Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS.

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Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation.

The skin mucus of gilthead sea bream was mapped by one-dimensional gel electrophoresis followed by liquid chromatography coupled to high resolution mass spectrometry using a quadrupole time-of-flight mass analyzer. More than 2000 proteins were identified with a protein score filter of 30. The identified proteins were represented in 418 canonical pathways of the Ingenuity Pathway software. After filtering by canonical pathway overlapping, the retained proteins were clustered in three groups. The mitochondrial cluster contained 59 proteins related to oxidative phosphorylation and mitochondrial dysfunction. The second cluster contained 79 proteins related to antigen presentation and protein ubiquitination pathways. The third cluster contained 257 proteins where proteins related to protein synthesis, cellular assembly, and epithelial integrity were over-represented. The latter group also included acute phase response signaling. In parallel, two-dimensional gel electrophoresis methodology identified six proteins spots of different protein abundance when comparing unstressed fish with chronically stressed fish in an experimental model that mimicked daily farming activities. The major changes were associated with a higher abundance of cytokeratin 8 in the skin mucus proteome of stressed fish, which was confirmed by immunoblotting. Thus, the increased abundance of markers of skin epithelial turnover results in a promising indicator of chronic stress in fish.

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Skin mucus of gilthead sea bream (sparus aurata l.). protein mapping and regulation in chronically stressed fish

Although glomerular filtration rate (GFR) in children can be measured using a gold-standard technique following injection of an exogenous marker, this invasive and cumbersome technique is not widely available and GFR is commonly estimated using serum levels of endogenous markers. Creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin are well-established endogenous markers of kidney function. These markers differ in site of production and effects of diet and medication, as well as renal-tubular handling and extra-renal elimination. For each marker, different methods are available for measurement. Importantly, the measurements of creatinine and cystatin C have recently been standardized with the introduction of international reference standards. In order to allow estimation of GFR from serum marker concentrations, different equations for estimated GFR (eGFR) have been developed in children, using simple or more complex regression strategies with gold standard GFR measurements as a dependent variable. As a rule, estimation strategies relying on more than one marker - either by calculating the average of single parameter equations or by using more complex equations incorporating several parameters - outperform eGFR estimations using only a single marker. This in-depth review will discuss the physiology, measurement and clinical use of creatinine, urea, cystatin C, beta-trace protein, and beta-2 microglobulin in children. It will also address the generation of eGFR equations in children and provide an overview of currently available eGFR equations for the pediatric age group.

Endogenous markers for kidney function in children: a review.

// Yu-Hang Zhang 1, 2, * , Tao Huang 2, * , Lei Chen 4, * , YaoChen Xu 5 , Yu Hu 2 , Lan-Dian Hu 2 , Yudong Cai 3 and Xiangyin Kong 2 1 Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of China 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China 3 School of Life Sciences, Shanghai University, Shanghai 200444, People’s Republic of China 4 College of Information Engineering, Shanghai Maritime University, Shanghai 201306, People’s Republic of China 5 Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Lan-Dian Hu, email: ldhu2013@163.com Yudong Cai, email: cai_yud@126.com Xiangyin Kong, email: xykong@sibs.ac.cn Keywords: cancer detection, liquid biopsy, RNA-seq data, support vector machine, maximum relevance minimum redundancy Received: June 15, 2017     Accepted: August 16, 2017     Published: September 15, 2017 ABSTRACT Detection and diagnosis of cancer are especially important for early prevention and effective treatments. Traditional methods of cancer detection are usually time-consuming and expensive. Liquid biopsy, a newly proposed noninvasive detection approach, can promote the accuracy and decrease the cost of detection according to a personalized expression profile. However, few studies have been performed to analyze this type of data, which can promote more effective methods for detection of different cancer subtypes. In this study, we applied some reliable machine learning algorithms to analyze data retrieved from patients who had one of six cancer subtypes (breast cancer, colorectal cancer, glioblastoma, hepatobiliary cancer, lung cancer and pancreatic cancer) as well as healthy persons. Quantitative gene expression profiles were used to encode each sample. Then, they were analyzed by the maximum relevance minimum redundancy method. Two feature lists were obtained in which genes were ranked rigorously. The incremental feature selection method was applied to the mRMR feature list to extract the optimal feature subset, which can be used in the support vector machine algorithm to determine the best performance for the detection of cancer subtypes and healthy controls. The ten-fold cross-validation for the constructed optimal classification model yielded an overall accuracy of 0.751. On the other hand, we extracted the top eighteen features (genes), including TTN, RHOH, RPS20, TRBC2, in another feature list, the MaxRel feature list, and performed a detailed analysis of them. The results indicated that these genes could be important biomarkers for discriminating different cancer subtypes and healthy controls.

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Identifying and analyzing different cancer subtypes using RNA-seq data of blood platelets.

PD1 blockade is effective in a subset of patients with B-cell lymphoma (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To study PD1 resistance, we used an isoform-selective histone deacetylase inhibitor (HDACi; OKI-179), and a mouse mature B-cell lymphoma, G1XP lymphoma, immunosuppressive features of which resemble those of human B-cell lymphomas, including downregulation of MHC class I and II, exhaustion of CD8+ and CD4+ tumor-infiltrating lymphocytes (TIL), and PD1-blockade resistance. Using two lymphoma models, we show that treatment of B-cell lymphomas refractory to PD1 blockade with both OKI-179 and anti-PD1 inhibited growth; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated with MHC class II expression level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. In addition, we found that different HDACis exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas. Our study highlights the immunologic effects of HDACis on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and the individual profiles of HDACi.

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Histone Deacetylase Inhibition Sensitizes PD1 Blockade-Resistant B-cell Lymphomas.

Objective:
This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin (β2M), a conservative immune molecule in vertebrate.

Xiao-Guang Wang

Papers

The Implication and Significance of Beta 2 Microglobulin: A Conservative Multifunctional Regulator.