Dataset Information

Composition of Rosenthal fibers in Alexander disease patients and mouse models

ABSTRACT: Alexander disease (AxD) is a fatal neurodegenerative disorder characterized by the presence in astrocytes of protein aggregates called Rosenthal fibers (RFs). In this work, we used a new biochemical fractionation method to enrich for RFs followed by analysis of this fraction using quantitative iTRAQ mass spectrometry. This work identified 77 proteins not previously associated with RFs. Multiple proteins selected for follow-up were confirmed by immunobloting to be enriched in the RF fraction of both the AxD mouse models and human AxD patients including receptor for activated protein C kinase 1 (RACK1), G1/S-specific cyclin D2, and ATP-dependent RNA helicase DDX3X.

INSTRUMENT(S): TripleTOF 5600, Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Michael Brenner

LAB HEAD: Michael Brenner

PROVIDER: PXD002448 | Pride | 2016-05-23

REPOSITORIES: Pride

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Publications

Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease.

Heaven Michael R MR Flint Daniel D Randall Shan M SM Sosunov Alexander A AA Wilson Landon L Barnes Stephen S Goldman James E JE Muddiman David C DC Brenner Michael M

Journal of proteome research 20160602 7

Alexander disease (AxD) is a neurodegenerative disorder characterized by astrocytic protein aggregates called Rosenthal fibers (RFs). We used mouse models of AxD to determine the protein composition of RFs to obtain information about disease mechanisms including the hypothesis that sequestration of proteins in RFs contributes to disease. A method was developed for RF enrichment, and analysis of the resulting fraction using isobaric tags for relative and absolute quantitation mass spectrometry id ...[more]

PMID: 27193225

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Project description:Introduction: The I-SPY 1 TRIAL was designed to evaluate complete pathologic response and tumor volume change, measured by magnetic resonance imaging (MRI), stratified by molecular subtypes and link response to 3-year recurrence free survival (RFS).Methods: Eligible patients had T =3 cm and received neoadjuvant chemotherapy with AC plus optional taxane. Serial MRI, biopsy, and blood draws were conducted over the course of treatment, and a database of multiple molecular profiles was assembled.Results: A total of 221 patients were eligible for analysis: median tumor size was 6.0 cm and median age was 49 years. The I-SPY 1 TRIAL patients had tumors with aggressive biology: 45% were estrogen receptor (ER) negative, 31% Her2+; and 91% high risk by the Netherlands Cancer Institute (NKI) 70-gene profile. After a median of 3.9 years, RFS was 77%. HR/HER2 status improved predictability of RFS with the greatest difference between HR+/HER2- and triple-negative disease (hazard ratio 0.39). Wound healing signature activation, p53 mutation, and Risk of Relapse (ROR) score were highly correlated and also significantly improved the accuracy of RFS predictions when added to stage. The rate of pathologic complete response (pCR) varied considerably from a low of 0-2% (NKI low risk, luminal A) to a high of 43-61% (17q Amplified, HER2 enriched, HR-/HER2+). Both pCR and the more refined residual cancer burden (RCB) were significant predictors of RFS for all patients and even more predictive when analyzed within biomarker subsets. Good risk (NKI low, ROR-S low risk, Wound Healing quiescent, p53 wild type) signatures were associated with significantly higher 3-year RFS than poor risk expression signatures (ROR-S high risk, Wound Healing Activated, p53 mutation, NKI high risk).Conclusion: Importantly, in this set of biologically poor prognosis tumors, pCR predicts for better outcome, especially when analyzed within breast cancer subsets. Keywords: reference x sample reference x sample

Dataset Information

Composition of Rosenthal fibers in Alexander disease patients and mouse models

Publications

Composition of Rosenthal Fibers, the Protein Aggregate Hallmark of Alexander Disease.

Similar Datasets

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