bims-prodis 2018-06-24 papers

Issue of 2018–06–24
six papers selected by
Nancy Gough, Bioserendipity

Med Sci Monit. 2018 Jun 17. 24 4146-4153

Application of Isobaric Tags for Relative and Absolute Quantification (iTRAQ) Coupled with Two-Dimensional Liquid Chromatography/Tandem Mass Spectrometry in Quantitative Proteomic Analysis for Discovery of Serum Biomarkers for Idiopathic Pulmonary Fibrosis.

Ying Zhang, Qian Xin, Zhen Wu, Chaochao Wang, Yongbin Wang, Qian Wu, Rui Niu.

BACKGROUND The present study was performed to explore the presence of informative protein biomarkers of human serum proteome in idiopathic pulmonary fibrosis (IPF). MATERIAL AND METHODS Serum samples were profiled using iTRAQ coupled with two-dimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) technique, and ELISA was used to validate candidate biomarkers. RESULTS A total of 394 proteins were identified and 97 proteins were associated with IPF. Four biomarker candidates generated from iTRAQ experiments - CRP, fibrinogen-α chain, haptoglobin, and kininogen-1 - were successfully verified using ELISA. CONCLUSIONS The present study demonstrates that levels of CRP and fibrinogen-a are higher and levels of haptoglobin and kininogen-1 are lower in patients with IPF compared to levels in healthy controls. We found they are useful candidate biomarkers for IPF.

DOI: https://doi.org/10.12659/MSM.908702

Lancet Oncol. 2018 Jun 13. pii: S1470-2045(18)30294-8. [Epub ahead of print]

Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis.

BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival.
METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation.
FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score).
INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies.
FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

DOI: https://doi.org/10.1016/S1470-2045(18)30294-8

Pathol Res Pract. 2018 May 17. pii: S0344-0338(17)31011-7. [Epub ahead of print]

Mass spectrometry in pathology - Vision for a future workflow.

Jörg Kriegsmann, Rita Casadonte, Katharina Kriegsmann, Rémi Longuespée, Mark Kriegsmann.

Mass spectrometric (MS) techniques are applied in various areas of medical diagnostics. For the detection of microbiological germs and genetic mutations, MS is a method used in routine. Since MS also allows the analysis of proteins and peptides, it seems an ideal candidate to supplement histopatholological diagnostics. Matrix-assisted laser desorption/ionization time-of-flight Imaging MS links molecular analysis of numerous analytes with morphological information about their spatial distribution in cells or tissues. Herein, we review principle MS techniques as well as potential applications in pathology and discuss our vision for a future workflow.

Keywords: MALDI Imaging; Mass Spectrometry; Molecular Pathology; Pathology Workflow

DOI: https://doi.org/10.1016/j.prp.2018.05.009

Biochim Biophys Acta. 2018 Jun 14. pii: S0167-4889(18)30134-4. [Epub ahead of print]

Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.

Robert Fuchs, Anika Stracke, Viktoria Holzmann, Gerfried Luschin-Ebengreuth, Nathalie Meier-Allard, Nadine Ebner, Teresa Maria Lassacher, Markus Absenger-Novak, Eleonore Fröhlich, Matthias Schittmayer, Sara Cano Crespo, Manuel Palacin, Beate Rinner, Ruth Birner-Gruenberger.

The quinazoline based drug prazosin (PRZ) is a potent inducer of apoptosis in human cancer cells. We recently reported that PRZ enters cells via endocytosis and induces tubulation of the endolysosomal system. In a proteomics approach aimed at identifying potential membrane proteins with binding affinity to quinazolines, we detected the oncoprotein CD98hc. We confirmed shuttling of CD98hc towards lysosomes and upregulation of CD98hc expression in PRZ treated cells. Gene knockout (KO) experiments revealed that endocytosis of PRZ still occurs in the absence of CD98hc - suggesting that PRZ does not enter the cell via CD98hc but misroutes the protein towards tubular lysosomes. Lysosomal tubulation interfered with completion of cytokinesis and provoked endoreplication. CD98hc KO cells showed reduced endoreplication capacity and lower sensitivity towards PRZ induced apoptosis than wild type cells. Thus, loss of CD98hc does not affect endocytosis of PRZ and lysosomal tubulation, but the ability for endoreplication and survival of cells. Furthermore, we found that glutamine, lysomototropic agents - namely chloroquine and NH4Cl - as well as inhibition of v-ATPase, interfere with the intracellular transport of CD98hc. In summary, our study further emphasizes lysosomes as target organelles to inhibit proliferation and to induce cell death in cancer. Most importantly, we demonstrate for the first time that the intracellular trafficking of CD98hc can be modulated by small molecules. Since CD98hc is considered as a potential drug target in several types of human malignancies, our study possesses translational significance suggesting, that old drugs are able to act on a novel target.

