bims-prodis 2018-08-12 papers

Issue of 2018–08–12
five papers selected by
Nancy Gough, Bioserendipity

Brain Res Bull. 2018 Aug 02. pii: S0361-9230(18)30335-6. [Epub ahead of print]142 224-232

Identification of plasma biomarkers for diffuse axonal injury in rats by iTRAQ-coupled LC-MS/MS and bioinformatics analysis.

Peng Zhang, Shisheng Zhu, Minzhu Zhao, Peng Zhao, Haiyi Zhao, Jianqiang Deng, Jianbo Li.

DAI is a serious and complex brain injury associated with significant morbidity and mortality. The lack of reliable objective diagnostic modalities for DAI delays administration of therapeutic interventions. Hence, identifying reliable biomarkers is urgently needed to enable early DAI diagnosis in the clinic. Herein, we established a rat model of DAI and applied an isobaric tags for a relative and absolute quantification (iTRAQ) coupled with nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) proteomics approach to screen differentially expressed plasma proteins associated with DAI. A total of 58 proteins were found to be significantly modulated in blood plasma samples of the injury group in at least one time point compared to controls. Bioinformatics analysis of the differentially expressed proteins revealed that the pathogenesis of axonal injury underlying DAI is multi-stage biological process involved. Two significantly changed proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and hemopexin (Hpx), were identified as potential diagnostic biomarkers for DAI, and were successfully confirmed by further western blot analysis. This proteomic profiling study not only identified novel plasma biomarkers that may facilitate the development of clinically diagnostic for DAI, but also provided enhanced understanding of the molecular mechanisms underlying DAI.

Keywords: Biomarkers; Diffuse axonal injury; Proteomics; Rats; iTRAQ

DOI: https://doi.org/10.1016/j.brainresbull.2018.07.015

Cell Physiol Biochem. 2018 Aug 03. 48(4): 1755-1770

A Novel Tumor-Suppressor, CDH18, Inhibits Glioma Cell Invasiveness Via UQCRC2 and Correlates with the Prognosis of Glioma Patients.

Ya-Hui Bai, Yun-Bo Zhan, Bin Yu, Wei-Wei Wang, Li Wang, Jin-Qiao Zhou, Ruo-Kun Chen, Feng-Jiang Zhang, Xin-Wei Zhao, Wen-Chao Duan, Yan-Min Wang, Jun Liu, Jian-Ji Bao, Zhen-Yu Zhang, Xian-Zhi Liu.

BACKGROUND/AIMS: CDH18 (cadherin 18) is specifically expressed in the central nervous system and associated with various neuropsychiatric disorders. In this study, the role of CDH18 in glioma carcinogenesis and progression was investigated.
METHODS: The expression of CDH18 and its prognostic value in patients with gliomas were analyzed in public database and validated by real-time PCR/immunohistochemical staining (IHC) in our cohort. CCK-8 assay, transwell migration assay, wound healing assay, clonogenic assay and tumorigenicity assay were used to compare the proliferation, invasion and migration ability of glioma cells with different expressions of CDH18. iTRAQ-based quantitative proteomic analysis were used to reveal the downstream target of CDH18. Rescue experiments were conducted to further validate the relationship between UQCRC2 and CDH18.
RESULTS: The expression of CDH18 was depressed in a ladder-like pattern from normal tissues to WHO IV gliomas, and was an independent prognostic factor in TCGA (The Cancer Genome Atlas), CGGA (the Chinese glioma genome-atlas) and our glioma cohorts (n=453). Functional experiments in vitro and in vivo demonstrated that CDH18 inhibited invasion/migration, enhanced chemoresistance and suppressed tumorigenicity of glioma cells. UQCRC2 was identified as the downstream target of CDH18 by proteomic analysis. The expression of UQCRC2 was gradually absent as the WHO grades of gliomas escalated and was positively correlated with the expression of CDH18. Furthermore, in vitro assays demonstrated that down-regulation of UQCRC2 partly reversed the inhibition of invasion/migration ability and chemoresistance in CDH18 overexpressed glioma cell lines. Survival analysis demonstrated that combined CDH18/UQCRC2 biomarkers significantly influenced the prognosis of glioma patients.
CONCLUSIONS: The present research demonstrated that CDH18 exerted its tumor-suppressor role via UQCRC2 in glioma cells and CDH18 might serve as a therapeutic target for treating gliomas.

Keywords: CDH18; Glioma; Invasion; Prognosis; UQCRC2

DOI: https://doi.org/10.1159/000492317

Gene. 2018 Aug 02. pii: S0378-1119(18)30858-8. [Epub ahead of print]

A four-protein expression prognostic signature predicts clinical outcome of lower-grade glioma.

Vikas Patil, Kulandaivelu Mahalingam.

