Central nervous system immune response in postinfectious hydrocephalus
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive Plus
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
R. Reid Townsend
PROVIDER: MSV000087068 | MassIVE | Thu Mar 18 09:08:00 GMT 2021
SECONDARY ACCESSION(S): PXD024842
REPOSITORIES: MassIVE
Similar Datasets
Project description:Background In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Minimal residual disease diagnostics predict most bone marrow (BM) relapses, but likely cannot predict isolated CNS relapses. Consequently, CNS relapses may become relatively more important. Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Methods Gene expression profiles of ALL cells from cerebrospinal fluid (CSF) and ALL cells from BM were compared and differences were confirmed by real-time quantitative PCR. For a selected set of overexpressed genes, protein expression levels of ALL cells in CSF at relapse and of ALL cells in diagnostic BM samples were evaluated by 8-color flow cytometry. Results CSF-derived ALL cells showed a clearly different gene expression profile than BM-derived ALL cells, with differentially-expressed genes (including SCD and OPN) involved in survival and apoptosis pathways and linked to the JAK-STAT pathway. Flowcytometric analysis showed that a subpopulation of ALL cells (>1%) with a â??CNS signatureâ?? (SCD positivity and increased OPN expression) was already present in BM at diagnosis in ALL patients who later developed a CNS relapse, but was <1% or absent in virtually all other patients. Conclusions The presence of a subpopulation of ALL cells with a â??CNS signatureâ?? at diagnosis may predict isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity. We compared gene expression profiles of ALL cells obtained from cerebrospinal fluid (n=8) with profiles of ALL cells obtained from bone marrow at diagnosis (n=22) or at relapse (n=20)
2015-12-31 | E-GEOD-60926 | biostudies-arrayexpress
Project description:Primary central nervous system lymphoma(PCNSL) is a rare extra-nodal non-Hodgkin’s lymphoma and accounts for 3%-4% of central nervous system tumors. Recent studies have highlighted the importance of cerebrospinal fluid derived extracellular vesicles in PCNSL. Extracellular vesicles(EVs) are nanoscale vesicles with bilayer lipid membrane released by almost all cell types. EVs are present in body fluids, including urine, blood and CSF. Cerebrospinal fluid(CSF) is a colorless fluid that surrounds the brain and spinal cord and acts as lymph in the central nervous system. CSF-derived EVs contain proteins from neurons, oligodendrocytes, astrocytes and microglias. Studies of CSF EVs are mainly limited by the amount of EVs isolated from per milliliter of CSF and the volume of CSF acquired from one patient. Here, we provide a label-free quantitative phospho-proteome profiling of EVs separated from PCNSL and non-PCNSL CSF samples by an earlier introduced functional magnetic beads called EVTRAP together with highly sensitive timsTOF Pro.
2023-07-12 | PXD040744 | JPOST Repository
Project description:Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebral spinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease.We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453).Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1×1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3×1013 GC/animal) was well tolerated (36–37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9’s proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2+ CNS malignancies.
2024-02-05 | GSE255027 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE37664: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 1A) GSE37670: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 2A) GSE37826: Human cerebrospinal fluid autoantibody lipid microarray profiling (Fig. 2C) Refer to individual Series
2012-05-08 | E-GEOD-37830 | biostudies-arrayexpress
Project description:Background. Flow cytometry (FCM) identifies leukemic blasts in cerebrospinal fluid (CSF) in approximately 30% of children with acute lymphoblastic leukemia (ALL), whereas conventional cytospin preparations frequently miss such involvement. <br>Procedure. To explore biological properties of leukemic cells that migrate into central nervous system (CNS), we compared gene expression profiles of leukemic cells from 26 patients with CNS involvement and 138 patients without CNS leukemia as determined by FCM and/or cytospin preparations. Results were validated by real-time quantitative PCR (qPCR). <br>Results. We found the cysteine endopeptidase legumain (LGMN) that plays a role in hydrolysis of proteins and small molecules to be significantly differentially expressed between FCM+ and FCM- B-cell precursor (BCP) ALL patients. When LGMN expression was validated by qPCR it stayed differentially expressed between FCM+ and FCM- BCP-ALL patients (P=0.006), and also between FCM+ and cytospin-negative BCP-ALL patients (P=0.01). In multivariate regression analysis including sex, age and WBC, LGMN expression levels above population median were associated with an odds ratio of 9.1 for CNS involvement as determined by FCM compared with expression less than the median (95% CI, 1.26 to 65.50; P=0.03). Conclusions. The use of more sensitive methods for detecting and quantifying CNS involvement, such as FCM, may facilitate detection of markers of leukemia biology, such as LGMN, which could have therapeutical implications for future CNS-directed therapy.<br>FCM+: Patients had leukemic cells in the cerebrospinal fluid (CSF) detected by flow cytometry and no blood contamination. FCM-: Patients had no leukemic cells in the CSF detected by flow cytometry with or without blood contamination.<br>CNS1: No leukemic cells in CSF detected by cytospin examination with or without blood contamination and no other clinical signs of central nervous system (CNS) leukaemia. CNS2: CSF leukocyte count <5 x106/µL with blasts on cytospin examination and no blood contamination. CNS3: CSF leukocyte count >5 x106/µL with blasts on cytospin examination and no blood contamination, and/or cranial nerve palsy, and/or CNS leukaemia by neuroimaging.
