Background: Mechanisms by which triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies inflammation are not fully defined. Results: TREM-1 induces anti-apoptotic protein Bcl-2. Conclusion: Macrophage survival is prolonged by TREM-1. Significance: TREM-1 activation can propagate inflammation by modulating the survival of inflammatory cells.
Recent studies have established that a complex community of microbes colonize the human urinary tract; however their role in kidney transplant patients treated with prophylactic antibiotics remains poorly investigated. Our aim was to investigate the urinary microbiome of kidney transplant recipients. Urine samples from 21 patients following kidney transplantation and 8 healthy controls, were collected. All patients received prophylactic treatment with the antibiotic trimethoprim/sulfamethoxazole. Metagenomic DNA was isolated from urine samples, sequenced using metagenomics shotgun sequencing approach on Illumina HiSeq2000 platform, and analyzed for microbial taxonomic and functional annotations. Our results demonstrate that the urine microbiome of kidney transplants was markedly different at all taxonomic levels from phyla to species, had decreased microbial diversity and increased abundance of potentially pathogenic species compared to healthy controls. Specifically, at the phylum level we detected a significant decrease in Actinobacteria and increase in Firmicutes due to increases in Enterococcus faecalis. In addition, there was an increase in the Proteobacteria due to increases in E. coli. Analysis of predicted functions of the urinary metagenome revealed increased abundance of enzymes in the folate pathway including dihydrofolate synthase that are not inhibited by trimethoprim/ sulfamethoxazole, but can augment folate metabolism. This report characterizes the urinary microbiome of kidney transplants using shotgun metagenomics approach. Our results indicate that the urinary microbiota may be modified in the context of prophylactic antibiotics, indicating that a therapeutic intervention may shift the urinary microbiota to select bacterial species with increased
Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. Synergy between TREM-1 and Toll-like receptor amplifies the inflammatory response; however, the mechanisms by which TREM-1 accentuates inflammation are not fully understood. In this study, we investigated the role of TREM-1 in a model of LPS-induced lung injury and neutrophilic inflammation. We show that TREM-1 is induced in lungs of mice with LPS-induced acute neutrophilic inflammation. TREM-1 knockout mice showed an improved survival after lethal doses of LPS with an attenuated inflammatory response in the lungs. Deletion of TREM-1 gene resulted in significantly reduced neutrophils and proinflammatory cytokines and chemokines, particularly IL-1β, TNF-α, and IL-6. Physiologically deletion of TREM-1 conferred an immunometabolic advantage with low oxygen consumption rate (OCR) sparing the respiratory capacity of macrophages challenged with LPS. Furthermore, we show that TREM-1 deletion results in significant attenuation of expression of miR-155 in macrophages and lungs of mice treated with LPS. Experiments with antagomir-155 confirmed that TREM-1-mediated changes were indeed dependent on miR-155 and are mediated by downregulation of suppressor of cytokine signaling-1 (SOCS-1) a key miR-155 target. These data for the first time show that TREM-1 accentuates inflammatory response by inducing the expression of miR-155 in macrophages and suggest a novel mechanism by which TREM-1 signaling contributes to lung injury. Inhibition of TREM-1 using a nanomicellar approach resulted in ablation of neutrophilic inflammation suggesting that TREM-1 inhibition is a potential therapeutic target for neutrophilic lung inflammation and acute respiratory distress syndrome (ARDS).
Stomatococcus mucilaginosus is an oral commensal that has been occasionally reported to cause severe infections in immunocompromised patients. There is no information about the pathogenic role of S. mucilaginosus in airway infections. In a cohort of 182 subjects with bronchiectasis, we found that 9% were colonized with S. mucilaginosus in their lower airways by culture growth from bronchoalveolar lavage. To address the pathogenic potential of S.mucilaginosus, we developed a murine model of S. mucilaginosus lung infection. Intratracheal injection of S. mucilaginosus in C57BL/6 mice resulted in a neutrophilic influx with production of proinflammatory cytokines, chemokines, and lipid mediators, mainly PGE2 with induction of cyclooxygenase-2 (COX-2) in the lungs. Presence of TLR2 was necessary for induction of COX-2 and production of PGE2 by S. mucilaginosus. TLR2-deficient mice showed an enhanced clearance of S. mucilaginosus compared with wild-type mice. Administration of PGE2 to TLR2−/− mice resulted in impaired clearance of S. mucilaginosus, suggesting a key role for COX-2–induced PGE2 production in immune response to S. mucilaginosus. Mechanistically, induction of COX-2 in macrophages was dependent on the p38-ERK/MAPK signaling pathway. Furthermore, mice treated with S. mucilaginosus and Pseudomonas aeruginosa showed an increased mortality compared with mice treated with PA103 or S. mucilaginosus alone. Inhibition of COX-2 significantly improved survival in mice infected with PA103 and S. mucilaginosus. These data provide novel insights into the bacteriology and personalized microbiome in patients with bronchiectasis and suggest a pathogenic role for S. mucilaginosus in patients with bronchiectasis.
