The p53-induced Wig-1 protein : identification of mRNA targets and role as a survival factor in development and cancer

The tumor suppressor p53 is activated in response to a variety of stress conditions. Upon activation, p53 can trigger apoptosis or cell cycle arrest, or regulate metabolism and other cellular processes by transactivation of its targets genes. Wig-1 (also named ZMAT3) is a p53 target gene, and both Wig-1 mRNA and protein levels increase upon p53 activation. Wig-1 is a zinc finger protein that binds to double strand RNA. It is an AU-rich element (ARE) binding proteins (ARE-BPs) and acts as a regulator of mRNA stability via direct binding to AREs. The Wig-1 gene is localized to the long arm of chromosome 3(3q26), a region that is frequently amplified in cancer. In this thesis, I aimed to identify new Wig-1 mRNA targets and investigate the biological implications of the regulation of selected targets. I also explored Wig-1 protein expression in tumors as well as its clinical relevance, and determined the role of Wig-1 in mouse development. In paper I, we performed a microarray analysis of HCT116 colon cancer cells with or without Wig-1 knockdown and identified Wig-1 regulated mRNAs. We also discovered that Wig-1 promotes cell cycle arrest rather than cell death upon cellular stress through regulation of p53 targets FAS and 14-3-3σ. Wig-1 regulates FAS mRNA negatively through binding to 3’UTR AREs in FAS mRNA. In paper II, we studied Wig-1 expression in cervical carcinoma samples and found that the Wig-1 protein expression pattern in tumors is associated with patient survival. Patients with moderate nuclear Wig-1 staining and positive cytoplasmic Wig-1 staining in their tumors show better survival than patients with high nuclear Wig-1 staining and negative cytoplasmic Wig-1 staining. In paper III, we showed that Wig-1 null mice embryos die before the blastocyst stage. We also found that Wig-1 knockdown in mouse embryonic stem cells (mESCs) leads to a reduction in proliferation rate. Wig-1 binds to and regulates both c-Myc and N-Myc mRNA in mESCs. Since Myc has essential roles during embryonic development, we suggest that deficient regulation of Myc in absence of Wig-1 may explain the observed embryonic lethality. In paper IV, we performed RNA-immunoprecipitation (RIP) followed by high throughput RNA sequencing in HCT116 and Saos2 cells. We identified Wig-1 bound mRNAs and found a significant enrichment of mRNAs with AREs in their 3’UTRs as compared to unbound mRNAs. In summary, this thesis greatly expands theWig-1 targets repertoire and further explores the role of Wig-1 as a survival factor in cell growth and early embryonic development. Our findings also suggest that Wig-1 may serve as a molecular biomarker together with other conventional clinical markers for cervical cancer prognosis

Mediating effect of sustainable development practices on the relationship between information management practices and green innovation in China

AbstractThis research examines the role of information management practices termed as knowledge acquisition, knowledge dissemination, and knowledge application towards green innovation among the Small and Medium Enterprises (SMEs) working in China’s region. Moreover, the mediating role of sustainable development practices is also observed in the relationship between knowledge management and green innovation. An online survey questionnaire collected a valid sample of 364 respondents from different SMEs after the COVID-19 period to integrate its aftershocks. Furthermore, structural equation modelling was applied, and the measurement model confirms the reliability, convergent validity, and discriminant validity of latent constructs and selected items’. We confirm a direct and significant relationship between knowledge acquisition, knowledge dissemination, application, and green innovations through PLS-SEM. Besides, sustainable development indicators confirm their mediating role in the relationship between knowledge management and green innovations. This research offers meaningful theoretical and empirical contributions and suggestions for SME industries and policymakers

P-score in preoperative biopsies accurately predicts P-score in final pathology at radical prostatectomy in patients with localized prostate cancer

BACKGROUND: Prostate cancer (PCa) is a highly heterogeneous, multifocal disease, and identification of clinically significant lesions is challenging, which complicates the choice of adequate treatment. The Prostatype® score (P-score) is intended to guide treatment decisions for newly diagnosed PCa patients based on a three-gene signature (IGFBP3, F3, and VGLL3) and clinicopathological information obtained at diagnosis. This study evaluated association of the P-score measured in preoperative magnetic resonance imaging/transrectal ultrasound fusion-guided core needle biopsies (CNBs) and the P-score measured in radical prostatectomy (RP) specimens of PCa patients. We also evaluated the P-score association with the pathology of RP specimens. Furthermore, concordance of the P-score in paired CNB and RP specimens, as well as in index versus concomitant nonindex tumor foci from the same RP was investigated. METHODS: The study included 100 patients with localized PCa. All patients were diagnosed by CNB and underwent RP between 2015 and 2018. Gene expression was assessed with the Prostatype® real-time quantitative polymerase chain reaction kit and the P-score was calculated. Patients were categorized into three P-score risk groups according to previously defined cutoffs. RESULTS: For 71 patients, sufficient CNB tumor material was available for comparison with the RP specimens. The CNB-based P-score was associated with the pathological T-stage in RP specimens (p = 0.02). Moreover, the CNB-based P-score groups were in substantial agreement with the RP-based P-score groups (weighted κ score: 0.76 [95% confidence interval, 95% CI: 0.60-0.92]; Spearman's rank correlation coefficient r = 0.83 [95% CI: 0.74-0.89]; p < 0.0001). Similarly, the P-score groups based on paired index tumor and concomitant nonindex tumor foci (n = 64) were also in substantial agreement (weighted κ score: 0.74 [95% CI: 0.57-0.91]; r = 0.83 [95% CI: 0.73-0.89], p < 0.0001). CONCLUSIONS: Our findings suggest that the P-score based on preoperative CNB accurately reflects the pathology of the whole tumor, highlighting its value as a decision support tool for newly diagnosed PCa patients

Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling

Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome

International audienceBACKGROUND. Corticosteroids are widely used in patients with COVID 19, although their benefit-to-risk ratio remains controversial. METHODS. Patients with severe COVID-19–related acute respiratory distress syndrome (ARDS) were included from December 29, 2019 to March 16, 2020 in 5 tertiary Chinese hospitals. Cox proportional hazards and competing risks analyses were conducted to analyze the impact of corticosteroids on mortality and SARS–CoV-2 RNA clearance, respectively. We performed a propensity score (PS) matching analysis to control confounding factors. RESULTS. Of 774 eligible patients, 409 patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1.0 day (IQR 0.0–3.0 days) . As compared with usual care, treatment with corticosteroids was associated with increased rate of myocardial (15.6% vs. 10.4%, P = 0.041) and liver injury (18.3% vs. 9.9%, P = 0.001), of shock (22.0% vs. 12.6%, P 200 mg) and early initiation (≤3 days from hospitalization) of corticosteroid therapy were associated with a higher 28-day mortality rate. Corticosteroid use was also associated with a delay in SARS–CoV-2 coronavirus RNA clearance in the competing risk analysis (subhazard ratio 1.59, 95% CI 1.17–2.15, P = 0.003). CONCLUSION. Administration of corticosteroids in severe COVID-19–related ARDS is associated with increased 28-day mortality and delayed SARS–CoV-2 coronavirus RNA clearance after adjustment for time-varying confounders

Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

International audienceBackground: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors.Method: Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data.Results: In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as "suspected sHLH positive". Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P 1922.58 ng/mL), low platelets (2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19.Conclusions: HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH

Efficacy of Thymosin Alpha 1 in the Treatment of COVID-19: A Multicenter Cohort Study

International audienceBackground: Thymosin alpha 1 (Tα1) is widely used to treat patients with COVID-19 in China; however, its efficacy remains unclear. This study aimed to explore the efficacy of Tα1 as a COVID-19 therapy. Methods: We performed a multicenter cohort study in five tertiary hospitals in the Hubei province of China between December 2019 and March 2020. The patient non-recovery rate was used as the primary outcome. Results: All crude outcomes, including non-recovery rate (65/306 vs. 290/1,976, p = 0.003), in-hospital mortality rate (62/306 vs. 271/1,976, p = 0.003), intubation rate (31/306 vs. 106/1,976, p = 0.001), acute respiratory distress syndrome (ARDS) incidence (104/306 vs. 499/1,976, p = 0.001), acute kidney injury (AKI) incidence (26/306 vs. 66/1,976, p < 0.001), and length of intensive care unit (ICU) stay (14.9 ± 12.7 vs. 8.7 ± 8.2 days, p < 0.001), were significantly higher in the Tα1 treatment group. After adjusting for confounding factors, Tα1 use was found to be significantly associated with a higher non-recovery rate than non-Tα1 use (OR 1.5, 95% CI 1.1–2.1, p = 0.028). An increased risk of non-recovery rate associated with Tα1 use was observed in the patient subgroups with maximum sequential organ failure assessment (SOFA) scores ≥2 (OR 2.0, 95%CI 1.4–2.9, p = 0.024), a record of ICU admission (OR 5.4, 95%CI 2.1–14.0, p < 0.001), and lower PaO2/FiO2 values (OR 1.9, 95%CI 1.1–3.4, p = 0.046). Furthermore, later initiation of Tα1 use was associated with a higher non-recovery rate. Conclusion: Tα1 use in COVID-19 patients was associated with an increased non-recovery rate, especially in those with greater disease severity

Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multicentre study

International audienceObjectives: Intravenous immunoglobulin (IVIG) is commonly used to treat severe COVID-19, although the clinical outcome of such treatment remains unclear. This study evaluated the effectiveness of IVIG treatment in severe COVID-19 patients. Methods: This retrospective multicentre study evaluated 28-day mortality in severe COVID-19 patients with or without IVIG treatment. Each patient treated with IVIG was matched with one untreated patient. Logistic regression and inverse probability weighting (IPW) were used to control confounding factors. Results: The study included 850 patients (421 IVIG-treated patients and 429 non-IVIG-treated patients). After matching, 406 patients per group remained. No significant difference in 28-day mortality was observed after IPW analysis (average treatment effect (ATE) = 0.008, 95% CI –0.081 to 0.097, p 0.863). There were no significant differences between the IVIG group and non-IVIG group for acute respiratory distress syndrome, diffuse intravascular coagulation, myocardial injury, acute hepatic injury, shock, acute kidney injury, non-invasive mechanical ventilation, invasive mechanical ventilation, continuous renal replacement therapy and extracorporeal membrane oxygenation except for prone position ventilation (ATE = –0.022, 95% CI –0.041 to –0.002, p 0.028). Discussion: IVIG treatment was not associated with significant changes in 28-day mortality in severe COVID-19 patients. The effectiveness of IVIG in treating patients with severe COVID-19 needs to be further investigated through future studies