereas WERI-RB1, NCI-H209 and NCI-H2171 expressed YAP<sup>5SA</sup>. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001 compared with untreated (untr) cells; <i>n</i> = 3–5 (<b>A</b> and <b>B</b>) or 3 (<b>C</b> and <b>D</b>). <b>E,</b> Rescue of YAP-induced cytostasis in control or UNC5B knockout Y79 cells treated with an Integrin-αV/β5 blocking antibody. *, <i>P</i> < 0.05 compared with untreated sgControl cells; <i>n</i> = 3. <b>F,</b> Summary of the mechanism of YAP-induced cytostasis in YAP<sup>off</sup> cancers.</p>
<div>Abstract<p>Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAP<sup>on</sup> and YAP<sup>off</sup> classes. These transcriptional coactivators are oncogenic in YAP<sup>on</sup> cancers. In contrast, <i>YAP/TAZ</i> are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAP<sup>off</sup> cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/β5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAP<sup>off</sup> cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAP<sup>off</sup> cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAP<sup>off</sup> cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/β5 axis as a critical effector of YAP tumor suppressor activity.</p>Significance:<p>Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.</p></div>
