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      Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness

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          Abstract

          Background

          Critically ill patients with sepsis and acute respiratory distress syndrome have severely altered physiology and immune system modifications. RNA splicing is a basic molecular mechanism influenced by physiologic alterations. Immune checkpoint inhibitors, such as B and T Lymphocyte Attenuator (BTLA) have previously been shown to influence outcomes in critical illness. We hypothesize altered physiology in critical illness results in alternative RNA splicing of the immune checkpoint protein, BTLA, resulting in a soluble form with biologic and clinical significance.

          Methods

          Samples were collected from critically ill humans and mice. Levels soluble BTLA (sBTLA) were measured. Ex vivo experiments assessing for cellular proliferation and cytokine production were done using splenocytes from critically ill mice cultured with sBTLA. Deep RNA sequencing was done to look for alternative splicing of BTLA. sBTLA levels were fitted to models to predict sepsis diagnosis.

          Results

          sBTLA is increased in the blood of critically ill humans and mice and can predict a sepsis diagnosis on hospital day 0 in humans. Alternative RNA splicing results in a premature stop codon that results in the soluble form. sBTLA has a clinically relevant impact as splenocytes from mice with critical illness cultured with soluble BTLA have increased cellular proliferation.

          Conclusion

          sBTLA is produced as a result of alternative RNA splicing. This isoform of BTLA has biological significance through changes in cellular proliferation and can predict the diagnosis of sepsis.

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          Most cited references21

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          PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis.

          Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1(-/-) mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1(-/-) mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.
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            MATS: a Bayesian framework for flexible detection of differential alternative splicing from RNA-Seq data

            Ultra-deep RNA sequencing has become a powerful approach for genome-wide analysis of pre-mRNA alternative splicing. We develop MATS (multivariate analysis of transcript splicing), a Bayesian statistical framework for flexible hypothesis testing of differential alternative splicing patterns on RNA-Seq data. MATS uses a multivariate uniform prior to model the between-sample correlation in exon splicing patterns, and a Markov chain Monte Carlo (MCMC) method coupled with a simulation-based adaptive sampling procedure to calculate the P-value and false discovery rate (FDR) of differential alternative splicing. Importantly, the MATS approach is applicable to almost any type of null hypotheses of interest, providing the flexibility to identify differential alternative splicing events that match a given user-defined pattern. We evaluated the performance of MATS using simulated and real RNA-Seq data sets. In the RNA-Seq analysis of alternative splicing events regulated by the epithelial-specific splicing factor ESRP1, we obtained a high RT–PCR validation rate of 86% for differential exon skipping events with a MATS FDR of <10%. Additionally, over the full list of RT–PCR tested exons, the MATS FDR estimates matched well with the experimental validation rate. Our results demonstrate that MATS is an effective and flexible approach for detecting differential alternative splicing from RNA-Seq data.
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              High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-Cell lymphoma: results from a French multicenter clinical trial.

              The dosage of soluble programmed cell death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed in a prospective patient cohort. We evaluated the clinical impact of sPD-L1 level measured at the time of diagnosis for newly diagnosed diffuse large B-cell lymphoma (DLBCL). Soluble PD-L1 was measured in the plasma of 288 patients enrolled in a multicenter, randomized phase III trial that compared R-high-dose chemotherapy with R-CHOP. The median follow-up was 41.4 months. A cutoff of 1.52 ng/ml of PD-L1 level was determined and related to overall survival (OS). Patients with elevated sPD-L1 experienced a poorer prognosis with a 3-year OS of 76% versus 89% (P<0.001). Considering clinical characteristics, the multivariate analysis retained this biomarker besides bone marrow involvement and abnormal lymphocyte-monocyte score as independently related to poor outcome. sPD-L1 was detectable in the plasma and not in the serum, found elevated in patients at diagnosis compared with healthy subjects and its level dropped back to normal value after CR. The intention-to-treat analysis showed that elevated sPD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). Plasma PD-L1 protein is a potent predicting biomarker in DLBCL and may indicate usefulness of alternative therapeutic strategies using PD-1 axis inhibitors.
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                Author and article information

                Contributors
                401-444-2826 , smonaghan@lifespan.org
                Journal
                Mol Med
                Mol. Med
                Molecular Medicine
                BioMed Central (London )
                1076-1551
                1528-3658
                18 June 2018
                18 June 2018
                2018
                : 24
                : 32
                Affiliations
                [1 ]ISNI 0000 0001 0557 9478, GRID grid.240588.3, Division of Surgical Research, Department of Surgery, , Alpert School of Medicine at Brown University and Rhode Island Hospital, ; 593 Eddy Street, Providence, RI 02903 USA
                [2 ]ISNI 0000 0001 0557 9478, GRID grid.240588.3, Division of Pulmonary and Critical Care, Department of Medicine, , Alpert School of Medicine at Brown University and Rhode Island Hospital, ; Providence, RI 02903 USA
                [3 ]ISNI 0000 0004 1936 9094, GRID grid.40263.33, MCB Department, , Brown University, ; Providence, RI 02903 USA
                Article
                36
                10.1186/s10020-018-0036-3
                6016894
                30134817
                c4bd8568-94b8-48cf-b126-411c5313f4e6
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 March 2018
                : 12 June 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: P20GM103652-Pilot
                Award ID: P20GM103652-Pilot
                Award ID: GM118097
                Award ID: P20GM103652
                Award ID: K08GM110495
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005301, American College of Surgeons;
                Award ID: C. James Carrico, MD, FACS, Faculty Research Fellowship for the Study of Trauma and Critical Care
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100012299, Warren Alpert Medical School, Brown University;
                Award ID: the Deans Emerging Area of New Science (DEANS) Award
                Award ID: the Deans Emerging Area of New Science (DEANS) Award
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                btla,ards,rna splicing,critical illness
                btla, ards, rna splicing, critical illness

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