IMPORTANCE Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. OBJECTIVE To test whether tocilizumab decreases mortality in this population. DESIGN, SETTING, AND PARTICIPANTS The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. EXPOSURES Treatment with tocilizumab in the first 2 days of ICU admission. MAIN OUTCOMES AND MEASURES Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. RESULTS Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
Purpose Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). Methods We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO 2 /FiO 2 < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model. Results Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41–58), 137 (72.1%) were men, and the median PaO 2 /FiO 2 prior to ECMO initiation was 72 (IQR 61–90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41–0.74). Results were similar in a secondary analysis limited to patients with PaO 2 /FiO 2 < 80 (HR 0.55; 95% CI 0.40–0.77). Conclusion In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-020-06331-9.
Mounting evidence demonstrates that long non-coding RNAs (lncRNAs) are novel transcripts governing multiple biological processes, and their dysregulation is involved in the development and progression of multiple types of cancers. Small Nucleolar RNA Host Gene 20 (SNHG20) is a 2183 bp lncRNA, and its overexpression predicts poor prognosis in colorectal cancer and hepatocellular carcinoma. However, the clinical relevance of SNHG20 and its molecular mechanisms affecting cancer cell phenotype have not been documented. Here, we found that SNHG20 was upregulated in non-small cell lung cancer (NSCLC) tissues compared with normal samples. Higher SNHG20 expression was significantly associated with advanced tumor, lymph node and metastases (TNM) stage and tumor size, as well as poorer overall survival. Moreover, knockdown of SNHG20 repressed NSCLC cell proliferation, migration and induced cell apoptosis. Mechanistic investigations revealed that SNHG20 could interact with EZH2 (enhancer of zeste homolog 2), thereby repressing P21 expression. Furthermore, rescue experiments indicated that SNHG20 functioned as an oncogene partly via repressing p21 in NSCLC cells. Taken together, our findings demonstrate that SNHG20 is a new candidate for use in NSCLC diagnosis, prognosis and therapy.
Recently, long non-coding RNAs (lncRNAs) have been recognized as playing key roles in regulating cellular processes, such as proliferation, invasion, and metastasis. These lncRNAs have been shown to be abnormally expressed in tumorigenic processes. However, the role and clinical relevance of LUCAT1 in non-small-cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of LUCAT1 was significantly up-regulated in NSCLC tissues compared to non-tumor tissues, and its expression was associated with tumor size, tumor–node–metastasis (TNM) stage and overall survival (OS). Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo. Mechanistic investigations showed that LUCAT1 plays a key role in G0/G1 arrest. We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation. In summary, our results show that LUCAT1 could regulate tumorigenesis of NSCLC and be biomarker for poor prognosis in NSCLC.
BackgroundOvarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined.ResultsIn this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3′ untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment.ConclusionsOur data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1412-6) contains supplementary material, which is available to authorized users.
This study is the first to suggest that HOTAIR plays an important role in the carcinogenesis of endometrial cancer. Targeting HOTAIR may be a novel therapeutic strategy for endometrial cancer.
ObjectivesRAB27B is a member of the Rab family GTPases involved in vesicle trafficking, and p53 has recently been implicated in regulating the exosome secretion pathway. Because exosome secretion plays an important role in modulating tumor microenvironment and invasive growth, we hypothesized that RAB27B and p53 expression might be associated with the aggressive behavior in pancreatic ductal adenocarcinoma, one of the most deadly human malignancies.MethodsWe determined protein expression of RAB27B and p53 in 260 pancreatic tissues (186 malignant and 74 normal or benign) by immunohistochemistry analysis on tissue microarray and their correlation with patients' clinical parameters and overall survival.ResultsWe found that a high RAB27B protein expression (RAB27B+) was significantly associated with perineural and vascular invasion, as well as distant metastasis. Patients with a high RAB27B expression had significantly poorer overall survival in both univariate and multivariate analyses. A significant correlation between RAB27B and p53 expression was observed.ConclusionsOur data indicate that RAB27B expression is an independent prognostic marker for pancreatic ductal adenocarcinoma and suggest that RAB27B-regulated exosome secretion pathway represents a novel therapeutic target in pancreatic cancer.
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