COMMD1 promotes the ubiquitination of NF‐κB subunits through a cullin‐containing ubiquitin ligase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102213/1/emboj7601489.pd

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

Tumor lysate versus peptide loaded dendritic cell vaccination strategies for active cancer immunotherapy.

Dendritic cells (DCs) have been exploited for use in tumor immunotherapy due to their unique ability to efficiently prime tumor specific T cells in vivo. Recent work has shown that using tumor lysate-pulsed DCs (TL-DCs) is more effective in treating established tumors than peptide-pulsed (PP) DC-based vaccines. We compared the capacity of these two vaccination strategies to elicit anti-tumor T cell responses in vitro and in vivo using the murine B16 melanoma model. DCs prepared from bone marrow cultures containing GM-CSF and IL-4 were endocytic, and expressed MHC and co-stimulatory molecules necessary for priming of naive T cells. Exposure of these DCs to necrotic B16 tumor lysate did not induce DC maturation. Vaccination with DCs loaded with tumor lysate or an MHC class I-restricted melanoma peptide (TRP2180--188 or hgp10025--33 ) promoted protective anti-tumor immunity. These results were associated with the elicitation of IFNgamma and cytotoxic tumor-specific T cell responses. TL-DC immunization promoted priming not restricted to defined MHC class I-restricted immunodominant epitopes, and also targeted the CD4+ T cell compartment. These findings suggest that eliciting a broader tumor-specific T cell response with TL-DC vaccination, may confer an enhanced ability to treat established tumors when compared to PP-DC vaccination strategies.Ph.D.Health and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124877/2/3163878.pd

CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa B signaling

NF-kappa B is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory I kappa B proteins. In addition, the inactivation of DNA-bound NF-kappa B is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-kappa B blockade. Indeed, patient-derived cells demonstrated impaired NF-kappa B activation due to decreased I kappa B ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of I kappa B proteins. Taken together, our results indicate that CCDC22 participates in NF-kappa B activation and that its deficiency leads to decreased I kappa B turnover in humans, highlighting an important regulatory component of this pathway

Assessment of the worldwide burden of critical illness: The Intensive Care Over Nations (ICON) audit

Background Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality.Methods 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel logistic regression with three levels: patient, hospital, and country.Findings 10 069 patients were included from ICUs in Europe (5445 patients; 54.1%), Asia (1928; 19.2%), the Americas (1723; 17.1%), Oceania (439; 4.4%), the Middle East (393; 3.9%), and Africa (141; 1.4%). Overall, 2973 patients (29.5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16.2% (95% CI 15.5-16.9) across the whole population and 25.8% (24.2-27.4) in patients with sepsis. Hospital mortality rates were 22.4% (21.6-23.2) in the whole population and 35.3% (33.5-37.1) in patients with sepsis. Using a multilevel analysis, the unconditional model suggested significant between-country variations (var=0.19, p=0.002) and between-hospital variations (var=0.43, p<0.0001) in the individual risk of in-hospital death. There was a stepwise increase in the adjusted risk of in-hospital death according to decrease in global national income.Interpretation This large database highlights that sepsis remains a major health problem worldwide, associated with high mortality rates in all countries. Our findings also show a significant association between the risk of death and the global national income and suggest that ICU organisation has an important effect on risk of death