The Protein Landscape of Chronic Lymphocytic Leukemia (CLL)

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry (DIA-MS) and integrated the results with genomic, transcriptomic, ex vivo drug response and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X, and MED12 to influence protein expression (FDR < 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal component analysis (1055 and 542 differentially expressed proteins, FDR=5%). Gene set enrichment analyses of CLL with trisomy 12 implicated BCR/PI3K/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors including BTK and MEK inhibitors. STAT2 was upregulated in U-CLL, trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a non-redundant layer of information in tumor biology, and provides a protein expression reference map for CLL

An Assessment Report on Issues of Concern: Chemicals and Waste Issues Posing Risks to Human Health and the Environment

Many countries and regions have set up regulatory and policy frameworks to achieve sound chemicals and waste management. In addition to national and regional efforts, the international community has taken concerted joint actions to address specific issues of concern, including chemicals that can be transported over long distances by wind and water, are transported through global trade in resources, products and waste, or are used or are present in many countries. Substantial progress has been made by the international community, including establishment of several multilateral environmental agreements (MEAs) and international initiatives. However, as assessed by the Global Chemicals Outlook II (GCO-II), the global goal of sound chemicals and waste management in ways that lead to minimised adverse effects on human health and the environment has not been achieved by 2020. Ambitious international action is urgently required to ensure reaching these goals in the foreseeable future. This report responds to Resolution 4/8 by the United Nations Environment Assembly (UNEA) and aims to inform the international community about the current situation of specific issues of concern, based on a review of evidence published within the past decade. It is meant to inform and support decision making at UNEA and other international forums working towards sound chemicals and waste management. After introduction and methods chapters, Chapter 3 assesses the eight emerging policy issues and issues of concern (for simplicity, hereafter both are referred to as “issues of concern”) identified by the International Conference on Chemicals Management (ICCM) under the Strategic Approach to International Chemicals Management (SAICM). It reviews how current regulatory and policy frameworks address them by specific instruments and actions, building on GCO-II findings and highlighting challenges and opportunities. Chapter 4 addresses the 11 issues with emerging evidence of risks identified by GCO-II. It assesses current exposure as well as instruments and actions under current regulatory and policy frameworks, highlighting challenges and opportunities. It also provides background information on environmental or human health effects of the issues based on existing assessments by national governments and intergovernmental institutions, to raise awareness among governments and stakeholders. Chapter 5 presents a “thought starter” on identification of issues of concern, including a review of existing approaches, a map of other current relevant initiatives, and considerations of potential areas in which future issues of concern might be identified and possible identification processes. Chapter 6 provides an overarching outlook for future international work on issues of concern

Mortality after surgery in Europe: a 7 day cohort study

Background: Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.Methods: We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ² and Fisher’s exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p&lt;0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.Findings: We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19 1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).Interpretation: The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.Funding: European Society of Intensive Care Medicine, European Society of Anaesthesiology