A Web-Based Digital Contact Tracing Strategy Addresses Stigma Concerns Among Individuals Evaluated for COVID-19.

Introduction: Conventional contact tracing approaches have not kept pace with the scale of the coronavirus disease 2019 (COVID-19) pandemic and the highly anticipated smartphone applications for digital contact tracing efforts are plagued by low adoption rates attributed to privacy concerns; therefore, innovation is needed in this public health capability. Materials and Methods: This study involved a cross-sectional, nonrepresentative, online survey in the United States of individuals tested for COVID-19. Testing survey items measured the performance of conventional contact tracing programs, quantified the stigma related to the notification of COVID-19 close contacts, and assessed the acceptability of a website service for digital contact tracing. Results: A sample of 668 (19.9%) individuals met the inclusion criteria and consented to participation. Among the 95 participants with COVID-19, results were received after a median of 2 days, 63.2% interacted with a contact tracing program a median of 2 days after receiving test results, 62.1% had close contacts, and 37.1% of participants with COVID-19 and close contacts did not disclose their results to all close contacts. Among all participants, 17% had downloaded a mobile application and 40.3% reported interest in a website service. One hundred and nine participants perceived stigma with the disclosure of COVID-19 test results; of these, 58.7% reported that a website service for close contact notification would decrease this stigma. Discussion: Conventional contact tracing programs did not comprehensively contact individuals who tested positive for COVID-19 nor did so within a meaningful time frame. Digital contact tracing innovations may address these shortcomings; however, the low penetration of mobile application services in the United States indicates that a suite of digital contact tracing tools, including website services, are warranted for a more exhaustive coverage of the population. Conclusions: Public health officials should develop a complementary toolkit of digital contact tracing strategies to enable effective pandemic containment strategies.

Alterations in the Global Proteome and Phosphoproteome in Third Generation EGFR TKI Resistance Reveal Drug Targets to Circumvent Resistance.

Lung cancer is the leading cause of cancer mortality worldwide. The treatment of patients with lung cancer harboring mutant EGFR with orally administered EGFR tyrosine kinase inhibitors (TKI) has been a paradigm shift. Osimertinib and rociletinib are third-generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard of care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here we characterized the proteome and phosphoproteome of a series of isogenic EGFR-mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs, comprising the most comprehensive proteomic dataset resource to date to investigate third generation EGFR TKI resistance in lung adenocarcinoma. Unbiased global quantitative mass spectrometry uncovered alterations in signaling pathways, revealed a proteomic signature of epithelial-mesenchymal transition, and identified kinases and phosphatases with altered expression and phosphorylation in TKI-resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition, resulting in subsequent inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Anticorrelation analyses of this phosphoproteomic dataset with published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures program predicted drugs with the potential to overcome EGFR TKI resistance. The PI3K/MTOR inhibitor dactolisib in combination with osimertinib overcame resistance both in vitro and in vivo. Taken together, this study reveals global proteomic alterations upon third generation EGFR TKI resistance and highlights potential novel approaches to overcome resistance. SIGNIFICANCE: Global quantitative proteomics reveals changes in the proteome and phosphoproteome in lung cancer cells resistant to third generation EGFR TKIs, identifying the PI3K/mTOR inhibitor dactolisib as a potential approach to overcome resistance.

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer.

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer-related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.