Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The GEOTRACES Intermediate Data Product 2014

The GEOTRACES Intermediate Data Product 2014 (IDP2014) is the first publicly available data product of the international GEOTRACES programme, and contains data measured and quality controlled before the end of 2013. It consists of two parts: (1) a compilation of digital data for more than 200 trace elements and isotopes (TEIs) as well as classical hydrographic parameters, and (2) the eGEOTRACES Electronic Atlas providing a strongly inter-linked on-line atlas including more than 300 section plots and 90 animated 3D scenes. The IDP2014 covers the Atlantic, Arctic, and Indian oceans, exhibiting highest data density in the Atlantic. The TEI data in the IDP2014 are quality controlled by careful assessment of intercalibration results and multi-laboratory data comparisons at cross-over stations. The digital data are provided in several formats, including ASCII spreadsheet, Excel spreadsheet, netCDF, and Ocean Data View collection. In addition to the actual data values the IDP2014 also contains data quality flags and 1-? data error values where available. Quality flags and error values are useful for data filtering. Metadata about data originators, analytical methods and original publications related to the data are linked to the data in an easily accessible way. The eGEOTRACES Electronic Atlas is the visual representation of the IDP2014 data providing section plots and a new kind of animated 3D scenes. The basin-wide 3D scenes allow for viewing of data from many cruises at the same time, thereby providing quick overviews of large-scale tracer distributions. In addition, the 3D scenes provide geographical and bathymetric context that is crucial for the interpretation and assessment of observed tracer plumes, as well as for making inferences about controlling processes

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

<div><p>Ovarian cancer is a highly lethal disease with poor prognosis and especially in high-grade tumor. Emerging evidence has reported that aberrant upregulation and activation of GRB7, ERK as well as FOXM1 are closely associated with aggresivenesss of human cancers. However, the interplay between these factors in the pathogenesis of human cancers still remains unclear. In this study, we found that GRB7 (<em>P</em><0.0001), ERK phosphorylation (<em>P</em><0.0001) and FOXM1 (<em>P</em> = 0.001) were frequently increased and associated with high-grade tumors, as well as a high tendency in association with advanced stage ovarian cancer by immunohistochemical analysis. Intriguingly, the expressions of GRB7 (<em>P</em><0.0001), ERK phosphorylation (<em>P</em><0.001) and FOXM1 (<em>P</em><0.001) showed a significant stepwise increase pattern along Grade 1 to Grade 3 ovarian cancers. Biochemical studies using western blot analysis demonstrated that enforced expression or knockdown of GRB7 showed GRB7 could elevate the levels of ERK phosphorylation and FOXM1, whereas enforced expression of FOXM1 could not alter levels of GRB7 and ERK phosphorylation. But inhibition of ERK signaling by U0126 or PD98059 could reduce the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, suggesting that GRB7, ERK and FOXM1 are regulated orderly. Moreover, inhibition of ERK activity by U0126 or PD98059, or decreased FOXM1 expression by Thiostrepton significantly inhibited cell migration/invasion, tumor growth <em>in vitro</em> and <em>in vivo</em>. Collectively, our findings confer that targeting GRB7/ERK/FOXM1 signaling cascade may be a promising molecular therapeutic choice in combating ovarian cancer.</p> </div

Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis

Abstract Background Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. Methods PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. Results Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. Conclusions This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases

Inhibition of ERK phosphorylation or FOXM1 expression reduced tumor growth in a mouse xenograft model.

<p>(A) The GRB7 stably expressing A2780cp cells (Acp-GRB7) were subcutaneously injected into the right flank of nude mice. Mice were divided into 5 groups (5 mice per group) and treated with either DMSO as a control, or U0126 (25 or 50 µM/kg) or Thiostrepton (200 or 300 µM/kg) for every 3-day since on day 6 (Arrows represent the injections). The relative tumor size was calculated relative to those of the first day of treatment (day 0) and are represented as relative mean size (%)±SE for each group (*<i>P</i> = 0. 032, **<i>P</i><0.01, and ***<i>P</i> = 0. 005, are significantly different from the DMSO control group, Student <i>t</i>-test). (B) The representative pictures and bar charts show the average tumor weight of each group taken on day 18. (*<i>P</i> = 0. 043, **<i>P</i> = 0. 001, and ***<i>P</i><0.02, are significantly different from the DMSO control group, Student <i>t</i>-test).</p

Clinico-pathological analysis of GRB7, ERK phosphorylation and FOXM1 expressions in ovarian cancer tissue array (OVC1021).

<p>Clinico-pathological analysis of GRB7, ERK phosphorylation and FOXM1 expressions in ovarian cancer tissue array (OVC1021).</p

GRB7/ERK/FOXM1 was regulated in the same signaling axis.

<p>(A) Treatment with U0126 (5 µM) showed a significant reduction in the expression of ERK phosphorylation accompanied with FOXM1 in ovarian cancer cells time dependently, whereas no change in GRB7 expression was found in A2780cp cells. (B) Treatment of Thiostrepton (20 µM) remarkably reduced the expression of FOXM1 only but no change in the expressions of GRB7 and ERK phosphorylation in A2780cp cells (<i>left</i>). Depletion of FOXM1 by siRNA knockdown did not alter the expression of GRB7 and ERK phosphorylation (<i>right</i>). C, siRNA scrambled control. si1, si2 and si3 siRNAs targeting three different regions of human FOXM1 and knockdown the expression of FOXM1 by 60%, 45% and 70% respectively. (C) Two out of four GRB7 shRNA constructs (sh1 and sh2) showed ∼70% knockdown of GRB7 accompanied with a reduction of ERK phosphorylation and FOXM1 expressions in OVCA433 cells. The scrambled control (NC) was used as negative control. (D) Enforced expression of GRB7 increased ERK phosphorylation and FOXM1. However, treatment with either U0126 (10 µM) or PD98059 (20 µM) could suppress the induced ERK phosphorylation and FOXM1 in A2780cp and OVCA433 ovarian cancer cells.</p

DVL3 and β-catenin are frequently up-regulated and associated with augmented Wnt/β-catenin signaling activity in cervical cancer.

<p>(A) Western blot analysis showed that only the level of DVL3 but not DVL1 and DVL2 was significantly up-regulated in cervical cancer cell lines when compared with the normal cervix cell lines. (B) Real time q-PCR revealed the mRNA of <i>DVL3</i> was obviously higher among cervical cancer cell lines when compared with the normal cervix cell lines. The value of NC105 was used to normalize other cell lines. (C) Immunohistochemical analysis showed that both DVL3 and β-catenin were upregulated on cervical cancer tissues when compared with normal cervix samples. DVL3 was distributed in the cytoplasmic region whereas β-catenin was located in both the cytoplasmic and nuclear regions. (Magnification: 20x) (D) Luciferase reporter assay revealed that transient transfection of DVL3-expressing plasmid could increase β-catenin transcriptional activity in HEK293 cells.</p