Psychosocial consequences related to coronavirus disease 2019 may place individuals at a heightened likelihood of opioid overdose or relapse. 1,2 In 1 study, 2 emergency medical services responses to opioid overdoses in Kentucky were increased in the early weeks following the COVID-19 state emergency declaration compared with the 52 previous days. This increased risk of opioid overdose may be particularly concerning among Black patients, who have been overrepresented in COVID-19-related infections, hospitalizations, and deaths, as well as associated socioeconomic consequences. [3][4][5] Given that emergency departments offer an opportune setting to initiate treatment, this study compared numbers of nonfatal, unintentional opioid-related opioid overdoses presenting to an urban emergency department during the early months of the pandemic relative to the previous year.
S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.
Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6β4 promotes cell survival. TP53 mutations and integrin α6β4 overexpression co-occur in many aggressive malignancies. Due to the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin β4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 expression is elevated in SCC compared to adenocarcinoma (P<0.0001), which was confirmed in external gene expression datasets (P<0.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=0.0048), and with reduced overall patient survival (Hazard ratio 1.46, 95% confidence interval 1.01 to 2.09, P=0.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression datasets (Hazard ratio 1.49, 95% confidence interval 1.31 to 1.69, P<0.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin β4 is overexpressed in NSCLC where it is an adverse prognostic marker.
The fibrosis-4 index (FIB-4), developed to predict fibrosis in liver disease, was used to identify patients with COVID-19 who will require ventilator support as well as associated with 30-day mortality. Multivariate analysis found obesity (OR 4.5), diabetes (OR 2.55), and FIB-4 ≥ 2.67 (OR 3.09) independently associated with need for mechanical ventilation. When controlling for ventilator use, gender, and comorbid conditions, FIB-4 ≥ 2.67 was also associated with increased 30-day mortality (OR 8.4; 95% CI 2.23-31.7). While it may not be measuring hepatic fibrosis, its components suggest that increases in FIB-4 may be reflecting systemic inflammation associated with poor outcomes
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