2019-01-01 | E-MTAB-4985 | biostudies-arrayexpress
Project description:The choroid plexus (ChP) secretes a half-liter of cerebrospinal fluid (CSF) per day into the cerebral ventricular system and gates immune cell entry into the brain as the blood-CSF barrier. Acquired hydrocephalus, characterized by ventriculomegaly from CSF accumulation, is caused by both brain infection or hemorrhage and is treated by neurosurgical CSF diversion with attendant morbidity and long-term disability. We interrogated novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) using a multi-omics, systems biology platform to elucidate mechanisms of disease. Integrated analysis of new genome-level transcriptomic and proteomic ChP datasets demonstrated that lipopolysaccharide in PIH, and blood breakdown products in PHH, trigger highly similar toll-like receptor-4 (TLR4)-dependent immune responses at the ChP-CSF interface. This includes the production of a CSF “cytokine storm” elicited from activated peripherally-derived and border-associated macrophages that accumulate at the ChP. Pro-inflammatory CSF signals stimulate their cognate receptors on ChP epithelial cells in paracrine manner to acutely increase CSF secretion rate via the TNF receptor associated SPAK kinase, which binds and activates a multi-ion transporter and channel complex at the ChP apical membrane. Genetic and pharmacological immunosuppression with repurposed drugs antagonizes SPAK-dependent CSF hypersecretion and prevents acute PIH and PHH. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related inflammatory disorders vulnerable to systemic immunomodulation, and identify a druggable hub of ChP immune-secretory function that holds promise for other neurological disorders.
2023-02-20 | PXD030678 | Pride
Project description:Neutrophils are crucial mediators of host defense and are recruited to the central nervous system in large numbers during acute bacterial meningitis caused by S. pneumoniae. Neutrophils can release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures and mainly consist of decondensed DNA and neutrophil-derived antimicrobial proteins. We report the extensive presence of NETs in the cerebrospinal fluid of patients with pneumococcal meningitis, and absence of NETs in other forms of meningitis caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the cerebrospinal fluid. Importantly, disrupting NETs using DNase I significantly reduced bacterial load, demonstrating that NETs contribute to the pathogenesis of pneumococcal meningitis in vivo. Targeting NETs using DNase may represent a novel indication for an already approved drug as a non-antibiotic therapeutic option to treat acute pneumococcal meningitis.
2019-11-12 | PXD011546 | Pride
Project description:Acute lymphoblastic leukemia (ALL) has a striking propensity to metastasize to the central nervous system (CNS).1 In contrast to solid tumor brain metastases, ALL seldom involves the parenchyma but is isolated to the leptomeninges, an infrequent site for carcinomatous invasion.2,3 While CNS metastasis is characteristic across ALL subtypes, a unifying mechanism for invasion has not been determined. Here we show that ALL cells in circulation are unable to breach the blood brain barrier; instead they migrate into the CNS along vessels that passage directly between vertebral or calvarial bone marrow (BM) and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, known to coordinate neuronal progenitor cell pathfinding in the CNS.4-6 The laminin receptor a6 integrin is expressed by most ALL.7,8 We found that a6/laminin mediated ALL migration toward cerebrospinal fluid (CSF) in vitro. ALL-xenografted mice treated with either a PI3Kd inhibitor that decreased ALL a6 expression or specific a6 neutralizing antibodies showed significantly less ALL transit along bridging vessels, CSF blast counts and CNS disease symptoms despite minimally decreased BM disease burden. Our data suggest that a6 integrin expression, common in ALL, allows cells to coopt neural migratory pathways to invade the CNS.
2018-07-12 | GSE114627 | GEO
Project description:Transcriptomes of Trypanosoma rhodesiense from human cerebrospinal fluid
2016-12-17 | E-MTAB-5294 | biostudies-arrayexpress
Project description:System level view of the vaccine induced immune response to identify perturbations at the level of gene expression in whole PBMC specifically in response to pertussis antigenic challenge in vivo (Tdap vaccine boost) as a proxy of infectious challenge, and whether this response differed in aP vs. wP primed individuals 15 years or more after the original vaccination. RNA-Seq analysis on PBMC samples collected longitudinally at baseline and following Tdap booster vaccination. For this purpose, we recruited addults primed with either aP and wP and proceeded to booster vaccination with aP. PBMCs were collected for transcriptomics at 0 days post boost (baseline) followed by 1, 3, 7 and 14 days post boost. Bulk PBMC RNA sequencing was performed for 39 donors with 5 timepoints (0, 1, 3, 7 and 14 days post boost) +1 donor with 3 timepoints (0, 1 and 3 days post boost)
2021-03-31 | GSE152683 | GEO