Keywords: Apoptosis; CD98hc/4F2/SLC3A2; Cancer; Lysomototropic agents; Lysosomes; Prazosin

DOI: https://doi.org/10.1016/j.bbamcr.2018.06.006

Environ Res. 2018 Jun 13. pii: S0013-9351(18)30145-2. [Epub ahead of print]166 310-323

Air pollution and the fetal origin of disease: A systematic review of the molecular signatures of air pollution exposure in human placenta.

Leen J Luyten, Nelly D Saenen, Bram G Janssen, Karen Vrijens, Michelle Plusquin, Harry A Roels, Florence Debacq-Chainiaux, Tim S Nawrot.

BACKGROUND: Fetal development is a crucial window of susceptibility in which exposure-related alterations can be induced on the molecular level, leading to potential changes in metabolism and development. The placenta serves as a gatekeeper between mother and fetus, and is in contact with environmental stressors throughout pregnancy. This makes the placenta as a temporary organ an informative non-invasive matrix suitable to investigate omics-related aberrations in association with in utero exposures such as ambient air pollution.
OBJECTIVES: To summarize and discuss the current evidence and define the gaps of knowledge concerning human placental -omics markers in association with prenatal exposure to ambient air pollution.
METHODS: Two investigators independently searched the PubMed, ScienceDirect, and Scopus databases to identify all studies published until January 2017 with an emphasis on epidemiological research on prenatal exposure to ambient air pollution and the effect on placental -omics signatures.
RESULTS: From the initial 386 articles, 25 were retained following an a priori set inclusion and exclusion criteria. We identified eleven studies on the genome, two on the transcriptome, five on the epigenome, five on the proteome category, one study with both genomic and proteomic topics, and one study with both genomic and transcriptomic topics. Six studies discussed the triple relationship between exposure to air pollution during pregnancy, the associated placental -omics marker(s), and the potential effect on disease development later in life. So far, no metabolomic or exposomic data discussing associations between the placenta and prenatal exposure to air pollution have been published.
CONCLUSIONS: Integration of placental biomarkers in an environmental epidemiological context enables researchers to address fundamental questions essential in unraveling the fetal origin of disease and helps to better define the pregnancy exposome of air pollution.

Keywords: -Omics; Air pollution; Barker hypothesis; Child development; Placenta

DOI: https://doi.org/10.1016/j.envres.2018.03.025

Toxicon. 2018 Jun 13. pii: S0041-0101(18)30283-6. [Epub ahead of print]

A proteomic study of the pulmonary injury induced by microcystin-LR in mice.

Sujuan Zhao, Hong Sun, Wei Yan, Dexiang Xu, Tong Shen.

MCLR has been shown to act as potent hepatotoxin, and recent studies showed that MCs can accumulate in lung tissue and exert adverse effects. However, the exact mechanism still remain unclear. The present study mainly focuses on the impairments of respiratory system after MCLR exposure in mice. After intratracheal instillation with MCLR (0, 10 and 25 μg/kg bw), histological change was examined in MCLR exposure groups. Results indicated that exposure of MCLR led to serious histopathology alteration and apoptosis in lung of mice. To further our understanding of the toxic effects of MCLR on the lung, we employed a proteomic method to search the mechanisms behind MCLR-induced pulmonary injury. In total, 38 proteins were identified to be significantly altered after MCLR exposure. These proteins involved in inflammatory response, apoptosis, cytoskeleton, and energetic metabolism, suggesting MCLR exerts complex toxic effects contributing to pulmonary injury. Furthermore, MCLR also induced pulmonary inflammation, as manifested by up-regulating the protein levels of interleukin-1β (IL-1β) and p65 subunit. Our results indicated that MCLR exerts lung injury mainly by generating inflammation and apoptosis.

Keywords: Apoptosis; Inflammatory response; MCLR; Proteomics; Pulmonary injury

DOI: https://doi.org/10.1016/j.toxicon.2018.06.072