Introduction: Composite neoplasms (CN) are rare, diagnostically challenging lesions that require differentiating between three possibilities: clonal tumors with divergent phenotypes (mixed tumors, MT), collision of two synchronous adjacent tumors (CT) and tumor-to-tumor metastasis (TTM). To make this distinction, pathologists have relied on morphology, immunohistochemistry and limited molecular techniques such as single-gene sequencing. In this study, we performed next-generation sequencing (NGS) on 4 CN to illustrate the diagnostic utility of NGS-based approach in these rare tumors. Materials and Methods: Of the 4 CN included in the study, 2 had been diagnosed as MT containing phenotypically different cell populations (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation), while the remaining 2 had been interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Pathology diagnoses were made using clinical, histologic and immunophenotypic information. Manual dissection of the tumor components was performed on formalin-fixed, paraffin-embedded tissue sections for extraction of DNA and RNA. NGS was performed using the Oncomine Comprehensive Panel on Ion S5XL sequencer. Ion Reporter variant caller pipeline was used for data analysis. Results: Sequencing results confirmed the histopathologic diagnosis in all cases (Table 1). Importantly, comparison of our results with data from TCGA studies allowed a meaningful interpretation of the genetic aberrations found, and shed light on the biology of these lesions. Table 1 – Integration of immunophenotypic and massively parallel sequencing data from 4 composite neoplasmsNDiagnosisComponentsIHCGeneType of aberrationVariant effect (AA change)InterpretationCN1Mixed adenoneuroendocrine carcinomaAdenocarcinomaCK20 -/p53 -/p63 -/CK7 +/ CDX2 +ERBB2CNV–Amplification8.57CCNE1CNV–Amplification16.7Large cell neuroendocrine carcinomaCK20 -/p53 -/p63 -/CK7 +/ CDX2 +/Chromo +/Synapto +CCND1CNV–Amplification4.63ATMCNV–Deletion0.39TP53CNV–Deletion0.56CCNE1CNV–Amplification402Metastatic papillary thyroid carcinoma with squamous dedifferentiationPapillary thyroid carcinomaCK 5/6 -/p40 -/PAX8 +/TTF1 +/TG +BRAFMutation (c.1799T>A)Missense (p.Val600Glu)Deleterious (GOF)–Squamous cell carcinomaCK5/6 +/p40 +/PAX8 +/TTF1 -/TG -BRAFMutation (c.1799T>A)Missense (p.Val600Glu)Deleterious (GOF)–PIK3CAMutation (c.1633G>A)Missense (p.Glu545Lys)Deleterious (GOF)–3Esophageal adenocarcinoma metastatic to lung adenocarcinomaLow grade adenocarcinoma (lung)TTF1 +/HER2 -CDKN2ACNV–Deletion0.76CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASMutation (c.35G>T)Missense (p.Gly12Val)Deleterious (GOF)–STK11Mutation (c.580G>T)Missense (p.Asp194Tyr)Deleterious (LOF)–High grade adenocarcinoma (lung)TTF1 -/HER2 +CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASMutation (c.35G>T)Missense (p.Gly12Val)Deleterious (GOF)–STK11Mutation (c.580G>T)Missense (p.Asp194Tyr)Deleterious (LOF)–High grade adenocarcinoma (esophagus)–CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASCNV–Amplification22.01TP53Mutation (c.614A>G)Missense (p.Tyr205Cys)Deleterious (LOF)–4Small cell carcinoma of the lung combined metastatic to meningeal melanomaSmall cell carcinomaTTF1 +/Synapto +/Chromo +/AE1+3 +/CAM 5.2 +/MelanA -/HMB 45 -RB1Mutation (c.1183C>T)NonsenseDeleterious (LOF)GAS6CNV–Amplification6.14TP53Mutation (c.473G>T)Missense (p.Arg158Leu)Deleterious (LOF)MelanomaTTF1 -/Synapto -/Chromo -/AE1+3 -/CAM 5.2 -/Melan-A +/Pan-M +/MITF +NRASMutation (c.35G>A)Missense (p.Gly12Asp)Deleterious (GOF)TERTCNV–Amplification21.34 Conclusion: This study illustrates the diagnostic utility of NGS in tumors with more than a single histologic component. Additionally, it demonstrates a potential role for NGS in the detection of clinically actionable targets in a group of neoplasms that lack standardized treatment. Citation Format: Andres M. Acosta, Mohamed Rizwan H. Al Rasheed, Dipti Panchal, Magdalena Rogozinska, Frederick G. Behm, Gayatry Mohapatra. Utility of a solid-tumor NGS panel in the differential diagnosis of composite neoplasms with divergent phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1617.
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