BACKGROUND: Glioma is a wide category of brain tumor originates from glial cells. Lower-Grade Glioma (LGG) consists of World Health Organization (WHO) grade II and grade III gliomas. Since the LGGs can infiltrate into adjacent areas, the complete removal of tumor is difficult and it results in recurrence and malignant progression to high grade glioma. Our study uncovers robust survival indicators in LGG which can be checked by immunohistochemistry to predict the outcome of lower grade. In addition, it unravelled the novel therapeutic targets in order to improve the survival of LGG patients.
METHODS: To identify a prognostic signature based on protein expression in LGGs, we analysed Reverse Phase Protein Array data of LGG samples (n = 380) from The Cancer Genome Atlas cohort. We made random stratification of samples into discovery (n = 228) and validation datasets (n = 152). We performed multivariate Cox proportional hazards regression analysis of proteins (n = 219) using discovery dataset with age, WHO grade and IDH mutation status.
RESULTS: We identified four-protein prognostic signature that can segregate patients into high- and low-risk. The signature estimates poor overall survival for high-risk patients in both discovery (hazard ratio [HR] = 4.11; 95% confidence interval [CI] = 2.18-7.75; p < 0.0001) and validation datasets (HR = 3.49; 95% CI = 1.52-8.01; p < 0.0001). Among the four markers, CHK2_pT68 was found to be protective, while MSH6, ARID1A and PAXILLIN were associated with poor survival. Additionally, Multivariate Cox proportional hazards regression analysis of this signature with age, WHO grade and IDH mutation status revealed this prognostic signature to be an independent prognosticator in both datasets.
CONCLUSIONS: Our finding discovered a set of potential protein biomarkers to predict survival and it will help in the subsequent treatment management of LGG patients.

Keywords: ARID1A; CHK2; Glioma; IDH mutation; Lower-grade glioma; MSH6; PAXILLIN; Prognostic signature; Reverse phase protein array (RPPA)

DOI: https://doi.org/10.1016/j.gene.2018.08.001

Cell Physiol Biochem. 2018 Aug 03. 48(4): 1710-1722

Therapeutic Potential of Human Adipose-Derived Stem Cell Exosomes in Stress Urinary Incontinence - An in Vitro and in Vivo Study.

Jianshu Ni, Hongchao Li, Yiwen Zhou, Baojun Gu, Yuemin Xu, Qiang Fu, Xufeng Peng, Nailong Cao, Qingchun Fu, Meng Jin, Guangxi Sun, Jihong Wang, Yinpeng Jin, Feng Liu.

BACKGROUND/AIMS: To evaluate whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model.
METHODS: For the in vitro study, a Cell Counting Kit-8 (CCK-8) array and proteomic analysis were performed. For the in vivo study, female rats were divided into four groups: sham, SUI, adipose-derived stem cell (ADSC), and exosomes (n = 12 each). The SUI model was generated by pudendal nerve transection and vaginal dilation. Vehicle, hADSCs, or exosomes were injected into the peripheral urethra. After 2, 4, and 8 weeks, the rats underwent cystometrography and leak point pressure (LPP) testing, and tissues were harvested for histochemical analyses.
RESULTS: The CCK-8 experiment demonstrated that ADSC-derived exosomes could enhance the growth of skeletal muscle and Schwann cell lines in a dose-dependent manner. Proteomic analysis revealed that ADSC-derived exosomes contained various proteins of different signaling pathways. Some of these proteins are associated with the PI3K-Akt, Jak-STAT, and Wnt pathways, which are related to skeletal muscle and nerve regeneration and proliferation. In vivo experiments illustrated that rats of the exosome group had higher bladder capacity and LPP, and had more striated muscle fibers and peripheral nerve fibers in the urethra than rats of the SUI group. Both urethral function and histology of rats in the exosome group were slightly better than those in the ADSC group.
CONCLUSIONS: Local injection of hADSC-derived exosomes improved functional and histological recovery after SUI.

Keywords: Adipose-derived stem cell; Exosome; Stress urinary incontinence; Therapy

DOI: https://doi.org/10.1159/000492298

Clin Immunol. 2018 Aug 01. pii: S1521-6616(18)30278-X. [Epub ahead of print]

Epitope mapping of anti-ALK antibodies in children with anaplastic large cell lymphoma.

Fabian Knörr, Simone Weber, Vijay K Singh, Karen Pulford, Alfred Reiter, Wilhelm Woessmann, Christine Damm-Welk.

Patients with Nucleophosmin (NPM)-Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount ALK autoantibodies. The titer of these autoantibodies inversely correlates with the risk of relapse. The epitopes recognized by these autoantibodies in NPM-ALK might be associated with different ALK-antibody levels. We used overlapping peptide microarray technology to analyze epitope-binding to NPM-ALK by plasma or serum from 129 ALK-positive ALCL patients and 21 controls. Antibodies present in sera from ALCL patients bound to epitopes mainly in the C-terminal region of the ALK portion of NPM-ALK (amino acid positions 469-496, 561-588, 617-644). Patients with higher ALK antibody titers detected the epitope 561-588 more frequently as well as three further epitopes at the N-terminus of the kinase domain compared to patients with intermediate and low titers. These results identify new potential target epitopes for immunotherapy in ALK-positive ALCL. The methodology can be adapted for more reproducible analyses of tumor antigen detection.

Keywords: ALCL; Antibodies; Epitope mapping; Lymphoma; Tumor immunology

DOI: https://doi.org/10.1016/j.clim.2018.07.008